Anatomical and Three-Dimensional Study of the Female Feline Abdominal and Pelvic Vascular System Using Dissections, Computed Tomography Angiography and Magnetic Resonance Angiography.

This study describes the anatomical characteristics of the abdominal and pelvic vascular system of two healthy mature female cats via three-dimensional contrast enhanced computed tomography angiography, non-contrast enhanced magnetic resonance angiography and three-dimensional printing. Volume-rendering computed tomography angiography images were acquired from the ventral aspect using RadiAnt, Amira and OsiriX MD Dicom three-dimensional formats, and three-dimensional printing was obtained and compared with the corresponding computed tomography angiography images. Non-contrast enhanced magnetic resonance angiography was made using the time-of-flight imaging in ventral, oblique and lateral views. In addition, three cadavers with colored latex injection were dissected to facilitate the identification of the vascular structures. Three-dimensional computed tomography angiography showed the main vascular structures, whereas with the time-of-flight blood appeared with a high signal intensity compared with associated abdominal and pelvic tissues. Three-dimensional computed tomography angiography images and time-of-flight sequences provided adequate anatomical details of the main arteries and veins that could be used for future feline anatomical and clinical vascular studies of the abdomen and pelvis.

Creation of Three-Dimensional Anatomical Vascular and Biliary Models for the Study of the Feline Liver (Felis silvestris catus L.): A Comparative CT, Volume Rendering (Vr), Cast and 3D Printing Study.

In this study, six adult feline cadavers were examined using CTA, 3D printing, and casts injected with epoxy. The aorta, the portal vein, and the gallbladder of 3 feline cadavers were separately injected with a 50% mixture of colored vulcanized latex and hydrated barium sulfate as contrast medium to analyze by CT the arterial, venous and biliary systems. The other three cadavers were injected with a mixture of epoxy resin in the aorta, gallbladder and hepatic veins, separately. After the corrosion and washing process, hepatic vascular and biliary casts were obtained. The images obtained by CT showed the vascular and biliary system using a soft tissue window. For the identification of vascular and biliary structures, the 3D prints together with the 3D reconstructions were analyzed, and the results were compared with the casts obtained with epoxy resin. Each of the arterial, venous and biliary branches associated with each of the liver lobes were identified with the help of the printings. In conclusion, the creation of 3D prototypes of nonpathological feline hepatic parenchyma can be used in the veterinary clinic as a basis for the detection of pathological problems in addition to obtaining future pathological hepatic 3D models.

Functional vitamin B12 deficiency: Improving methylmalonic acid reference intervals in urine.

BACKGROUND-AIM: Most laboratory requests focus on the detection of possible vitamin B12 deficiency. In this context, methylmalonic acid (MMA) is reported as the best biomarker. The aim of our study was to establish the biological reference interval for MMA in urine, and assess the influence of age, sex, and vitamin B12 status on MMA concentrations. METHODS: This is a prospective observational study considering individuals with normal results for blood count and liver and kidney function. Individuals who presented supplementation, any pathology or treatment that could cause cobalamin metabolism disorders, and pregnant women were excluded. Likewise, individuals whose vitamin B12 result presented antibody-mediated interference were excluded. Individuals were grouped by age-group and sex. Reference intervals were determined by non-parametric calculation (percentiles 1-99). RESULTS: It was established a single reference interval [0.52 (CI90%: 0.50-0.54) - 5.75 (CI90%: 5.57-6.17) mmolMMA/mol creatinine], with 100 % of individuals with MMA above the upper limit of reference presenting a total vitamin B12 concentration ≤ 238 pmol/L. CONCLUSION: The establishment of optimal reference intervals for methylmalonic acid excretion in urine is crucial in individuals with a suspicion of functional vitamin B12 deficiency. However, the possibility of establishing a cut-off value for total vitamin B12 suggesting subclinical deficiency remains a challenge for this magnitude.

Challenges in the diagnosis of hypervitaminemia B12. Interference by immunocomplexes.

