T-Shaped Palladium and Platinum {MNO}10 Nitrosyl Complexes.

The synthesis and characterization of a homologous series of T-shaped {MNO}10 nitrosyl complexes of the form [M(PR3)2(NO)]+ (M = Pd, Pt; R = tBu, Ad) are reported. These diamagnetic nitrosyls are obtained from monovalent or zerovalent precursors by treatment with NO and NO+, respectively, and are notable for distinctly bent M-NO angles of ∼123° in the solid state. Adoption of this coordination mode in solution is also supported by the analysis of isotopically enriched samples by 15N NMR spectroscopy. Effective oxidation states of M0/NO+ are calculated, and metal-nitrosyl bonding has been interrogated using DFT-based energy decomposition analysis techniques. While a linear nitrosyl coordination mode was found to be electronically preferred, the M-NO and P-M-P angles are inversely correlated to the extent that binding in this manner is prevented by steric repulsion between the bulky ancillary phosphine ligands.

Stability and C-H Bond Activation Reactions of Palladium(I) and Platinum(I) Metalloradicals: Carbon-to-Metal H-Atom Transfer and an Organometallic Radical Rebound Mechanism.

One-electron oxidation of palladium(0) and platinum(0) bis(phosphine) complexes enables isolation of a homologous series of linear d9 metalloradicals of the form [M(PR3)2]+ (M = Pd, Pt; R = tBu, Ad), which are stable in 1,2-difluorobenzene (DFB) solution for >1 day at room temperature when partnered with the weakly coordinating [BArF4]- (ArF = 3,5-(CF3)2C6H3) counterion. The metalloradicals exhibit reduced stability in THF, decreasing in the order palladium(I) > platinum(I) and PAd3 > PtBu3, especially in the case of [Pt(PtBu3)2]+, which is converted into a 1:1 mixture of the platinum(II) complexes [Pt(PtBu2CMe2CH2)(PtBu3)]+ and [Pt(PtBu3)2H]+ upon dissolution at room temperature. Cyclometalation of [Pt(PtBu3)2]+ can also be induced by reaction with the 2,4,6-tri-tert-butylphenoxyl radical in DFB, and a common radical rebound mechanism involving carbon-to-metal H-atom transfer and formation of an intermediate platinum(III) hydride complex, [Pt(PtBu2CMe2CH2)H(PtBu3)]+, has been substantiated by computational analysis. Radical C-H bond oxidative addition is correlated with the resulting MII-H bond dissociation energy (M = Pt > Pd), and reactions of the metalloradicals with 9,10-dihydroanthracene in DFB at room temperature provide experimental evidence for the proposed C-H bond activation manifold in the case of platinum, although conversion into platinum(II) hydride derivatives is considerably faster for [Pt(PtBu3)2]+ (t1/2 = 1.2 h) than [Pt(PAd3)2]+ (t1/2 ∼ 40 days).

Staphylococcus aureus Bacteremia Among Patients Receiving Maintenance Hemodialysis: Trends in Clinical Characteristics and Outcomes.

