Clinical Application of Liquid Biopsy in Pancreatic Cancer: A Narrative Review.

Pancreatic ductal adenocarcinoma contributes significantly to global cancer-related deaths, featuring only a 10% survival rate over five years. The quest for novel tumor markers is critical to facilitate early diagnosis and tailor treatment strategies for this disease, which is key to improving patient outcomes. In pancreatic ductal adenocarcinoma, these markers have been demonstrated to play a crucial role in early identification, continuous monitoring, and prediction of its prognosis and have led to better patient outcomes. Nowadays, biopsy specimens serve to ascertain diagnosis and determine tumor type. However, liquid biopsies present distinct advantages over conventional biopsy techniques. They offer a noninvasive, easily administered procedure, delivering insights into the tumor's status and facilitating real-time monitoring. Liquid biopsies encompass a variety of elements, such as circulating tumor cells, circulating tumor DNA, extracellular vesicles, microRNAs, circulating RNA, tumor platelets, and tumor endothelial cells. This review aims to provide an overview of the clinical applications of liquid biopsy as a technique in the management of pancreatic cancer.

An HLA-I signature favouring KIR-educated Natural Killer cells mediates immune control of HIV in children and contrasts with the HLA-B-restricted CD8+ T-cell-mediated immune control in adults.

Natural Killer (NK) cells contribute to HIV control in adults, but HLA-B-mediated T-cell activity has a more substantial impact on disease outcome. However, the HLA-B molecules influencing immune control in adults have less impact on paediatric infection. To investigate the contribution NK cells make to immune control, we studied >300 children living with HIV followed over two decades in South Africa. In children, HLA-B alleles associated with adult protection or disease-susceptibility did not have significant effects, whereas Bw4 (p = 0.003) and low HLA-A expression (p = 0.002) alleles were strongly associated with immunological and viral control. In a comparator adult cohort, Bw4 and HLA-A expression contributions to HIV disease outcome were dwarfed by those of protective and disease-susceptible HLA-B molecules. We next investigated the immunophenotype and effector functions of NK cells in a subset of these children using flow cytometry. Slow progression and better plasma viraemic control were also associated with high frequencies of less terminally differentiated NKG2A+NKp46+CD56dim NK cells strongly responsive to cytokine stimulation and linked with the immunogenetic signature identified. Future studies are indicated to determine whether this signature associated with immune control in early life directly facilitates functional cure in children.

Acquisition of Desiccation Tolerance Unveiled: Polar Lipid Profiles of Streptophyte Algae Offer Insights.

Terrestrialization by photosynthetic eukaryotes took place in the two branches of green microalgae: Chlorophyta and Charophyta. Within the latter, the paraphyletic streptophytic algae divide into two clades. These are named Klebsormidiophyceae-Chlorokybophyceae-Mesostigmatophyceae (KCM), which is the oldest, and Zygnematophyceae-Coleochaetophyceae-Charophyceae (ZCC), which contains the closest relatives of vascular plants. Terrestrialization required the emergence of adaptations in response to new challenges, such as irradiance, temperature oscillations and water deprivation. In this study, we evaluated lipid composition in species representative of distinct phylogenetic clusters within Charophyta and Chlorophyta. We aim to study whether the inherent thylakoid lipid composition, as well as its adaptability in response to desiccation, were fundamental factors for the evolutionary history of terrestrial plants. The results showed that the lipid composition was similar to that found in flowering land plants, differing only in betaine lipids. Likewise, the largest constitutive pool of oligogalactolipids (OGL) was found only in the fully desiccation-tolerant species Klebsormidium nitens. After desiccation, the content of polar lipids decreased in all species. Conversely, the content of OGL increased, particularly trigalactosyldiacylglycerol and tetragalactosyldiacylglycerol in the ZCC clade. The analysis of the molecular species composition of the newly formed OGL may suggest a different biosynthetic route for the KCM and ZCC clades. We speculate that the appearance of a new OGL synthesis pathway, which eventually arose during the streptophyte evolutionary process, endowed algae with a much more dynamic regulation of thylakoid composition in response to stress, which ultimately contributed to the colonization of terrestrial habitats.

