Biochemical functions and structure of Caenorhabditis elegans ZK177.8 protein: Aicardi-Goutières syndrome SAMHD1 dNTPase ortholog.

Mutations in sterile alpha motif domain and histidine-aspartate domain-containing protein 1 (SAMHD1) are found in a neurodevelopmental disorder, Aicardi-Goutières syndrome, and cancers, and SAMHD1, which is a deoxynucleoside triphosphate (dNTP) triphosphorylase, was identified as a myeloid-specific HIV-1 restriction factor. Here, we characterized the enzymology and structure of an SAMHD1 ortholog of Caenorhabditis elegans, ZK177.8, which also reportedly induces developmental defects upon gene knockdown. We found ZK177.8 protein is a dNTPase allosterically regulated by dGTP. The active site of ZK177.8 recognizes both 2' OH and triphosphate moieties of dNTPs but not base moiety. The dGTP activator induces the formation of the enzymatically active ZK177.8 tetramers, and ZK177.8 protein lowers cellular dNTP levels in a human monocytic cell line. Finally, ZK177.8 tetramers display very similar X-ray crystal structure with human and mouse SAMHD1s except that its lack of the canonical sterile alpha motif domain. This striking conservation in structure, function, and allosteric regulatory mechanism for the hydrolysis of the DNA building blocks supports their host developmental roles.

Adrenal Mass Biopsy in Patients Without Extraadrenal Primary Malignancy: A Multicenter Study.

BACKGROUND. Adrenal washout CT is not useful for evaluating incidental adrenal masses in patients without known or suspected primary extraadrenal malignancy. OBJECTIVE. The purpose of our study was to evaluate the diagnostic utility of adrenal mass biopsy in patients without known or suspected extraadrenal primary malignancy. METHODS. This retrospective six-center study included 69 patients (mean age, 56 years; 32 men, 37 women) without known or suspected extraadrenal primary malignancy who underwent image-guided core needle biopsy between January 2004 and June 2021 of a mass suspected to be arising from the adrenal gland. Biopsy results were classified as diagnostic or nondiagnostic. For masses resected after biopsy, histopathologic concordance was assessed between diagnoses from biopsy and resection. Masses were classified as benign or malignant by resection or imaging follow-up, and all nondi-agnostic biopsies were classified as false results. RESULTS. The median mass size was 7.4 cm (range, 1.9-19.2 cm). Adrenal mass biopsy had a diagnostic yield of 64% (44/69; 95% CI, 51-75%). After biopsy, 25 masses were resected, and 44 had imaging follow-up. Of the masses that were resected after diagnostic biopsy, diagnosis was concordant between biopsy and resection in 100% (12/12). Of the 13 masses that were resected after nondiagnostic biopsy, the diagnosis from re-section was benign in eight masses and malignant in five masses. The 44 masses with imaging follow-up included one mass with diagnostic biopsy yielding benign adenoma and two masses with nondiagnostic biopsy results that were classified as malignant by imaging follow-up. Biopsy had overall sensitivity and specificity for malignancy of 73% (22/30) and 54% (21/39), respectively; diagnostic biopsies had sensitivity and specificity for malignancy of 96% (22/23) and 100% (21/21), respectively. Among nine nondi-agnostic biopsies reported as adrenocortical neoplasm, six were classified as malignant by the reference standard (resection showing adrenocortical carcinoma in four, resection showing adrenocortical neoplasm of uncertain malignant potential in one, imaging follow-up consistent with malignancy in one). CONCLUSION. Adrenal mass biopsy had low diagnostic yield, with low sensitivity and low specificity for malignancy. A biopsy result of adrenocortical neoplasm did not reliably differentiate benign and malignant adrenal masses. CLINICAL IMPACT. Biopsy appears to have limited utility for the evaluation of incidental adrenal masses in patients without primary extraadrenal malignancy.

How i do it: microscope augmented pancreaticojejunostomy.

PURPOSE: Post-operative pancreatic fistula (POPF) is perhaps one of most dreaded pancreatoduodenectomy-related complications. Various approaches to mitigate this risk have been explored, with conflicting results and no clear consensus on the comparative superiority of any one technique. We postulate that regardless of technique, the key to reducing POPF is a robust pancreatic anastomosis with careful apposition of tissues, in particular the duct-to-mucosa anastomosis. METHOD: We describe the fashioning of a pancreatojejunostomy with an external pancreatic stent in the setting of a high-risk anastomosis with help of a 10 × magnification surgical microscope. A technical description with a short, edited video is presented.

Crystal structure of a guanine nucleotide exchange factor encoded by the scrub typhus pathogen Orientia tsutsugamushi.