RATIONALE & OBJECTIVE: Staphylococcus aureus (Saureus) bacteremia (SAB) is associated with morbidity and mortality in patients receiving maintenance hemodialysis (HD). We evaluated changes in clinical and bacterial characteristics, and their associations with clinical outcomes with SAB in this population over a 21-year period. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: 453 hospitalized, non-neutropenic adults receiving maintenance HD who developed monomicrobial SAB between 1995 and 2015. EXPOSURE: Clinical characteristics and bacterial genotype. OUTCOME: All-cause and SAB-attributable mortality, persistent bacteremia, and metastatic complications. ANALYTICAL APPROACH: Proportions of participants experiencing each outcome were calculated overall and by calendar year. Secular trends were estimated using binomial risk regression, a generalized linear model with the log link function for a binomial outcome. Associations with outcomes were estimated using logistic regression. RESULTS: Over the 21-year study period, patients receiving maintenance HD experienced significant increases in age- and diabetes-adjusted SAB-attributable mortality (0.45% [95% CI, 0.36%-0.46%] per year), persistent bacteremia (0.86% [95% CI, 0.14%-1.55%] per year), metastatic complications (0.84% [95% CI, 0.11%-1.56%] per year), and infection with the virulent Saureus clone USA300 (1.47% [95% CI, 0.33%-2.52%] per year). Over time, the suspected source of SAB was less likely to be a central venous catheter (-1.32% [95% CI, -2.05 to-0.56%] per year) or arteriovenous graft (-1.08% [95% CI, -1.54 to-0.56] per year), and more likely to be a nonvascular access source (1.89% [95% CI, 1.29%-2.43%] per year). Patients with a nonvascular access suspected source of infection were more likely to die as a result of their S aureus infection (OR, 3.20 [95% CI, 1.36-7.55]). The increase in USA300 infections may have contributed to the observed increase in persistent bacteremia (OR, 2.96 [95% CI, 1.12-7.83]) but did not explain the observed increases in SAB-attributable mortality (OR, 0.83 [95% CI, 0.19-3.61]) or metastatic complications (OR, 1.34 [95% CI, 0.53-3.41]). LIMITATIONS: Single-center, inpatient cohort. CONCLUSIONS: The clinical and molecular epidemiology of SAB in patients receiving maintenance HD has changed over time, with an increase in SAB-attributable mortality and morbidity despite a decline in catheter-related infections.

Exploring a new paradigm for the fetal anomaly ultrasound scan: Artificial intelligence in real time.

OBJECTIVE: Advances in artificial intelligence (AI) have demonstrated potential to improve medical diagnosis. We piloted the end-to-end automation of the mid-trimester screening ultrasound scan using AI-enabled tools. METHODS: A prospective method comparison study was conducted. Participants had both standard and AI-assisted US scans performed. The AI tools automated image acquisition, biometric measurement, and report production. A feedback survey captured the sonographers' perceptions of scanning. RESULTS: Twenty-three subjects were studied. The average time saving per scan was 7.62 min (34.7%) with the AI-assisted method (p < 0.0001). There was no difference in reporting time. There were no clinically significant differences in biometric measurements between the two methods. The AI tools saved a satisfactory view in 93% of the cases (four core views only), and 73% for the full 13 views, compared to 98% for both using the manual scan. Survey responses suggest that the AI tools helped sonographers to concentrate on image interpretation by removing disruptive tasks. CONCLUSION: Separating freehand scanning from image capture and measurement resulted in a faster scan and altered workflow. Removing repetitive tasks may allow more attention to be directed identifying fetal malformation. Further work is required to improve the image plane detection algorithm for use in real time.

Bacteremia in solid organ transplant recipients as compared to immunocompetent patients: Acute phase cytokines and outcomes in a prospective, matched cohort study.

We undertook a prospective, matched cohort study of patients with Staphylococcus aureus bacteremia (SAB) and gram-negative bacteremia (GNB) to compare the characteristics, outcomes, and chemokine and cytokine response in transplant recipients to immunocompetent, nontransplant recipients. Fifty-five transplant recipients (GNB n = 29; SAB n = 26) and 225 nontransplant recipients (GNB n = 114; SAB n = 111) were included for clinical analysis. Transplant GNB had a significantly lower incidence of septic shock than nontransplant GNB (10.3% vs 30.7%, p = .03). Thirty-day mortality did not differ significantly between transplant and nontransplant recipients with GNB (10.3% vs 15.8%, p = .57) or SAB (0.0% vs 11.7%, p = .13). Next, transplant patients were matched 1:1 with nontransplant patients for the chemokine and cytokine analysis. Five cytokines and chemokines were significantly lower in transplant GNB vs nontransplant GNB: IL-2 (median [IQR]: 7.1 pg/ml [7.1, 7.1] vs 32.6 pg/ml [7.1, 88.0]; p = .001), MIP-1ß (30.7 pg/ml [30.7, 30.7] vs 243.3 pg/ml [30.7, 344.4]; p = .001), IL-8 (32.0 pg/ml [5.6, 53.1] vs 59.1 pg/ml [39.2, 119.4]; p = .003), IL-15 (12.0 pg/ml [12.0, 12.0] vs 12.0 pg/ml [12.0, 126.7]; p = .03), and IFN-α (5.1 pg/mL [5.1, 5.1] vs 5.1 pg/ml [5.1, 26.3]; p = .04). Regulated upon Activation, Normal T Cell Expressed and Secreted (RANTES) was higher in transplant SAB vs nontransplant SAB (mean [SD]: 750.2 pg/ml [194.6] vs 656.5 pg/ml [147.6]; p = .046).