Synthesis of a novel magnetic nanomaterial for the development of a multielemental speciation method of lead, mercury, and vanadium via HPLC-ICP MS.

A new magnetic functionalized material based on graphene oxide magnetic nanoparticles named by us, M@GO-TS, was designed and characterized in order to develop a magnetic solid-phase extraction method (MSPE) to enrich inorganic and organic species of lead, mercury, and vanadium. A flow injection (FI) system was used to preconcentrate the metallic and organometallic species simultaneously, while the ultra-trace separation and determination of the selected species were achieved by high-performance liquid chromatography coupled to inductively coupled plasma mass spectrometry (HPLC-ICP MS). Therefore, preconcentration and separation/determination processes were automated and conducted separately. To the best of our knowledge, this is the first method combining an online MSPE and HPLC-ICP MS for multielemental speciation. Under the optimized conditions, the enrichment factor obtained for PbII, trimethyllead (TML), HgII, methylmercury (MetHg), and VV was 27. The calculated LOD for all studied species were as follows: 5 ng L-1, 20 ng L-1, 2 ng L-1, 10 ng L-1, and 0.4 ng L-1, respectively. The RSD values calculated with a solution containing 0.5 µg L-1 of all species were between 2.5 and 4.5%. The developed method was validated by analyzing Certified Reference Materials TMDA 64.3 for total concentration and also by recovery analysis of the species in human urine from volunteers and a seawater sample collected in Málaga. The t statistical test showed no significant differences between the certified and found values for TMDA 64.3. All the recoveries obtained from spiked human urine and seawater samples were close to 100%. All samples were analyzed using external calibration. The developed method is sensitive and promising for routine monitoring of the selected species in environmental waters and biological samples.

Altered T-cell subset distribution in the viral reservoir in HIV-1-infected individuals with extremely low proviral DNA (LoViReTs).

BACKGROUND: HIV cure strategies aim to eliminate viral reservoirs that persist despite successful antiretroviral therapy (ART). We have previously described that 9% of HIV-infected individuals who receive ART harbor low levels of provirus (LoViReTs). METHODS: We selected 22 LoViReTs matched with 22 controls ART suppressed for more than 3 years with fewer than 100 and more than 100 HIV-DNA copies/106  CD4+ T cells, respectively. We measured HIV reservoirs in blood and host genetic factors. Fourteen LoViReTs underwent leukapheresis to analyze replication-competent virus, and HIV-DNA in CD4+ T-cell subpopulations. Additionally, we measured HIV-DNA in rectum and/or lymph node biopsies from nine of them. RESULTS: We found that LoViReTs harbored not only lower levels of total HIV-DNA, but also significantly lower intact HIV-DNA, cell-associated HIV-RNA, and ultrasensitive viral load than controls. The proportion of intact versus total proviruses was similar in both groups. We found no differences in the percentage of host factors. In peripheral blood, 71% of LoViReTs had undetectable replication-competent virus. Minimum levels of total HIV-DNA were found in rectal and lymph node biopsies compared with HIV-infected individuals receiving ART. The main contributors to the reservoir were short-lived transitional memory and effector memory T cells (47% and 29%, respectively), indicating an altered distribution of the HIV reservoir in the peripheral T-cell subpopulations of LoViReTs. CONCLUSION: In conclusion, LoViReTs are characterized by low levels of viral reservoir in peripheral blood and secondary lymphoid tissues, which might be explained by an altered distribution of the proviral HIV-DNA towards more short-lived memory T cells. LoViReTs can be considered exceptional candidates for future interventions aimed at curing HIV.

Efficacy of diet on fatigue, quality of life and disability status in multiple sclerosis patients: rapid review and meta-analysis of randomized controlled trials.