Rho family GTPases regulate an array of cellular processes and are often modulated by pathogens to promote infection. Here, we identify a cryptic guanine nucleotide exchange factor (GEF) domain in the OtDUB protein encoded by the pathogenic bacterium Orientia tsutsugamushi A proteomics-based OtDUB interaction screen identified numerous potential host interactors, including the Rho GTPases Rac1 and Cdc42. We discovered a domain in OtDUB with Rac1/Cdc42 GEF activity (OtDUBGEF), with higher activity toward Rac1 in vitro. While this GEF bears no obvious sequence similarity to known GEFs, crystal structures of OtDUBGEF alone (3.0 Å) and complexed with Rac1 (1.7 Å) reveal striking convergent evolution, with a unique topology, on a V-shaped bacterial GEF fold shared with other bacterial GEF domains. Structure-guided mutational analyses identified residues critical for activity and a mechanism for nucleotide displacement. Ectopic expression of OtDUB activates Rac1 preferentially in cells, and expression of the OtDUBGEF alone alters cell morphology. Cumulatively, this work reveals a bacterial GEF within the multifunctional OtDUB that co-opts host Rac1 signaling to induce changes in cytoskeletal structure.

Moving toward improved access to medicines and health technologies for cardiovascular disease.

The objectives of this article are to describe the interventions carried out by the Strategic Fund of the Pan American Health Organization to facilitate access to and availability of antihypertensive medicines and devices for measuring blood pressure across the Region of the Americas as part of the HEARTS initiative, and to present the preliminary results of price analyses of antihypertensive medicines. The study methodology included a review of reports made by the Strategic Fund between 2019 and 2020, an evaluation of modalities of procurement, a review of the public procurement databases for five antihypertensive medicines, and a comparison with the price obtained by the Strategic Fund. Differences in price ranging from 20% to 99% were identified, indicating significant opportunities for savings. The study also presents interprogrammatic actions that can support the HEARTS initiative, such as the inclusion of antihypertensive medicines recommended by the World Health Organization, consolidation of regional demand and competitively-priced long-term agreements to manage the procurement of quality generic products, and the definition of technical specifications and regulatory requirements to support the procurement of devices to measure blood pressure. This mechanism will enable Member States to reduce their costs significantly, while extending treatment and diagnostic coverage to more people.

Los objetivos del presente artículo son describir las intervenciones realizadas por el Fondo Estratégico de Organización Panamericana de la Salud, para facilitar el acceso y disponibilidad de medicamentos antihipertensivos y dispositivos para la medición de la presión arterial a los países de la Región de las Américas en apoyo a la implementación de la Iniciativa HEARTS; y presentar los resultados preliminares de los análisis de los precios de los medicamentos antihipertensivos. La metodología del estudio incluyó la revisión de informes realizados por el Fondo Estratégico durante los años 2019-2020, la evaluación de las modalidades de adquisición y revisión de las bases de datos de compras públicas para 5 medicamentos antihipertensivos, y el análisis comparativo con el precio obtenido por el Fondo Estratégico. Se identificaron diferencias que oscilaron entre 20% y 99%, lo que evidencia oportunidades de ahorro significativas. Asimismo, se presentan las acciones interprogramáticas desarrolladas en apoyo a la Iniciativa HEARTS, entre las que se destacan la inclusión de medicamentos antihipertensivos recomendados por la Organización Mundial de la Salud; la consolidación de la demanda regional y el establecimiento de precios competitivos con acuerdos a largo plazo para gestionar la adquisición de productos genéricos de calidad; y la definición de especificaciones técnicas y requisitos regulatorios para apoyar con la adquisición de dispositivos para la medición de la presión arterial. A través de este mecanismo, los Estados Miembros pueden disminuir sus costos significativamente, extendiendo cobertura del tratamiento y diagnóstico a más personas.

Os objetivos deste artigo são descrever as intervenções realizadas pelo Fundo Estratégico da Organização Pan-Americana da Saúde para facilitar o acesso e a disponibilidade de medicamentos anti-hipertensivos e aparelhos de medição de pressão arterial aos países da Região das Américas, em apoio à implementação da iniciativa HEARTS; e apresentar os resultados preliminares da análise dos preços dos medicamentos anti-hipertensivos. A metodologia do estudo incluiu a revisão de relatórios feitos pelo Fundo Estratégico durante os anos de 2019 e 2020, a avaliação das modalidades de aquisição e revisão dos dados de compras públicas de 5 medicamentos anti-hipertensivos e uma análise comparativa com o preço obtido pelo Fundo Estratégico. Foram identificadas diferenças que oscilaram entre 20% e 99%, o que evidencia oportunidades de economia significativas. Da mesma forma, são apresentadas as ações interprogramáticas desenvolvidas em apoio à iniciativa HEARTS, entre as quais se destacam a inclusão de medicamentos anti-hipertensivos recomendados pela Organização Mundial da Saúde; a consolidação da demanda regional e o estabelecimento de preços competitivos com acordos de longo prazo para gerenciar a aquisição de genéricos de qualidade; e a definição de especificações técnicas e requisitos regulatórios para subsidiar a aquisição de aparelhos de medição de pressão arterial. Por meio desse mecanismo, os Estados Membros podem reduzir seus custos significativamente, ampliando a cobertura de tratamento e diagnóstico para atingir mais pessoas.