Infective endocarditis and solid organ transplantation: Only worse outcomes during initial transplantation hospitalization.

BACKGROUND: The epidemiology, and outcome of infective endocarditis (IE) among solid organ transplant (SOT) recipients is unknown. METHODS: We used data from the 2013-2018 Nationwide Readmissions Database (NRD). IE- and SOT-associated hospitalizations were identified using diagnosis and procedure codes. Outcomes included inpatient mortality, length of stay, and inpatient costs. Adjusted analyses were performed using weighted regression models. RESULTS: A total of 99,052 IE-associated hospitalizations, corresponding to a weighted national estimate of 193,164, were included for analysis. Of these, 794 (weighted n = 1,574) were associated with transplant history (SOT-IE). Mortality was not significantly different between SOT-IE and non-SOT-IE (17.2% vs. 15.8%, adjusted relative risk [aRR]: 0.86, 95% confidence interval [CI] [0.71, 1.03]), and fewer SOT-IE patients underwent valve repair or replacement than non-SOT-IE (12.5% vs. 16.2%, aRR 0.82, 95% CI [0.71, 0.95]). We then compared outcomes of patients diagnosed with IE during their index transplant hospitalization (index-SOT-IE) to patients without IE during their transplant hospitalization (index-SOT). Index-SOT-IE occurred most frequently among heart transplant recipients (45.1%), and was associated with greater mortality (27.1% vs. 2.3%, aRR 6.07, 95% CI [3.32, 11.11]). CONCLUSION: Dual diagnosis of SOT and IE was associated with worse outcomes among SOT recipients during index hospitalization, but not overall among patients with IE.

Bacterial genotype and clinical outcomes in solid organ transplant recipients with Staphylococcus aureus bacteremia.

INTRODUCTION: Outcomes from Staphylococcus aureus bacteremia (SAB) in solid organ transplant (SOT) recipients are poorly understood. METHODS: This is a prospective cohort study comparing the bacterial genotype and clinical outcomes of SAB among SOT and non-transplant (non-SOT) recipients from 2005 to 2019. Each subject's initial S. aureus bloodstream isolate was genotyped using spa typing and assigned to a clonal complex. RESULTS: A total of 103 SOT and 1783 non-SOT recipients with SAB were included. Bacterial genotype did not differ significantly between SOT and non-SOT recipients (p = .4673), including the proportion of SAB caused by USA300 (13.2% vs. 16.0%, p = .2680). Transplant status was not significantly associated with 90-day mortality (18.4% vs. 29.5%; adjusted odds ratio [aOR] 0.74; 95% confidence interval [CI]: 0.44, 1.25), but was associated with increased risk for septic shock (50.0% vs. 21.8%; aOR 2.31; 95% CI: 1.48, 3.61) and acute respiratory distress syndrome (21.4% vs. 13.7%; aOR 2.03; 95% CI: 1.22, 3.37), and a significantly lower risk of metastatic complications (33.0% vs. 45.5%; aOR 0.49; 95% CI: 0.32, 0.76). No association was found between bacterial genotype and 90-day mortality (p = .6222) or septic shock (p = .5080) in SOT recipients with SAB. CONCLUSIONS: SOT recipients with SAB do not experience greater mortality than non-SOT recipients. The genotype of S. aureus bloodstream isolates in SOT recipients is similar to that of non-SOT recipients, and does not appear to be an important determinant of outcome in SOT recipients with SAB.