BACKGROUND: Multiple sclerosis is an inflammatory and neurodegenerative disease. People with multiple sclerosis (pwMS) experience chronic fatigue which is difficult to deal with therapeutically and greatly affects health-related quality of life (QOL). PwMS are aware of the lack of generalized dietary advice related to their disease, leading to self-experimentation with diet. It is necessary to provide objective information about dietary interventions for pwMS. We aim to provide an objective synthesis of the evidence for efficacy and safety of specific diets in pwMS through a rapid review and meta-analyses of randomized controlled trials (RCTs), examining symptomatic fatigue (MFIS), QOL, Expanded-Disability-Status-Scale (EDSS), and severe adverse events. METHODS: We have carried out a rapid review (MEDLINE and EMBASE) up to December 2021, with PRISMA methodology, and meta-analyses, of (RCTs). All statistical analyses were performed using the comprehensive meta-analysis (CMA) -RStudio 4.1.3. The analysis used weighted mean differences (WMD) and a 95% confidence interval (CI) using a random-effects model to compare the effects of the dietary intervention with the control. RESULTS: Eight studies met the inclusion criteria. Of these eight studies, five analyzed EDSS, three MFIS, and three QOL. A total of 515 patients were analyzed. These meta-analyses cumulative evidence support that dietary intervention is associated with a trend of reduction in fatigue (308 patients studied) -the difference between means (SMD) of the control group and intervention group was -2,033, 95%-IC (-3,195, -0,152), a p-value of 0.0341)-, an increase in QOL (77 patients studied), no significant effect on EDSS (337 patients studied), and no severe adverse events. CONCLUSIONS: It is difficult to reach a high level of evidence in dietary studies. Our findings show that dietary intervention is associated with a trend of reduction in fatigue in MS. Taking into account the potential of dietary interventions and the benefit/risk ratio in their favor, neurologists must be aware of the great importance of making interventions on diet in MS if necessary. There are dietary interventions with some evidence of benefit for patients with MS, which could be chosen based on adherence, patient preferences, and individual outcomes. Large prospective clinical trials are needed to shed further light on this topic.

Quality of life against seasonal vs perennial allergens: ESPRINT-15 modified in the pediatric population.

INTRODUCTION: Allergic rhinitis (AR) is a clinical syndrome characterized by IgE-mediated inflammation of the nasal mucosa. The present study investigates the quality of life (QoL) with AR among adults, using widely validated questionnaires, unlike in pediatric patients. MATERIALS AND METHODS: A cross-sectional descriptive observational study was conducted, analyzing the QoL of 102 children with AR aged between 10-15 years, belonging to two health centers (HC) in Zaragoza and two HC in Coruña. The comparison of means between the two groups is carried out using the Student's test or the Mann-Whitney test, considering a value of p˂0.05 to be significant. RESULTS: Around 102 children were studied, with a majority (59.8%) being male and a mean age of 12 years. Around 76.5% have a family history of atopy. It was found that AR is more prevalent in Zaragoza (p ˂0.005), and asthmais highly prevalent in Coruña (p ˂0.001). The most important sensitizations are pollen in Zaragoza (p ˂0.05) and dust mites in A Coruña (p ˂0.001). More treatment needs and associated comorbidities (p˂0.05) were observed in A Coruña. The results of the ESPRINT-15 show that 63% of the patients have a good QoL, 27% fair, and 8.8%, poor. Those sensitized to mites have a worse score (p = 0.02). It was found that 52% of children experienced improvement during home confinement, with no notable differences between the two populations. The use of the mask favored QoL in patients from Zaragoza (p ˂0.001). CONCLUSION: It was concluded that AR influences the QoL in pediatric patients. Greater QoL involvement, need for treatment, and comorbidities are observed in patients sensitized to dust mites compared to those sensitized to pollens. It was also observed that masks improved the symptoms, stopping patients being sensitized to pollens.