Peritoneal dialysis catheter insertion techniques by the nephrologist.

Peritoneal dialysis (PD) catheter is the lifeline of PD patients, and despite the overall strength of the PD program in many countries, PD catheter survival remains the major weakness of the program. The prompt and effective implantation of the PD catheter, as well as speedy management of complications arising from catheter insertion, remains crucial for the success of the program.

[Moving toward improved access to medicines and health technologies for cardiovascular diseaseAvançando para melhorar o acesso a medicamentos e tecnologias de saúde para as doenças cardiovasculares]. / Avanzando para mejorar el acceso a los medicamentos y tecnologías sanitarias para las enfermedades cardiovasculares.

The objectives of this article are to describe the interventions carried out by the Strategic Fund of the Pan American Health Organization to facilitate access to and availability of antihypertensive drugs and devices for measuring blood pressure in the countries of the Region of the Americas, supporting implementation of the HEARTS initiative; and to present the preliminary results of price analyses of antihypertensive drugs.The study methodology included a review of reports made by the Strategic Fund during 2019-2020, evaluation of modalities of procurement, a review of the public procurement databases for five antihypertensive drugs, and a comparison with the price obtained by the Strategic Fund. Differences ranging from 20% to 99% were identified, indicating significant opportunities for savings. Interprogrammatic actions in support of the HEARTS initiative are also presented, such as the inclusion of antihypertensive drugs recommended by the World Health Organization; consolidation of regional demand and establishment of competitive prices with long-term agreements to manage the procurement of quality generic products; and the definition of technical specifications and regulatory requirements to support the procurement of devices to measure blood pressure. Through this mechanism, Member States can reduce their costs significantly, enabling them to extend treatment and diagnostic coverage to more people.

Os objetivos deste artigo são descrever as intervenções realizadas pelo Fundo Estratégico da Organização Pan-Americana da Saúde para facilitar o acesso e a disponibilidade de medicamentos anti-hipertensivos e aparelhos de medição de pressão arterial aos países da Região das Américas, em apoio à implementação da iniciativa HEARTS; e apresentar os resultados preliminares da análise dos preços dos medicamentos anti-hipertensivos.A metodologia do estudo incluiu a revisão de relatórios feitos pelo Fundo Estratégico durante os anos de 2019 e 2020, a avaliação das modalidades de aquisição e revisão dos dados de compras públicas de 5 medicamentos anti-hipertensivos e uma análise comparativa com o preço obtido pelo Fundo Estratégico. Foram identificadas diferenças que oscilaram entre 20% e 99%, o que evidencia oportunidades de economia significativas. Da mesma forma, são apresentadas as ações interprogramáticas desenvolvidas em apoio à iniciativa HEARTS, entre as quais se destacam a inclusão de medicamentos anti-hipertensivos recomendados pela Organização Mundial da Saúde; a consolidação da demanda regional e o estabelecimento de preços competitivos com acordos de longo prazo para gerenciar a aquisição de genéricos de qualidade; e a definição de especificações técnicas e requisitos regulatórios para subsidiar a aquisição de aparelhos de medição de pressão arterial. Por meio desse mecanismo, os Estados Membros podem reduzir seus custos significativamente, ampliando a cobertura de tratamento e diagnóstico para atingir mais pessoas.

A Conserved Acidic-Cluster Motif in SERINC5 Confers Partial Resistance to Antagonism by HIV-1 Nef.