An international cohort study of autosomal dominant tubulointerstitial kidney disease due to REN mutations identifies distinct clinical subtypes.

There have been few clinical or scientific reports of autosomal dominant tubulointerstitial kidney disease due to REN mutations (ADTKD-REN), limiting characterization. To further study this, we formed an international cohort characterizing 111 individuals from 30 families with both clinical and laboratory findings. Sixty-nine individuals had a REN mutation in the signal peptide region (signal group), 27 in the prosegment (prosegment group), and 15 in the mature renin peptide (mature group). Signal group patients were most severely affected, presenting at a mean age of 19.7 years, with the prosegment group presenting at 22.4 years, and the mature group at 37 years. Anemia was present in childhood in 91% in the signal group, 69% prosegment, and none of the mature group. REN signal peptide mutations reduced hydrophobicity of the signal peptide, which is necessary for recognition and translocation across the endoplasmic reticulum, leading to aberrant delivery of preprorenin into the cytoplasm. REN mutations in the prosegment led to deposition of prorenin and renin in the endoplasmic reticulum-Golgi intermediate compartment and decreased prorenin secretion. Mutations in mature renin led to deposition of the mutant prorenin in the endoplasmic reticulum, similar to patients with ADTKD-UMOD, with a rate of progression to end stage kidney disease (63.6 years) that was significantly slower vs. the signal (53.1 years) and prosegment groups (50.8 years) (significant hazard ratio 0.367). Thus, clinical and laboratory studies revealed subtypes of ADTKD-REN that are pathophysiologically, diagnostically, and clinically distinct.

Automated quantification of myocardial tissue characteristics from native T1 mapping using neural networks with uncertainty-based quality-control.

BACKGROUND: Tissue characterisation with cardiovascular magnetic resonance (CMR) parametric mapping has the potential to detect and quantify both focal and diffuse alterations in myocardial structure not assessable by late gadolinium enhancement. Native T1 mapping in particular has shown promise as a useful biomarker to support diagnostic, therapeutic and prognostic decision-making in ischaemic and non-ischaemic cardiomyopathies. METHODS: Convolutional neural networks (CNNs) with Bayesian inference are a category of artificial neural networks which model the uncertainty of the network output. This study presents an automated framework for tissue characterisation from native shortened modified Look-Locker inversion recovery ShMOLLI T1 mapping at 1.5 T using a Probabilistic Hierarchical Segmentation (PHiSeg) network (PHCUMIS 119-127, 2019). In addition, we use the uncertainty information provided by the PHiSeg network in a novel automated quality control (QC) step to identify uncertain T1 values. The PHiSeg network and QC were validated against manual analysis on a cohort of the UK Biobank containing healthy subjects and chronic cardiomyopathy patients (N=100 for the PHiSeg network and N=700 for the QC). We used the proposed method to obtain reference T1 ranges for the left ventricular (LV) myocardium in healthy subjects as well as common clinical cardiac conditions. RESULTS: T1 values computed from automatic and manual segmentations were highly correlated (r=0.97). Bland-Altman analysis showed good agreement between the automated and manual measurements. The average Dice metric was 0.84 for the LV myocardium. The sensitivity of detection of erroneous outputs was 91%. Finally, T1 values were automatically derived from 11,882 CMR exams from the UK Biobank. For the healthy cohort, the mean (SD) corrected T1 values were 926.61 (45.26), 934.39 (43.25) and 927.56 (50.36) for global, interventricular septum and free-wall respectively. CONCLUSIONS: The proposed pipeline allows for automatic analysis of myocardial native T1 mapping and includes a QC process to detect potentially erroneous results. T1 reference values were presented for healthy subjects and common clinical cardiac conditions from the largest cohort to date using T1-mapping images.

Automated cardiovascular magnetic resonance image analysis with fully convolutional networks.