Manipulation of Amino Acid Levels with Artificial Diets Induces a Marked Anticancer Activity in Mice with Renal Cell Carcinoma.

Targeted therapies with antiangiogenic drugs (e.g., sunitinib) and immune checkpoint inhibitors (e.g., anti-PD-1 antibodies) are the standard of care for patients with metastatic renal cell carcinoma. Although these treatments improve patient survival, they are rarely curative. We previously hypothesized that advanced cancers might be treated without drugs by using artificial diets in which the levels of specific amino acids (AAs) are manipulated. In this work, after showing that AA manipulation induces selective anticancer activity in renal cell carcinoma cells in vitro, we screened 18 artificial diets for anticancer activity in a challenging animal model of renal cell carcinoma. The model was established by injecting murine renal cell carcinoma (Renca) cells into the peritoneum of immunocompetent BALB/cAnNRj mice. Mice survival was markedly improved when their normal diet was replaced with our artificial diets. Mice fed a diet lacking six AAs (diet T2) lived longer than mice treated with sunitinib or anti-PD-1 immunotherapy; several animals lived very long or were cured. Controlling the levels of several AAs (e.g., cysteine, methionine, and leucine) and lipids was important for the anticancer activity of the diets. Additional studies are needed to further evaluate the therapeutic potential and mechanism of action of this simple and inexpensive anticancer strategy.

Reducing extreme weather impacts in greenhouses: the effect of a new passive climate control system on nutritional quality of pepper fruits.

BACKGROUND: Environmental conditions affect the quality of the fruits and their organoleptic properties. In low-tech greenhouses, these environmental conditions are frequently not optimal for crops. Therefore, the present study demonstrates the effects of the use of an integrated passive heating and cooling system in a greenhouse located in the Mediterranean area on the quality of pepper fruits. RESULTS: The results indicate that the passive system utilized (i) improved many parameters, such as average weight of fruits, °Brix, glucose and fructose content, and P and K content; (ii) increased the values of b* and hab *; and (iii) reduced total phenolic compounds, total amino acids content, and Fe and Zn content. However, the degree of the effect of the climatic factors on these parameters was also affected by harvest time. CONCLUSION: This novel study highlights the possibility of improving the nutritional quality of pepper fruits by modifying the environmental conditions through the use of passive heating and cooling systems at the same time as reducing the carbon footprint. © 2021 Society of Chemical Industry.

Early Initiation of Antiretroviral Therapy Following In Utero HIV Infection Is Associated With Low Viral Reservoirs but Other Factors Determine Viral Rebound.

BACKGROUND: Early HIV diagnosis allows combination antiretroviral therapy (cART) initiation in the first days of life following in utero (IU) infection. The impact of early cART initiation on infant viral reservoir size in the setting of high-frequency cART nonadherence is unknown. METHODS: Peripheral blood total HIV DNA from 164 early treated (day 0-21 of life) IU HIV-infected South African infants was measured using droplet digital PCR at birth and following suppressive cART. We evaluated the impact of cART initiation timing on HIV reservoir size and decay, and on the risk of subsequent plasma viremia in cART-suppressed infants. RESULTS: Baseline HIV DNA (median 2.8 log10 copies/million peripheral blood mononuclear cells, range 0.7-4.8) did not correlate with age at cART initiation (0-21 days) but instead with maternal antenatal cART use. In 98 infants with plasma viral suppression on cART, HIV DNA half-life was 28 days. However, the probability of maintenance of plasma aviremia was low (0.46 at 12 months) and not influenced by HIV DNA load. Unexpectedly, longer time to viral suppression was associated with protection against subsequent viral rebound. CONCLUSIONS: With effective prophylaxis against mother-to-child transmission, cART initiation timing in the first 3 weeks of life is not critical to reservoir size.

Time Trends in Intracerebral Hemorrhage Associated with Oral Anticoagulation and Its Risks Factors in Spain from 2008 to 2015.