The cellular protein SERINC5 inhibits the infectivity of diverse retroviruses, and its activity is counteracted by the glycosylated Gag (glycoGag) protein of murine leukemia virus (MLV), the S2 protein of equine infectious anemia virus (EIAV), and the Nef protein of human immunodeficiency virus type 1 (HIV-1). Determining the regions within SERINC5 that provide restrictive activity or Nef sensitivity should inform mechanistic models of the SERINC5/HIV-1 relationship. Here, we report that deletion of the conserved sequence EDTEE, which is located within a cytoplasmic loop of SERINC5 and which is reminiscent of an acidic-cluster membrane trafficking signal, increases the sensitivity of SERINC5 to antagonism by Nef, while it has no effect on the intrinsic activity of the protein as an inhibitor of infectivity. These effects correlated with enhanced removal of the ΔEDTEE mutant relative to that of wild-type SERINC5 from the cell surface and with enhanced exclusion of the mutant protein from virions by Nef. Mutational analysis indicated that the acidic residues, but not the threonine, within the EDTEE motif are important for the relative resistance to Nef. Deletion of the EDTEE sequence did not increase the sensitivity of SERINC5 to antagonism by the glycoGag protein of MLV, suggesting that its virologic role is Nef specific. These results are consistent with the reported mapping of the cytoplasmic loop that contains the EDTEE sequence as a general determinant of Nef responsiveness, but they further indicate that sequences inhibitory to as well as supportive of Nef activity reside in this region. We speculate that the EDTEE motif might have evolved to mediate resistance against retroviruses that use Nef-like proteins to antagonize SERINC5.IMPORTANCE Cellular membrane proteins in the SERINC family, especially SERINC5, inhibit the infectivity of retroviral virions. This inhibition is counteracted by retroviral proteins, specifically, HIV-1 Nef, MLV glycoGag, and EIAV S2. One consequence of such a host-pathogen "arms race" is a compensatory change in the host antiviral protein as it evolves to escape the effects of viral antagonists. This is often reflected in a genetic signature, positive selection, which is conspicuously missing in SERINC5 Here we show that despite this lack of genetic evidence, a sequence in SERINC5 nonetheless provides relative resistance to antagonism by HIV-1 Nef.

Quantitative Prostate MRI.

Prostate MRI is reported in clinical practice using the Prostate Imaging and Data Reporting System (PI-RADS). PI-RADS aims to standardize, as much as possible, the acquisition, interpretation, reporting, and ultimately the performance of prostate MRI. PI-RADS relies upon mainly subjective analysis of MR imaging findings, with very few incorporated quantitative features. The shortcomings of PI-RADS are mainly: low-to-moderate interobserver agreement and modest accuracy for detection of clinically significant tumors in the transition zone. The use of a more quantitative analysis of prostate MR imaging findings is therefore of interest. Quantitative MR imaging features including: tumor size and volume, tumor length of capsular contact, tumor apparent diffusion coefficient (ADC) metrics, tumor T1 and T2 relaxation times, tumor shape, and texture analyses have all shown value for improving characterization of observations detected on prostate MRI and for differentiating between tumors by their pathological grade and stage. Quantitative analysis may therefore improve diagnostic accuracy for detection of cancer and could be a noninvasive means to predict patient prognosis and guide management. Since quantitative analysis of prostate MRI is less dependent on an individual users' assessment, it could also improve interobserver agreement. Semi- and fully automated analysis of quantitative (radiomic) MRI features using artificial neural networks represent the next step in quantitative prostate MRI and are now being actively studied. Validation, through high-quality multicenter studies assessing diagnostic accuracy for clinically significant prostate cancer detection, in the domain of quantitative prostate MRI is needed. This article reviews advances in quantitative prostate MRI, highlighting the strengths and limitations of existing and emerging techniques, as well as discussing opportunities and challenges for evaluation of prostate MRI in clinical practice when using quantitative assessment. LEVEL OF EVIDENCE: 5 TECHNICAL EFFICACY: Stage 2.

Prevalence of prostate cancer in PI-RADS version 2.1 T2-weighted transition zone 'nodule in nodule' and 'homogeneous mildly hypointense area between nodules' criteria: MRI-radical prostatectomy histopathological evaluation.

OBJECTIVES: To evaluate the prevalence of prostate cancer (PCa) of two PI-RADS version (v) 2.1 transition zone (TZ) features (PI-RADS 1 ['nodule in nodule'] and 2 ['homogeneous mildly hypointense area between nodules']). METHODS: With an institutional review board approval, from a 5-year cohort between 2012 and 2017, we retrospectively identified 53 consecutive men with radical prostatectomy (RP) confirmed TZ tumors and MRI. Three blinded radiologists (R1/2/3) independently evaluated T2-weighted and diffusion-weighted imaging (DWI) using PI-RADS v2.1 for the presence of (1) 'nodule in nodule' (recording 'cystic change', inner nodule encapsulation, size, and DWI score) and (2) 'homogeneous mildly hypointense area between nodules' (also recording size and DWI score). MRI-RP maps established ground truth. Primary tumor was evaluated assessing PI-RADS v2.1 category, size, and presence of imaging variants. RESULTS: R1/2/3 identified 26/18/22 'nodule in nodule' respectively with 7.7% (2/26; 95% confidence interval [95% CI]: 0.1-17.9%), 5.6% (1/18; 95% CI: 0.01-16.1%), and 4.5% (1/22; 95% CI: 0.01-13.3%) PCa (both Gleason score 3 + 4 = 7). Agreement was fair-to-substantial, kappa = 0.222-0.696. 'Cystic change', inner nodule absent/incomplete encapsulation and DWI score ≥ 4 for R1/R2/R2 were present in 80.8% (21/26), 46.2% (12/26), 7.7% (2/26); 94.4% (17/18), 33.3% (6/18), 5.6% (1/18); and 59.1% (13/22), 63.6% (14/22), 9.1% (2/22). Both PCa had inner nodule absent/incomplete encapsulation and DWI score ≥ 4. No other TZ tumors demonstrated 'nodule in nodule', nodule 'cystic change', or 'homogeneous mildly hypointense area between nodules'. R1/2/3 identified 5/6/13 'homogeneous mildly hypointense area between nodules' with zero PCa for any reader (upper bound 95% CI: 24.7-52.2%). Interobserver agreement was fair-to-substantial, kappa = 0.104-0.779. CONCLUSION: The proportion of cancers in PI-RADS v2.1 'nodule in nodule' was low (~5-8%) with zero cancers detected in 'homogeneous mildly hypointense area between nodules'. When 'nodule in nodule' inner nodule shows absent or incomplete encapsulation with marked restricted diffusion, PCa may be considered; however, this warrants further studies. KEY POINTS: • The prevalence of clinically significant prostate cancers in PI-RADS v2.1 'nodule in nodule' was low (5-8%, 95% CI: 0.1-17.9%). • Clinically significant prostate cancer was only detected in the 'nodule in nodule' variant when the inner nodule showed absent or incomplete encapsulation ('atypical nodule') with marked restricted diffusion. • 'Homogeneous mildly hypointense area between nodules' is likely benign with no cancers identified in the current study, however, with a wide 95% CI due to low prevalence.