BACKGROUND: Cardiovascular resonance (CMR) imaging is a standard imaging modality for assessing cardiovascular diseases (CVDs), the leading cause of death globally. CMR enables accurate quantification of the cardiac chamber volume, ejection fraction and myocardial mass, providing information for diagnosis and monitoring of CVDs. However, for years, clinicians have been relying on manual approaches for CMR image analysis, which is time consuming and prone to subjective errors. It is a major clinical challenge to automatically derive quantitative and clinically relevant information from CMR images. METHODS: Deep neural networks have shown a great potential in image pattern recognition and segmentation for a variety of tasks. Here we demonstrate an automated analysis method for CMR images, which is based on a fully convolutional network (FCN). The network is trained and evaluated on a large-scale dataset from the UK Biobank, consisting of 4,875 subjects with 93,500 pixelwise annotated images. The performance of the method has been evaluated using a number of technical metrics, including the Dice metric, mean contour distance and Hausdorff distance, as well as clinically relevant measures, including left ventricle (LV) end-diastolic volume (LVEDV) and end-systolic volume (LVESV), LV mass (LVM); right ventricle (RV) end-diastolic volume (RVEDV) and end-systolic volume (RVESV). RESULTS: By combining FCN with a large-scale annotated dataset, the proposed automated method achieves a high performance in segmenting the LV and RV on short-axis CMR images and the left atrium (LA) and right atrium (RA) on long-axis CMR images. On a short-axis image test set of 600 subjects, it achieves an average Dice metric of 0.94 for the LV cavity, 0.88 for the LV myocardium and 0.90 for the RV cavity. The mean absolute difference between automated measurement and manual measurement is 6.1 mL for LVEDV, 5.3 mL for LVESV, 6.9 gram for LVM, 8.5 mL for RVEDV and 7.2 mL for RVESV. On long-axis image test sets, the average Dice metric is 0.93 for the LA cavity (2-chamber view), 0.95 for the LA cavity (4-chamber view) and 0.96 for the RA cavity (4-chamber view). The performance is comparable to human inter-observer variability. CONCLUSIONS: We show that an automated method achieves a performance on par with human experts in analysing CMR images and deriving clinically relevant measures.

Impact of coronary bifurcation morphology on wave propagation.

The branching pattern of the coronary vasculature is a key determinant of its function and plays a crucial role in shaping the pressure and velocity wave forms measured for clinical diagnosis. However, although multiple scaling laws have been proposed to characterize the branching pattern, the implications they have on wave propagation remain unassessed to date. To bridge this gap, we have developed a new theoretical framework by combining the mathematical formulation of scaling laws with the wave propagation theory in the pulsatile flow regime. This framework was then validated in multiple species using high-resolution cryomicrotome images of porcine, canine, and human coronary networks. Results demonstrate that the forward well-matchedness (no reflection for pressure/flow waves traveling from the coronary stem toward the microcirculation) is a salient feature in the coronary vasculature, and this result remains robust under many scenarios of the underlying pulse wave speed distribution assumed in the network. This result also implies a significant damping of the backward traveling waves, especially for smaller vessels (radius, <0.3 mm). Furthermore, the theoretical prediction of increasing area ratios (ratio between the area of the mother and daughter vessels) in more symmetric bifurcations found in the distal circulation was confirmed by experimental measurements. No differences were observed by clustering the vessel segments in terms of transmurality (from epicardium to endocardium) or perfusion territories (left anterior descending, left circumflex, and right coronary artery).

Microsphere skimming in the porcine coronary arteries: Implications for flow quantification.