BACKGROUND: Intracerebral hemorrhage (ICH) is 7- to 10-fold higher in anticoagulated patients. Given the more extended use of oral anticoagulants, an increase in the prevalence of ICH associated with oral anticoagulation (ICH-OAC) could be expected. However, there is no previous study that assesses the time trends of ICH-OAC in Spain. METHODS: We conducted a combined data analysis after creating a joint database of the 3 most important epidemiological studies on ICH-OAC of our country: the EPICES study (2008-2009), the TAC Registry (TR) study (2012-2013) and the TAC Registry 2 (TR2) study (2015). We finally included 65, 235, and 366 patients from the EPICES, TR, and TR2 studies, respectively. RESULTS: We have observed a 3.73-fold increase in the crude annual incidence of ICH-OAC throughout the period of study, with proportion of ICH-OAC out of total ICH increasing from 8.4% in 2008 to 18.2% in 2015. Age, dyslipidemia, and prior antiplatelet treatment increased during the study, but we found no statistically significant differences in other risk factors for ICH-OAC. CONCLUSIONS: The incidence of ICH-OAC is increasing in our country. It might at least be partly explained by aging of the population, with mean age at presentation being higher in the last years.

Crystal structure and mechanism of human carboxypeptidase O: Insights into its specific activity for acidic residues.

Human metallocarboxypeptidase O (hCPO) is a recently discovered digestive enzyme localized to the apical membrane of intestinal epithelial cells. Unlike pancreatic metallocarboxypeptidases, hCPO is glycosylated and produced as an active enzyme with distinctive substrate specificity toward C-terminal (C-t) acidic residues. Here we present the crystal structure of hCPO at 1.85-Å resolution, both alone and in complex with a carboxypeptidase inhibitor (NvCI) from the marine snail Nerita versicolor The structure provides detailed information regarding determinants of enzyme specificity, in particular Arg275, placed at the bottom of the substrate-binding pocket. This residue, located at "canonical" position 255, where it is Ile in human pancreatic carboxypeptidases A1 (hCPA1) and A2 (hCPA2) and Asp in B (hCPB), plays a dominant role in determining the preference of hCPO for acidic C-t residues. Site-directed mutagenesis to Asp and Ala changes the specificity to C-t basic and hydrophobic residues, respectively. The single-site mutants thus faithfully mimic the enzymatic properties of CPB and CPA, respectively. hCPO also shows a preference for Glu over Asp, probably as a consequence of a tighter fitting of the Glu side chain in its S1' substrate-binding pocket. This unique preference of hCPO, together with hCPA1, hCPA2, and hCPB, completes the array of C-t cleavages enabling the digestion of the dietary proteins within the intestine. Finally, in addition to activity toward small synthetic substrates and peptides, hCPO can also trim C-t extensions of proteins, such as epidermal growth factor, suggesting a role in the maturation and degradation of growth factors and bioactive peptides.

Genetic parameters for canalization analysis of morphological traits in the Pura Raza Español horse.

Measurements from 13 different morphological traits of importance in the Pura Raza Español (PRE) horse were used to estimate genetic and environmental parameters following a heteroscedastic model in which data were assigned to stallions. Data sets used ranged from 20,610 (height at withers) to 48,486 measurements (length of shoulder), and the number of animals analysed in the pedigrees varied from 17,662 (height at withers) to 23,962 (dorsal-sternal diameter). Results of heritabilities of the traits varied from 0.09 (width of chest and upper neck line) to 0.30 (muscular development). Further, genetic correlations between traits and their environmental variability were estimated, obtaining values from -0.56 (muscular development) to 0.69 (height at withers). Also, predicted breeding values for the mean and for the environmental variability were obtained for all horses in the pedigrees, providing individual information about not only the expected phenotypic value of their offspring but also the expected heterogeneity among them. Results proved the possibility of improving morphological traits and reducing the heterogeneity of offspring at a time by the selection of animals and levels of systematic effects.