Prevalence of Prostate Cancer in PI-RADS Version 2.1 Transition Zone Atypical Nodules Upgraded by Abnormal DWI: Correlation With MRI-Directed TRUS-Guided Targeted Biopsy.

BACKGROUND. In PI-RADS version 2.1 (v2.1), atypical transition zone (TZ) nodules (homogeneous circumscribed nodules without full encapsulation) assigned category 2 can be upgraded to category 3 when showing markedly restricted diffusion. The prevalence of prostate cancer (PCa) in DWI-upgraded atypical nodules is unknown. OBJECTIVE. The purpose of this study was to evaluate the prevalence of PCa in DWI-upgraded TZ atypical nodules and compare PCa diagnosis rate with that for conventional score 3 TZ nodules. METHODS. We retrospectively identified 104 consecutive cases of men who underwent MRI-directed transrectal ultrasound-guided targeted biopsy of 109 TZ category 3 or lower nodules performed between January 2015 and July 2018. Three radiologists who were blinded to the scores independently rescored lesions using PI-RADS v2.1. Agreement was assessed by Cohen kappa score. Consensus diagnosis was established by a second-round joint review. The number of TZ atypical nodules with or without DWI-upgraded and conventional score 3 TZ nodules were recorded and compared with targeted biopsy results including any PCa or clinically significant PCa (csPCa, defined as International Society of Urological Pathology [ISUP] grade group ≥ 2) using chi-square analysis. RESULTS. There were 95 PI-RADS v2.1 category 3 (55 conventional T2-weighted MRI score 3 and 40 DWI-upgraded atypical nodules) and 14 category 2 or 1 nodules at consensus review with patient mean age of 64.8 ± 8.4 (SD) years, PSA of 10.6 ± 7.2 ng/mL, and nodule size of 15.1 ± 5.5 mm. Interobserver agreement ranged from slight to substantial for radiologists 1 and 2 (κ = 0.329), radiologists 1 and 3 (κ = 0.548), and radiologists 2 and 3 (κ = 0.652). From the 40 upgraded atypical nodules, 27.5% (11/40) had PCa and 7.5% (3/40) had csPCa (8 ISUP grade 1, 2 ISUP grade 2, 1 ISUP grade 3), compared with 43.6% (24/55) PCa and 20.0% (11/55) csPCa (13 ISUP grade 1, 6 ISUP grade 2, 3 ISUP grade 3, 2 ISUP grade 4) diagnosed in conventional T2-weighted score 3 nodules (p = .09 for csPCA and p = .11 for PCa). PCa was not diagnosed in any atypical nodule that was not upgraded on DWI. CONCLUSION. The prevalence of PCa in DWI-upgraded TZ atypical nodules was low (≈ 28% for any PCa and ≈ 8% for csPCa) and compared favorably to csPCa diagnosis rates in conventional TZ score 3 nodules. CLINICAL IMPACT. This study validates the DWI upgrade rule introduced in PI-RADS v2.1 for atypical nodules, which showed significant prostate cancer detection rates at targeted biopsy similar to those of conventional T2-weighted MRI TZ score 3 nodules.

Accuracy of the Liver Imaging Reporting and Data System in Computed Tomography and Magnetic Resonance Image Analysis of Hepatocellular Carcinoma or Overall Malignancy-A Systematic Review.