BACKGROUND-AIM: High vitamin B12 concentrations are considered a common finding in clinical practice. Thanks to immunoassay accessibility, vitamin B12 has become a usual test in routine health checkups. However, these analytical methods usually present antibody-mediated interferences. Our aim was to propose an algorithm for the screening of antibody-mediated analytical interferences on vitamin B12 immunoassays on the Alinity platform. METHODS: Observational, prospective, case-control study was performed during 12 months. Individuals with persistently elevated cobalamin concentrations [>554 pmol/L] were considered as cases in the absence of supplementation or other justifying cause. Individuals under treatment with vitamin B12, or in the context of alcoholism were included as controls. A thorough interference study by macromolecules in immunoassays was performed in serum samples: PEG precipitation, rheumatoid factor, heterophile antibodies and gel permeation chromatography (GPC). Albumin, total B12, IgG and IgM were measured in every GPC collected fraction and chromatograms were drafted. RESULTS: Up to 45% of cases presented interference by B12-immunocomplexes and the precipitation for all of them was >50%. The individual with the lowest interfered vitamin B12 result was 661 pmol/L. CONCLUSION: The presence of antibody-mediated interferences, mainly B12-immunocomplexes, is a relatively common phenomenon. A simple algorithm for the screening of interferences is useful and reliable in ruling out healthy individuals and highly cost-effective.

Online intervention to prevent postnatal depression and anxiety in Chilean new mothers: Protocol for a feasibility trial.

Symptoms of postpartum depression and anxiety in new mothers are prevalent and negatively impact maternal emotional wellbeing and infant development. Barriers to accessing treatment prevent women from receiving mental health care, a situation that has worsened due to the COVID-19 pandemic. mHealth interventions hold the potential to support women during the transition to parenthood despite these barriers and to promote the use of preventive interventions. This study uses a mixed methods design to assess the feasibility and preliminary effectiveness of a psychoeducational, guided mHealth intervention to prevent postpartum mental health difficulties in women who receive care in primary health centers in Chile. The study will contribute to evidence-based research on the effectiveness of mHealth interventions for new mothers from an understudied cultural background. The findings will also enable the development of a larger randomized controlled trial to assess the effectiveness of the intervention, which, if effective, could significantly contribute to the emotional wellbeing of women and their families.

Neurocognitive outcome and mental health in children with tyrosinemia type 1 and phenylketonuria: A comparison between two genetic disorders affecting the same metabolic pathway.

Tyrosinemia type 1 (TT1) and phenylketonuria (PKU) are both inborn errors of phenylalanine-tyrosine metabolism. Neurocognitive and behavioral outcomes have always featured in PKU research but received less attention in TT1 research. This study aimed to investigate and compare neurocognitive, behavioral, and social outcomes of treated TT1 and PKU patients. We included 33 TT1 patients (mean age 11.24 years; 16 male), 31 PKU patients (mean age 10.84; 14 male), and 58 age- and gender-matched healthy controls (mean age 10.82 years; 29 male). IQ (Wechsler-subtests), executive functioning (the Behavioral Rating Inventory of Executive Functioning), mental health (the Achenbach-scales), and social functioning (the Social Skills Rating System) were assessed. Results of TT1 patients, PKU patients, and healthy controls were compared using Kruskal-Wallis tests with post-hoc Mann-Whitney U tests. TT1 patients showed a lower IQ and poorer executive functioning, mental health, and social functioning compared to healthy controls and PKU patients. PKU patients did not differ from healthy controls regarding these outcome measures. Relatively poor outcomes for TT1 patients were particularly evident for verbal IQ, BRIEF dimensions "working memory", "plan and organize" and "monitor", ASEBA dimensions "social problems" and "attention problems", and for the SSRS "assertiveness" scale (all p values <0.001). To conclude, TT1 patients showed cognitive impairments on all domains studied, and appeared to be significantly more affected than PKU patients. More attention should be paid to investigating and monitoring neurocognitive outcome in TT1 and research should focus on explaining the underlying pathophysiological mechanism.

Clinical Trajectories of Neuropsychiatric Symptoms in Mild-Moderate to Advanced Dementia.