Particle skimming is a phenomenon where particles suspended in fluid flowing through vessels distribute disproportionately to bulk fluid volume at junctions. Microspheres are considered a gold standard of intra-organ perfusion measurements and are used widely in studies of flow distribution and quantification. It has previously been hypothesised that skimming at arterial junctions is responsible for a systematic over-estimation of myocardial perfusion from microspheres at the subendocardium. Our objective is to integrate coronary arterial structure and microsphere distribution, imaged at high resolution, to test the hypothesis of microsphere skimming in a porcine left coronary arterial (LCA) network. A detailed network was reconstructed from cryomicrotome imaging data and a Poiseuille flow model was used to simulate flow. A statistical approach using Clopper-Pearson confidence intervals was applied to determine the prevalence of skimming at bifurcations in the LCA. Results reveal that microsphere skimming is most prevalent at bifurcations in the larger coronary arteries, namely the epicardial and transmural arteries. Bifurcations at which skimming was identified have significantly more asymmetric branching parameters. This finding suggests that when using thin transmural segments to quantify flow from microspheres, a skimming-related deposition bias may result in underestimation of perfusion in the subepicardium, and overestimation in the subendocardium.

Quantitative assessment of magnetic resonance derived myocardial perfusion measurements using advanced techniques: microsphere validation in an explanted pig heart system.

BACKGROUND: Cardiovascular Magnetic Resonance (CMR) myocardial perfusion imaging has the potential to evolve into a method allowing full quantification of myocardial blood flow (MBF) in clinical routine. Multiple quantification pathways have been proposed. However at present it remains unclear which algorithm is the most accurate. An isolated perfused, magnetic resonance (MR) compatible pig heart model allows very accurate titration of MBF and in combination with high-resolution assessment of fluorescently-labeled microspheres represents a near optimal platform for validation. We sought to investigate which algorithm is most suited to quantify myocardial perfusion by CMR at 1.5 and 3 Tesla using state of the art CMR perfusion techniques and quantification algorithms. METHODS: First-pass perfusion CMR was performed in an MR compatible blood perfused pig heart model. We acquired perfusion images at physiological flow ("rest"), reduced flow ("ischaemia") and during adenosine-induced hyperaemia ("hyperaemia") as well as during coronary occlusion. Perfusion CMR was performed at 1.5 Tesla (n = 4 animals) and at 3 Tesla (n = 4 animals). Fluorescently-labeled microspheres and externally controlled coronary blood flow served as reference standards for comparison of different quantification strategies, namely Fermi function deconvolution (Fermi), autoregressive moving average modelling (ARMA), exponential basis deconvolution (Exponential) and B-spline basis deconvolution (B-spline). RESULTS: All CMR derived MBF estimates significantly correlated with microsphere results. The best correlation was achieved with Fermi function deconvolution both at 1.5 Tesla (r = 0.93, p < 0.001) and at 3 Tesla (r = 0.9, p < 0.001). Fermi correlated significantly better with the microspheres than all other methods at 3 Tesla (p < 0.002). B-spline performed worse than Fermi and Exponential at 1.5 Tesla and showed the weakest correlation to microspheres (r = 0.74, p < 0.001). All other comparisons were not significant. At 3 Tesla exponential deconvolution performed worst (r = 0.49, p < 0.001). CONCLUSIONS: CMR derived quantitative blood flow estimates correlate with true myocardial blood flow in a controlled animal model. Amongst the different techniques, Fermi function deconvolution was the most accurate technique at both field strengths. Perfusion CMR based on Fermi function deconvolution may therefore emerge as a useful clinical tool providing accurate quantitative blood flow assessment.

Social and Behavioral Barriers to Effective Care During the Transition to End-Stage Kidney Care.

Individuals living with CKD are disproportionately burdened by a multitude of adverse clinical and person-centered outcomes. When patients transition from advanced kidney disease to kidney failure, the psychosocial effects as well as social determinants of health challenges are magnified, making this a particularly difficult time for patients beginning kidney replacement therapy. The key social determinants of health challenges often include food and housing insecurity, poverty, unreliable transportation, low level education and/or health literacy, lack of language interpreters and culturally concordant educational materials, lack of health care insurance coverage, and mistrust of the health care system. Psychosocial and physical stressors, such as depression, anxiety, sexual dysfunction, sleep difficulty, fatigue, and pain, are often part of the illness burden among individuals living with CKD and can interact synergistically with the social challenges making the transition to kidney replacement therapy particularly challenging. To better support patients during this time, it is critical that social and structural determinants of health as well as mental health be assessed and if needs are identified, that services be provided.