BACKGROUND & AIMS: The Liver Imaging Reporting and Data System (LI-RADS) categorizes observations from imaging analyses of high-risk patients based on the level of suspicion for hepatocellular carcinoma (HCC) and overall malignancy. The categories range from definitely benign (LR-1) to definitely HCC (LR-5), malignancy (LR-M), or tumor in vein (LR-TIV) based on findings from computed tomography or magnetic resonance imaging. However, the actual percentage of HCC and overall malignancy within each LI-RADS category is not known. We performed a systematic review to determine the percentage of observations in each LI-RADS category for computed tomography and magnetic resonance imaging that are HCCs or malignancies. METHODS: We searched the MEDLINE, Embase, Cochrane CENTRAL, and Scopus databases from 2014 through 2018 for studies that reported the percentage of observations in each LI-RADS v2014 and v2017 category that were confirmed as HCCs or other malignancies based on pathology, follow-up imaging analyses, or response to treatment (reference standard). Data were assessed on a per-observation basis. Random-effects models were used to determine the pooled percentages of HCC and overall malignancy for each LI-RADS category. Differences between categories were compared by analysis of variance of logit-transformed percentage of HCC and overall malignancy. Risk of bias and concerns about applicability were assessed with the Quality Assessment of Diagnostic Accuracy Studies 2 tool. RESULTS: Of 454 studies identified, 17 (all retrospective studies) were included in the final analysis, consisting of 2760 patients, 3556 observations, and 2482 HCCs. The pooled percentages of observations confirmed as HCC and overall malignancy, respectively, were 94% (95% confidence interval [CI] 92%-96%) and 97% (95% CI 95%-99%) for LR-5, 74% (95% CI 67%-80%) and 80% (95% CI 75%-85%) for LR-4, 38% (95% CI 31%-45%) and 40% (95% CI 31%-50%) for LR-3, 13% (95% CI 8%-22%) and 14% (95% CI 9%-21%) for LR-2, 79% (95% CI 63%-89%) and 92% (95% CI 77%-98%) for LR-TIV, and 36% (95% CI 26%-48%) and 93% (95% CI 87%-97%) for LR-M. No malignancies were found in the LR-1 group. The percentage of HCCs and overall malignancies confirmed differed significantly among LR groups 2-5 (P < .00001). Patient selection was the most frequent factor that affected bias risk, because of verification bias and case-control study design. CONCLUSIONS: In a systematic review, we found that increasing LI-RADS categories contained increasing percentages of HCCs and overall malignancy based on reference standard confirmation. Of observations categorized as LR-M, 93% were malignancies and 36% were confirmed as HCCs. The percentage of HCCs found in the LR-2 and LR-3 categories indicate the need for a more active management strategy than currently recommended. Prospective studies are needed to validate these findings. PROSPERO number CRD42018087441.

Chemical Composition, Spatial Homogeneity, and Growth of Indoor Surface Films.

Organic films on indoor surfaces are ubiquitous, but details about their composition and growth over timescales less than a month are not fully understood. To address these gaps in understanding, organic film samples in an apartment unit were collected over the course of 17 days using passive samplers and analyzed in a non-targeted manner using direct analysis in real-time mass spectrometry (DART-MS). Overall, the chemical composition observed across various locations within the apartment are very similar. Mass spectra also show clear evidence for the growth of semi-volatile compounds from natural sources and consumer products, such as carboxylic acids and plasticizers. Certain compounds show evidence for equilibration, mostly consistent with surface partitioning models based on octanol-air partition coefficients (Koa). Compounds which have higher molecular weight or larger Koa values tend to equilibrate later, leading to an overall shift in the composition of the film as a function of collection time. Growth rates of film thickness are at least 0.05 nm/day based on a limited number of individually calibrated ions.

Oxygenated Aromatic Compounds are Important Precursors of Secondary Organic Aerosol in Biomass-Burning Emissions.

Biomass burning is the largest combustion-related source of volatile organic compounds (VOCs) to the atmosphere. We describe the development of a state-of-the-science model to simulate the photochemical formation of secondary organic aerosol (SOA) from biomass-burning emissions observed in dry (RH <20%) environmental chamber experiments. The modeling is supported by (i) new oxidation chamber measurements, (ii) detailed concurrent measurements of SOA precursors in biomass-burning emissions, and (iii) development of SOA parameters for heterocyclic and oxygenated aromatic compounds based on historical chamber experiments. We find that oxygenated aromatic compounds, including phenols and methoxyphenols, account for slightly less than 60% of the SOA formed and help our model explain the variability in the organic aerosol mass (R2 = 0.68) and O/C (R2 = 0.69) enhancement ratios observed across 11 chamber experiments. Despite abundant emissions, heterocyclic compounds that included furans contribute to ∼20% of the total SOA. The use of pyrolysis-temperature-based or averaged emission profiles to represent SOA precursors, rather than those specific to each fire, provide similar results to within 20%. Our findings demonstrate the necessity of accounting for oxygenated aromatics from biomass-burning emissions and their SOA formation in chemical mechanisms.