BACKGROUND: There is high prevalence of neuropsychiatric symptoms (NPS) among dementia patients. NPS are correlated with dementia progression, functional decline, early institutionalization, and death. There is scarce evidence on the progression of NPS in the latest stages of dementia. OBJECTIVE: To describe the prevalence of NPS in mild-moderate to severe dementia and to reveal the progression of each NPS over time. METHODS: We studied 317 patients (77.3% female, average age: 81.5 years) with a DSM-IV-TR diagnosis of dementia. This is a cross-sectional, and a prospective longitudinal study with 78-month follow-up. We assessed cognitive status (Mini-Mental State Examination and Severe Mini-Mental State Examination), dementia severity (Global Deterioration Scale and Clinical Dementia Rating), and psychopathological measures (Neuropsychiatric Inventory, APADEM-Nursing Home, Apathy Inventory, Cornell Scale for Depression in Dementia, and Cohen-Mansfield Agitation Inventory). RESULTS: Overall prevalence of NPS was 94.6%, being apathy the most prevalent (66.7%) and the one whose severity increased the most with progression of dementia. Agitation/aggression, irritability, and sleeping and eating disorders also increased over time. Delusions and depressive symptoms decreased in severity with disease progression. In severe dementia, female displayed more depressive symptoms and eating disorders, while male displayed more agitation/aggression and sleep disturbances. CONCLUSION: NPS in dementia follow a heterogeneous course. Apathy is the most prevalent NPS and the one that worsens most significantly over time. The course of some NPS differs between sexes. Further research is required to understand the evolution of NPS at advanced stages of dementia.

Peptide Receptor Radionuclide Therapy with [177Lu]Lu-DOTA-TATE in Patients with Advanced GEP NENS: Present and Future Directions.

This review article summarizes findings published in the last years on peptide receptor radionuclide therapy in GEP NENs, as well as potential future developments and directions. Unanswered questions remain, such as the following: Which is the correct dose and individual dosimetry? Which is the place for salvage PRRT-Lu? Whicht is the role of PRRT-Lu in the pediatric population? Which is the optimal sequencing of PRRT-Lu in advanced GEP NETs? Which is the place of PRRT-Lu in G3 NENs? These, and future developments such as inclusion new radiopharmaceuticals and combination therapy with different agents, such as radiosensitizers, will be discussed.

Thermosensitive Bioadhesive Hydrogels Based on Poly(N-isopropylacrilamide) and Poly(methyl vinyl ether-alt-maleic anhydride) for the Controlled Release of Metronidazole in the Vaginal Environment.

The development of thermosensitive bioadhesive hydrogels as multifunctional platforms for the controlled delivery of microbicides is a valuable contribution for the in situ treatment of vagina infections. In this work, novel semi-interpenetrating network (s-IPN) hydrogels were prepared by the entrapment of linear poly(methyl vinyl ether-alt-maleic anhydride) (PVME-MA) chains within crosslinked 3D structures of poly(N-isopropylacrylamide) (PNIPAAm). The multifunctional platforms were characterized by Fourier transform infrared spectroscopy, scanning electron microscopy, thermal techniques, rheological analysis, swelling kinetic measurements, and bioadhesion tests on porcine skin. The hydrogels exhibited an interconnected porous structure with defined boundaries. An elastic, solid-like behavior was predominant in all formulations. The swelling kinetics were strongly dependent on temperature (25 °C and 37 °C) and pH (7.4 and 4.5) conditions. The s-IPN with the highest content of PVME-MA displayed a significantly higher detachment force (0.413 ± 0.014 N) than the rest of the systems. The metronidazole loading in the s-IPN improved its bioadhesiveness. In vitro experiments showed a sustained release of the antibiotic molecules from the s-IPN up to 48 h (94%) in a medium simulating vaginal fluid, at 37 °C. The thermosensitive and bioadhesive PNIPAAm/PVME-MA systems showed a promising performance for the controlled release of metronidazole in the vaginal environment.

Thyroid panel reference intervals in healthy children and adolescents: A Spanish cohort.