Heterolytic carbon-iodine bond cleavage by a palladium(I) metalloradical.

The well-defined Pd(I) metalloradical [Pd(PtBu3)2]+ reacts with aryl and alkyl iodides at room temperature, yielding [Pd(PtBu3)(µ-I)]2 and phosphonium salts. Pd(II) aryl/alkyl derivates, reflecting net radical oxidative addition of the substrate to the metalloradical, are generated during the reaction and two examples have been isolated and crystallographically characterised.

Atlas-ISTN: Joint segmentation, registration and atlas construction with image-and-spatial transformer networks.

Deep learning models for semantic segmentation are able to learn powerful representations for pixel-wise predictions, but are sensitive to noise at test time and may lead to implausible topologies. Image registration models on the other hand are able to warp known topologies to target images as a means of segmentation, but typically require large amounts of training data, and have not widely been benchmarked against pixel-wise segmentation models. We propose the Atlas Image-and-Spatial Transformer Network (Atlas-ISTN), a framework that jointly learns segmentation and registration on 2D and 3D image data, and constructs a population-derived atlas in the process. Atlas-ISTN learns to segment multiple structures of interest and to register the constructed atlas labelmap to an intermediate pixel-wise segmentation. Additionally, Atlas-ISTN allows for test time refinement of the model's parameters to optimize the alignment of the atlas labelmap to an intermediate pixel-wise segmentation. This process both mitigates for noise in the target image that can result in spurious pixel-wise predictions, as well as improves upon the one-pass prediction of the model. Benefits of the Atlas-ISTN framework are demonstrated qualitatively and quantitatively on 2D synthetic data and 3D cardiac computed tomography and brain magnetic resonance image data, out-performing both segmentation and registration baseline models. Atlas-ISTN also provides inter-subject correspondence of the structures of interest.

Association of Follow-up Blood Cultures With Mortality in Patients With Gram-Negative Bloodstream Infections: A Systematic Review and Meta-analysis.

Importance: Obtaining follow-up blood cultures (FUBCs) in patients with Staphylococcus aureus bloodstream infection (BSI) is standard practice, although its utility in patients with gram-negative bacterial BSI (GN-BSI) is unclear. Objective: To examine whether obtaining FUBCs is associated with decreased mortality (key question [KQ] 1) and whether positive vs negative FUBCs are associated with increased mortality (KQ2). Data Sources: MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Web of Science, and gray literature were searched from inception to March 11, 2022. Study Selection: Two investigators used predefined eligibility criteria to independently screen titles, abstracts, and relevant full texts. Randomized clinical trials or observational studies that matched or statistically adjusted for differences in, at minimum, level of acute illness between patients in the intervention (eg, FUBCs obtained) and control (eg, FUBCs not obtained) groups were included in primary analyses. Articles published in languages other than English were excluded. Data Extraction and Synthesis: Data abstraction and quality assessments were performed by one investigator and verified by a second investigator. Risk of bias was assessed with the Newcastle-Ottawa Scale. Effect sizes were pooled using random-effects models. The study followed the Meta-analysis of Observational Studies in Epidemiology (MOOSE) reporting guideline. Main Outcomes and Measures: Mortality before hospital discharge or up to 30 days from the index blood culture. Results: From 3495 studies, 15 were included (all nonrandomized). In the 5 studies (n = 4378 patients) that met criteria for the KQ1 primary analysis, obtaining FUBCs was associated with decreased mortality (hazard ratio, 0.56; 95% CI, 0.45-0.71). For KQ2, 2 studies met criteria for the primary analysis (ie, matched or statistically adjusted for differences in patients with positive vs negative FUBCs), so an exploratory meta-analysis of all 9 studies that investigated KQ2 (n = 3243 patients) was performed. Positive FUBCs were associated with increased mortality relative to negative blood cultures (odds ratio, 2.27; 95% CI, 1.54-3.34). Limitations of the literature included a lack of randomized studies and few patient subgroup analyses. Conclusions and Relevance: In this systematic review and meta-analysis, obtaining FUBCs in patients with GN-BSI was associated with decreased mortality. The benefit of FUBCs may stem from identification of patients with positive FUBCs, which was a poor prognostic marker.