Investigating Physical and Nutritional Changes During Prolonged Intermittent Fasting in Hemodialysis Patients: A Prospective Cohort Study.

OBJECTIVE: Studies investigating the health effects of prolonged intermittent fasting during Ramadan among Muslim patients on hemodialysis (HD) are limited and reported heterogeneous findings. This study aimed to evaluate the effects of intermittent fasting during Ramadan on nutritional and functional status of patients on maintenance HD. DESIGN AND METHODS: This was a 12-week, multicenter, prospective observational study. The study setting included three HD centers. Adult Muslim patients, who were undergoing HD session thrice weekly and planned to fast during Ramadan, were screened for eligibility and recruited. Nutritional and functional status assessments were carried out 2 weeks before (V0), at the fourth week of Ramadan (V1), and 4 weeks after Ramadan (V2). Nutritional status parameters included anthropometry (body mass index, interdialytic weight gain, waist circumference), body composition (mid-arm circumference, triceps skinfold, body fat percentage), blood biochemistry (albumin, renal profile, lipid profile, and inflammatory markers), blood pressure, dietary intake, and handgrip strength. Changes in nutritional and functional status parameters across study timepoints were analyzed using repeated-measures analysis of variance. RESULTS: A total of 87 patients completed the study, with 68 patients (78.2%) reporting fasting ≥20 days. Ramadan fasting led to significant reductions (all P < .05) in body mass index, interdialytic weight gain, waist circumference, mid-arm circumference, fat tissue mass, and body fat percentage, but these were not accompanied by any significant change in lean tissue mass (P > .05). Significant improvement was observed in serum phosphate levels, but serum albumin, urea, and creatinine were also reduced significantly during Ramadan (P < .05). There were no significant changes in lipid profile and inflammatory markers. Interestingly, energy and protein intakes remain unchanged during Ramadan. Handgrip strength improved significantly during Ramadan and further improved after Ramadan. CONCLUSION: Intermittent Ramadan fasting leads to temporary changes in nutritional status parameters and poses nondetrimental nutritional risk for patients on maintenance HD.

What do surviving children wish for from a dying parent? A qualitative exploration.

Legacy may play an important role in how children integrate the loss of a parent. Sixteen adults (19-40 years old, 69% women) who experienced the death of a parent from an illness before age 12 were interviewed, exploring legacies from their deceased parent. Transcribed interviews were iteratively analyzed by three independent coders. Extracted themes described their experiences and wish for remembrances and specific communication left for them, information about the parent's values and feelings about them, and personal possessions. This study provides novel data about legacies that bereaved children wish for in adulthood.

Phosphoserine acidic cluster motifs bind distinct basic regions on the µ subunits of clathrin adaptor protein complexes.

Protein trafficking in the endosomal system involves the recognition of specific signals within the cytoplasmic domains (CDs) of transmembrane proteins by clathrin adaptors. One such signal is the phosphoserine acidic cluster (PSAC), the prototype of which is in the endoprotease furin. How PSACs are recognized by clathrin adaptors has been controversial. We reported previously that HIV-1 Vpu, which modulates cellular immunoreceptors, contains a PSAC that binds to the µ subunits of clathrin adaptor protein (AP) complexes. Here, we show that the CD of furin binds the µ subunits of AP-1 and AP-2 in a phosphorylation-dependent manner. Moreover, we identify a potential PSAC in a cytoplasmic loop of the cellular transmembrane Serinc3, an inhibitor of the infectivity of retroviruses. The two serines within the PSAC of Serinc3 are phosphorylated by casein kinase II and mediate interaction with the µ subunits in vitro The sites of these serines vary among mammals in a manner suggesting host-pathogen conflict, yet the Serinc3 PSAC seems dispensable for anti-HIV activity and for counteraction by HIV-1 Nef. The CDs of Vpu and furin and the PSAC-containing loop of Serinc3 each bind the µ subunit of AP-2 (µ2) with similar affinities, but they appear to utilize different basic regions on µ2. The Serinc3 loop requires a region previously reported to bind the acidic plasma membrane lipid phosphatidylinositol 4,5-bisphosphate. These data suggest that the PSACs within different proteins recognize different basic regions on the µ surface, providing the potential to inhibit the activity of viral proteins without necessarily affecting cellular protein trafficking.

Update on Indications for Percutaneous Renal Mass Biopsy in the Era of Advanced CT and MRI.

OBJECTIVE. The objective of this article is to review the burgeoning role of percutaneous renal mass biopsy (RMB). CONCLUSION. Percutaneous RMB is safe, accurate, and indicated for an expanded list of clinical scenarios. The chief scenarios among them are to prevent treatment of benign masses and help select patients for active surveillance (AS). Imaging characterization of renal masses has improved; however, management decisions often depend on a histologic diagnosis and an assessment of biologic behavior of renal cancers, both of which are currently best achieved with RMB.