Periodontal phenotype: A review of historical and current classifications evaluating different methods and characteristics.

OBJECTIVE: To review the historical and current periodontal phenotype classifications evaluating methods and characteristics. Moreover, to identify and classify the methods based on periodontal phenotype components. OVERVIEW: Several gingival morphology studies have been frequently associated with different terms used causing confusion among the readers. In 2017, the World Workshop on the Classification of Periodontal and Peri-Implant Diseases and Conditions recommended to adopt the term "periodontal phenotype". This term comprises two terms, gingival phenotype (gingival thickness and keratinized tissue width) and bone morphotype (buccal bone plate thickness). Furthermore, gingival morphology has been categorized on "thin-scalloped", "thick-scalloped" and "thick-flat" considering the periodontal biotype. However, by definition, the term phenotype is preferred over biotype. Periodontal phenotype can be evaluated through clinical or radiographic assessments and may be divided into invasive/non-invasive (for gingival thickness), static/functional (for keratinized tissue width), and bi/tridimensional (for buccal bone plate thickness) methods. CONCLUSIONS: "Thin-scalloped," "thick-scalloped," and "thick-flat" periodontal biotypes were identified. These three periodontal biotypes have been considered in the World Workshop but the term periodontal phenotype is recommended. Periodontal phenotype is the combination of the gingival phenotype and the bone morphotype. There are specific methods for periodontal phenotype evaluation. CLINICAL SIGNIFICANCE: The term periodontal phenotype is currently recommended for future investigations about gingival phenotype and bone morphotype. "Thin-scalloped," "thick-scalloped," and "thick-flat" periodontal phenotypes can be evaluated through specific methods for gingival thickness, keratinized tissue width, and buccal bone plate thickness evaluation.

Production of a NiO/Al primary battery employing powder-based electrodes.

This paper describes the use of aluminum and zinc as anodic materials for a battery employing nickel (II) oxide (NiO) as cathode. Comparison of both materials resulted in the development of a compact, cost effective, and easy to use primary NiO/Al battery employing an alkaline electrolyte. The system features electrodes composed of powder forms of the active materials on modified paper substrates that are contained in a simple multilayer design utilizing thin laminated plastic materials to provide structure and flexibility to the battery as well as a paper separator. Various concentrations of potassium hydroxide (KOH) electrolyte were examined and maximum performance was observed at 6 M KOH. A maximum current density and power density of 1.94 mA/cm2 and 1 mW/cm2 , respectively was achieved. This user-friendly device was able to produce a maximum capacity of 2.33 mAh/g when 2 mA/g was applied. This work demonstrates the viability of a paper-based battery featuring powder electrodes as a possible power source for microelectronic devices.

A Multidisciplinary Consultation-Liaison Team Approach to Reduce Enhanced Observer Usage.

BACKGROUND: There are few evidence-informed guidelines and findings to show that the use of sitters improves patient safety; overall, it is a costly intervention to address patients with disruptive behaviors. OBJECTIVE: The purpose of this article is to demonstrate that the creation of a multidisciplinary consultation-liaison (C-L) team, integrated with a psychiatric C-L team, together can decrease sitter use and improve outcomes using nonpharmacologic interventions. METHODS: This retrospective study describes the planning, implementation, and data collection using in creating an multidisciplinary C-L team to collaborate with the psychiatric C-L team and outcomes to support the approach. The multidisciplinary C-L team was composed of advanced practice registered nurses and creative art therapists. The teams worked closely with the medical units to develop and monitor criteria for sitter use. The key outcomes of the intervention improved patient safety and reduced overall cost. RESULTS: In the first year of implementation of a multidisciplinary C-L approach, sitter use decreased by 72%. Nonpharmacologic interventions improved patient outcomes by providing education to medical staff that enhanced the assessment and implementation of enhanced observer use across all the medical units. Subsequent data also reflect a sustained reduction in cost over the next 2-year period, saving the institution nearly $70K a month. CONCLUSION: An multidisciplinary C-L and psychiatric C-L team collaborated on the need for psychiatric medications, or nonpharmacologic interventions to address behaviors and decrease the need for an enhanced observer. The teams worked together to make policy revisions and algorithms and provide education, the result of which was significant financial savings and improved patient safety.