OBJECTIVES: In children, thyroid hormones are essential for correct physical and neurological development. The recommended process for defining reference intervals (RIs) is the direct approach; however, indirect methods are an effective alternative. This study aimed to explore age- and sex-dependent relationships between serum concentrations of thyroid hormones in a large population-based cohort of healthy Spanish Caucasian children and calculate RIs. MATERIAL AND METHODS: Results of serum thyroid-stimulating hormone (TSH) and free thyroxine (fT4) were collected from laboratory data of N (TSH = 23201; fT4 = 20728) patients aged 1 month - 15 years. These results were validated with a prospective study. Analyses of serum concentrations of TSH and fT4 were performed on ARCHITECT i2000 (Abbott Diagnostics, US). Percentiles (2.5th to 97.5th) were determined for each variable and taken as the RI. RESULTS: No difference was found between serum TSH concentrations in male and female children of all age groups. A difference between serum fT4 concentrations in males and females and an age-dependent correlation for both sexes were found. CONCLUSION: There is very little consensus on RIs in children. Our data confirm it is possible to use data mining techniques to calculate reliable and clinically useful RIs.

Optimization of the thyroid panel for diagnostic purposes: Thyrotropin cut-off values for the reflex addition of free thyroxine.

BACKGROUND-AIM: Measurement of serum thyrotropin is currently the recommended test for the screening of thyroid dysfunction, while serum free thyroxine is kept as a reflex test. In our laboratory, the strategy followed in adult individuals from Primary Care includes a 'safety margin' for requests with a thyrotropin ≤1.0 or ≥4.0 mIU/L (normal: 0.35-4.95 mIU/L). Our aim was to optimize the thyrotropin cut-off values for the addition of free thyroxine and, based on these cut-offs, to retrospectively analyze avoidable free thyroxine measurements and possible adverse clinical consequences. METHODS: Retrospective observational study performed in a tertiary care hospital between 2013 and 2018. We considered all laboratory requests for screening of thyroid dysfunction (TD) in adult patients from Primary Care. Requests from patients with a previous diagnosis of thyroid disease or pregnant women were excluded. Different receiver operating characteristic (ROC) curves were performed and the obtained thyrotropin cut-off values were compared. Economic savings were assessed considering the current cost of free thyroxin assays in our laboratory. RESULTS: From a total of 554,529 TD protocols included, 119,504 requests had free thyroxine added. From the ROC curve that enables ≥95% of abnormal free thyroxine results to be detected, the thyrotropin values obtained were ≥4.58 mIU/L and ≤0.94 mIU/L. These thyrotropin cut-off values would lead to a saving of 22.7% of annual free thyroxine measurements without adverse clinical consequences. DISCUSSION: Setting optimized thyrotropin cutoffs for reflex testing of free thyroxine would reduce the need for this test. Clinical laboratories need to offer not only true results, but also become the cornerstone in the optimization of resources.

Genetic predictors of long-term response and trough levels of infliximab in crohn's disease.

INTRODUCTION: Several factors, such as trough serum anti-TNF levels, have been associated with response to therapy in Crohn's disease. However, this association is observed after initiation of treatment. Identifying DNA variants may prove useful for predicting long-term response or failure to these drugs before initiation of treatment. OBJECTIVE: To identify genetic variants associated with long-term response to infliximab and trough levels in Crohn's disease. PATIENTS AND METHODS: An observational, longitudinal study was conducted. We analyzed blood samples from 132 infliximab-treated patients diagnosed with Crohn's disease from 2 hospitals. We genotyped 21 polymorphisms previously related to anti-TNF response in genes involved in the NFkB-mediated inflammatory response, TNFα-signaling and cytokines regulated by NFkB, using real-time PCR. Trough infliximab levels were measured using ELISA. The association between SNPs and time-to-failure (defined as the time from the initiation of induction therapy to the date of treatment withdrawal due to a primary or secondary failure) was analyzed using log-rank test. The association between SNPs and supra-(>7 µg/mL) or infratherapeutic (<3 µg/mL) infliximab trough levels was analyzed using a linear-by-linear association chi-squared test. RESULTS: Two SNPs in TLR2, rs1816702 and rs3804099, and 1 SNP in TNFRSF1B, rs1061624, were associated with long-term response (up to ten years follow-up) to infliximab (HR, 0.13 [95%CI, 0.02-1.00], p < 0.05; HR, 0.39 [95%CI, 0.18-0.88], p < 0.05; and HR, 0.04 [95%CI, 0.18-0.92] p > 0.05, respectively). In addition, IL6 rs10499563 C and IL10 rs1800872 A were associated with supratherapeutic trough infliximab levels; IL10 rs3024505 T was associated with infratherapeutic levels (p < 0.05). CONCLUSION: Genotyping of the variants identified in the genes encoding TLR2, TNFRSF1B, IL6 and IL10 reported herein represent a promising tool for the identification and selection of those patients who will benefit most from infliximab.