Regional and Racial Disparities in HIV-Related Kidney Disease.

Clinical Background and Epidemiology: Worldwide, an estimated 38 million people are living with HIV infection. The classic kidney disease of HIV infection, commonly known as HIV-associated nephropathy, is a collapsing form of focal segmental glomerulosclerosis that almost exclusively affects individuals of African descent with advanced HIV disease. People living with HIV are also at risk for immune-complex kidney diseases, antiretroviral nephrotoxicity, and kidney disease due to co-infections and comorbidities. Challenges: The burden of HIV-related kidney disease is greatest in traditionally disadvantaged populations in resource-limited settings in sub-Saharan Africa and the Caribbean and among minority populations in the United States and Europe. Factors contributing to these disparities include a higher prevalence of HIV infection, limited access to optimal antiretroviral therapy, and genetic susceptibility to kidney disease. Treatment and Prevention: Current treatment guidelines recommend the initiation of life-long antiretroviral therapy in all people living with HIV to prevent AIDS and non-AIDS complications, including kidney disease. People living with HIV who progress to end-stage kidney disease despite treatment are candidates for dialysis and kidney transplant, including the possibility of accepting organs from HIV-positive donors in some settings. Although HIV prevention is currently the only definitive solution, expanding access to antiretroviral therapy, dialysis, and kidney transplantation in people living with HIV are important intermediate steps to address the global burden of HIV-related kidney disease.

Renin-angiotensin system blockade in the COVID-19 pandemic.

In the early months of the coronavirus disease 2019 (COVID-19) pandemic, a hypothesis emerged suggesting that pharmacologic inhibitors of the renin-angiotensin system (RAS) may increase COVID-19 severity. This hypothesis was based on the role of angiotensin-converting enzyme 2 (ACE2), a counterregulatory component of the RAS, as the binding site for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), allowing viral entry into host cells. Extrapolations from prior evidence led to speculation that upregulation of ACE2 by RAS blockade may increase the risk of adverse outcomes from COVID-19. However, counterarguments pointed to evidence of potential protective effects of ACE2 and RAS blockade with regard to acute lung injury, as well as substantial risks from discontinuing these commonly used and important medications. Here we provide an overview of classic RAS physiology and the crucial role of ACE2 in systemic pathways affected by COVID-19. Additionally, we critically review the physiologic and epidemiologic evidence surrounding the interactions between RAS blockade and COVID-19. We review recently published trial evidence and propose important future directions to improve upon our understanding of these relationships.

Myocardial Perfusion Simulation for Coronary Artery Disease: A Coupled Patient-Specific Multiscale Model.

Patient-specific models of blood flow are being used clinically to diagnose and plan treatment for coronary artery disease. A remaining challenge is bridging scales from flow in arteries to the micro-circulation supplying the myocardium. Previously proposed models are descriptive rather than predictive and have not been applied to human data. The goal here is to develop a multiscale patient-specific model enabling blood flow simulation from large coronary arteries to myocardial tissue. Patient vasculatures are segmented from coronary computed tomography angiography data and extended from the image-based model down to the arteriole level using a space-filling forest of synthetic trees. Blood flow is modeled by coupling a 1D model of the coronary arteries to a single-compartment Darcy myocardium model. Simulated results on five patients with non-obstructive coronary artery disease compare overall well to [[Formula: see text]O][Formula: see text]O PET exam data for both resting and hyperemic conditions. Results on a patient with severe obstructive disease link coronary artery narrowing with impaired myocardial blood flow, demonstrating the model's ability to predict myocardial regions with perfusion deficit. This is the first report of a computational model for simulating blood flow from the epicardial coronary arteries to the left ventricle myocardium applied to and validated on human data.