Genetic inbreeding depression load for morphological traits and defects in the Pura Raza Española horse.

BACKGROUND: Inbreeding is caused by mating between related individuals and is associated with reduced fitness and performance (inbreeding depression). Several studies have detected heterogeneity in inbreeding depression among founder individuals. Recently, a procedure was developed to predict hidden inbreeding depression load that is associated with founders using the Mendelian sampling of non-founders. The objectives of this study were to: (1) analyse the population structure and general inbreeding, and (2) test this recent approach for predicting hidden inbreeding depression load for four morphological traits and two morphology defects in the Pura Raza Española (PRE) horse breed. RESULTS: The regression coefficients that were calculated between trait performances and inbreeding coefficients demonstrated the existence of inbreeding depression. In total, 58,772,533 partial inbreeding coefficients (Fij) were estimated for the whole PRE population (328,706 horses). We selected the descendants of horses with a Fij ≥ 6.25% that contributed to at least four offspring and for which morphological traits were measured for the subsequent analysis of inbreeding depression load (639 horses). A pedigree was generated with the last five generations (5026 animals) used as the reference population (average inbreeding coefficient of 8.39% and average relatedness coefficient of 10.76%). Heritability estimates ranged from 0.08 (cresty neck) to 0.80 (height at withers), whereas inbreeding depression load ratios ranged from 0.01 (knock knee) to 0.40 (length of shoulder), for an inbreeding coefficient of 10%. Most of the correlations between additive and inbreeding depression load genetic values and correlations between inbreeding depression load genetic values for the different traits were positive or near 0. CONCLUSIONS: Although the average inbreeding depression loads presented negative values, a certain percentage of the animals showed neutral or even positive values. Thus, high levels of inbreeding do not always lead to a decrease in mean phenotypic value or an increase in morphological defects. Hence, individual inbreeding depression loads could be used as a tool to select the most appropriate breeding animals. The possibility of selecting horses that have a high genetic value and are more resistant to the deleterious effects of inbreeding should help improve selection outcomes.

Systemic lupus Erythematosus activity and Hydroxychloroquine use before and after end-stage renal disease.

BACKGROUND: SLE manifestations after ESRD may be underdiagnosed and undertreated, contributing to increased morbidity and mortality. Whether specific symptoms persist after ESRD or a shift towards new manifestations occurs has not been extensively studied, especially in the non-Caucasian patients in the United States. In addition, hydroxychloroquine (HCQ) prescribing patterns post-ESRD have not been described. The objective of this study was to assess lupus activity and HCQ prescribing before and after ESRD development. Knowledge gained from this study may aid in the identification of SLE manifestations and improve medication management post-ESRD. METHODS: We performed a retrospective cohort study of SLE patients with incident ESRD between 2010 and 2017. SLE-related symptoms, serologic markers of disease activity, and medication use were collected from medical records before and after ESRD development. RESULTS: Fifty-nine patients were included in the study. Twenty-five (43%) patients had at least one clinical (non-renal) SLE manifestation documented within 12 months before ESRD. Of them, 11/25 (44%) continued to experience lupus symptoms post-ESRD; 9 patients without clinical or serological activity pre-ESRD developed new symptoms of active SLE. At the last documented visit post-ESRD, 42/59 (71%) patients had one or more clinical or serological markers of lupus activity; only 17/59 (29%) patients achieved clinical and serological remission. Thirty-three of 59 (56%) patients had an active HCQ prescription at the time of ESRD. Twenty-six of the 42 (62%) patients with active SLE manifestations post-ESRD were on HCQ. Patients who continued HCQ post-ESRD were more likely to be followed by a rheumatologist (26 [87%] vs 17 [61%], p = 0.024), had a higher frequency of documented arthritis (10 [32%] vs 1 [4%], p = 0.005), CNS manifestations (6 [20%] vs 1 [4%], p = 0.055), and concurrent immunosuppressive medication use (22 [71%] vs 12 [43%], p = 0.029). CONCLUSIONS: Lupus activity may persist after the development of ESRD. New onset arthritis, lupus-related rash, CNS manifestations, low complement and elevated anti-dsDNA may develop. HCQ may be underutilized in patients with evidence of active disease pre- and post ESRD. Careful clinical and serological monitoring for signs of active disease and frequent rheumatology follow up is advised in SLE patients both, pre and post-ESRD.