Use of Quantitative T2-Weighted and Apparent Diffusion Coefficient Texture Features of Bladder Cancer and Extravesical Fat for Local Tumor Staging After Transurethral Resection.

OBJECTIVE. The purpose of this study was to determine whether quantitative T2-weighted imaging and apparent diffusion coefficient (ADC) texture features of bladder cancer and extravesical fat are predictive of muscle invasive bladder cancer (category ≥ T2) and extravesical (category ≥ T3) disease after transurethral resection of a bladder tumor (TURBT). MATERIALS AND METHODS. In this retrospective study, 36 patients (27 men, nine women; mean age, 71 years) were identified who underwent post-TURBT MRI followed by cystectomy without intervening treatment from August 2011 through October 2016. Texture features of bladder cancer and extravesical fat adjacent to the tumor on T2-weighted and ADC images were extracted and compared between category ≤ T2 versus ≥ T3 and category T1 versus ≥ T2 tumors by means of Kruskal-Wallis or Mann-Whitney U test. Multivariate logistic regression analysis was performed, and ROC curves were calculated. RESULTS. Twenty-six of the 36 (72%) tumors were ≥ T2, and 53% (19/36) were ≥ T3. In multivariate analysis, bladder cancer entropy on T2-weighted images (p = 0.006; odds ratio [OR], 4.56; 95% CI, 1.49-20.41; AUC, 0.85) and ADC maps (p = 0.019; OR, 2.24; 95% CI, 1.13-5.31; AUC, 0.80) and extravesical fat entropy on T2-weighted images (p = 0.005; OR, 17.50; 95% CI, 3.01-200.80; AUC, 0.84) and ADC maps (p = 0.002; OR, 6.54; 95% CI, 1.90-32.40; AUC, 0.82) remained greater for ≥ T3 than for ≤ T2 tumors. In multivariate analysis, bladder cancer entropy on ADC maps (p = 0.027; OR, 2.11; 95% CI, 1.08-5.03; AUC, 0.76) and extravesical fat entropy on T2-weighted images (p = 0.010; OR, 5.33; 95% CI, 1.25-3.79; AUC, 0.78) and ADC maps (p = 0.029; OR, 3.80; 95% CI, 1.25-16.97; AUC, 0.74) remained greater for category ≥ T2 compared with category T1 tumors. CONCLUSION. Greater entropy of primary bladder cancers and extravesicular fat was observed in category ≥ T3 than in category ≤ T2 and in category ≥ T2 than in category T1 tumors. MRI texture analysis can help with local bladder cancer staging in patients who have undergone TURBT and may serve as a biomarker for higher local category bladder cancers.

Rapid decline of renal function in patients with type 2 diabetes with heavy proteinuria: a report of three cases.

BACKGROUND: Although there is a large volume of literature regarding the definition and epidemiology of. Type 2 diabetes nephropathy (T2DN). There has been a paucity of data focused on the rate of transition of T2 DN. Based on our personal observation a certain percentage of our incident end stage renal disease (ESRD) patients from T2DN experienced a rapid decline of renal function. Their rapid decline nature of glomerular filtration rate (GFR) of 46 to 60 mL/min per 1.73m2 per year have far exceeded the KDIGO definitions of acute kidney injury (abrupt decrease in kidney function occurring over 7 days or less), acute kidney disease (acute or subacute damage and/or loss of kidney function for a duration of between 7 and 90 days after exposure to an acute kidney injury initiating event (Chawla et al Nat Rev Nephrol 241-57 2017) or even rapid decliner (eGFR declines > 5 mL/min per 1.73m2 per year) (Chawla et al Nat Rev Nephrol 241-57 2017; Andrassy Kidney Int 622-623 2013). CASE PRESENTATION: We describe here three cases of type 2 diabetic patients that have rapid renal deterioration with rate of decline 46 - 60 mL/min per 1.73m2 per year. All the patients are heavily nephrotic. All of the renal biopsies done showed the classical diabetic changes, hypertensive changes, diffuse tubulointerstitial damage, and interstitial nephritis. All of the patients admitted to taking various form of traditional medications in hope of curing their renal disease. CONCLUSION: We wish to highlight that type 2 diabetics with massive nephrotic range proteinuria have enhanced risk of rapid renal function deterioration. The patients should be educated about the risks of rapid renal function deterioration when there is presence of heavy proteinuria. High grade proteinuria is likely to inflict the diffuse tubulointerstitial inflammation. The interstitial nephritis could be further worsened by traditional supplements consumption. Timely health education and advice must be undertaken to retard this unwanted rapid renal disease progression.