Substrate Specificity and Structural Modeling of Human Carboxypeptidase Z: A Unique Protease with a Frizzled-Like Domain.

Metallocarboxypeptidase Z (CPZ) is a secreted enzyme that is distinguished from all other members of the M14 metallocarboxypeptidase family by the presence of an N-terminal cysteine-rich Frizzled-like (Fz) domain that binds Wnt proteins. Here, we present a comprehensive analysis of the enzymatic properties and substrate specificity of human CPZ. To investigate the enzymatic properties, we employed dansylated peptide substrates. For substrate specificity profiling, we generated two different large peptide libraries and employed isotopic labeling and quantitative mass spectrometry to study the substrate preference of this enzyme. Our findings revealed that CPZ has a strict requirement for substrates with C-terminal Arg or Lys at the P1' position. For the P1 position, CPZ was found to display specificity towards substrates with basic, small hydrophobic, or polar uncharged side chains. Deletion of the Fz domain did not affect CPZ activity as a carboxypeptidase. Finally, we modeled the structure of the Fz and catalytic domains of CPZ. Taken together, these studies provide the molecular elucidation of substrate recognition and specificity of the CPZ catalytic domain, as well as important insights into how the Fz domain binds Wnt proteins to modulate their functions.

Techniques for retrievability and for registering screw access holes in cement-retained implant-supported prostheses: A scoping review of the literature.

STATEMENT OF PROBLEM: After implant rehabilitation, clinicians may need to remove a restoration because of technical and biological complications. For cement-retained implant-supported prostheses (ISPs), the retrievability process may damage the components of the prosthesis, the intaglio surface of the implant, or the abutment screw. To avoid that, the screw access hole (SAH) of the dental implant abutment (DIA) should be registered. Although several clinical reports and dental techniques have been proposed, a review of existing techniques is lacking. PURPOSE: The purpose of this scoping review was to evaluate the different techniques described for retrievability and for registering the SAH of cement-retained ISPs. MATERIAL AND METHODS: An electronic search of English language dental literature in the PubMed, Scopus, Google Scholar, and SciELO databases was conducted from 1980 to December 2017 with appropriate keywords and phrases. A hand search of relevant dental journals was also completed, and exclusion criteria were applied after full-text evaluation. RESULTS: The electronic and hand search revealed 325 articles. However, 252 publications were discarded after duplicates were removed. After reading the title and abstracts, 15 studies were excluded, and the full text of 64 publications was screened for inclusion and exclusion criteria. Forty studies were selected and included for final evaluation. The evaluation revealed 6 techniques for retrievability and 9 techniques for registering the position of the SAH, divided into 2-dimensional (2D) and 3-dimensional (3D) techniques. CONCLUSIONS: Cement-retained ISPs can be effectively retrieved by using interim cements and possibly by using a combined cement- and screw-retained design. Vacuum guides with guiding sleeves and computer-aided design and computer-aided manufacturing (CAD-CAM) guide templates are possible effective 3D techniques for registering the screw access channel (SAC) location and angulation.