Assessment of a laboratory critical risk result notification protocol in a tertiary care hospital and their use in clinical decision making.

INTRODUCTION: Communication of laboratory critical risk results is essential for patient safety, as it allows early decision making. Our aims were: 1) to retrospectively evaluate the current protocol for telephone notification of critical risk results in terms of rates, efficiency and recipient satisfaction, 2) to assess their use in clinical decision making and 3) to suggest alternative tools for a better assessment of notification protocols. MATERIALS AND METHODS: The biochemical critical risk result notifications reported during 12 months by routine and STAT laboratories in a tertiary care hospital were reviewed. Total number of reports, time for the notification and main magnitudes with critical risk results were calculated. The use of notifications in clinical decision making was assessed by reviewing medical records. Satisfaction with the notification protocol was assessed through an online questionnaire to requesting physicians and nurses. RESULTS: Critical result was yielded by 0.1% of total laboratory tests. Median time for notification was 3.2 min (STAT) and 16.9 min (routine). The magnitudes with a greater number of critical results were glucose and potassium for routine analyses, and troponin, sodium for STAT. Most notifications were not reflected in the medical records. Overall mean satisfaction with the protocol was 4.2/5. CONCLUSION: The results obtained indicate that the current protocol is appropriate. Nevertheless, there are some limitations that hamper the evaluation of the impact on clinical decision making. Alternatives were proposed for a proper and precise evaluation.

Clinical utility of ABCB1 genotyping for preventing toxicity in treatment with irinotecan.

Preventing severe irinotecan-induced adverse reactions would allow us to offer better treatment and improve patients' quality of life. Transporters, metabolizing enzymes, and genes involved in the folate pathway have been associated with irinotecan-induced toxicity. We analyzed 12 polymorphisms in UGT1A1, ABCB1, ABCG2, ABCC4, ABCC5, and MTHFR in 158 patients with metastatic colorectal cancer treated with irinotecan and studied the association with grade >2 adverse reactions (CTCAE). Among the most frequent ADRs, the SNPs rs1128503, rs2032582, and rs1045642 in ABCB1 and rs1801133 in MTHFR were associated with hematological toxicity and overall toxicity. The SNP rs11568678 in ABCC4 was also associated with overall toxicity. After correction of P values using a false discovery rate, only ABCB1 variants remained statistically significant. Haplotype analysis in ABCB1 showed an 11.3-fold and 4.6-fold increased risk of hematological toxicity (95% CI, 1.459-88.622) and overall toxicity (95% CI, 2.283-9.386), respectively. Consequently, genotyping of the three SNPs in ABCB1 can predict overall toxicity and hematological toxicity with a diagnostic odds ratio of 4.40 and 9.94, respectively. Genotyping of ABCB1 variants can help to prevent severe adverse reactions to irinotecan-based treatments in colorectal cancer.

Use of exome sequencing to determine the full profile of genetic variants in the fluoropyrimidine pathway in colorectal cancer patients affected by severe toxicity.

AIM: To identify genetic variants associated with capecitabine toxicity in fluoropyrimidine pathway genes using exome sequencing. PATIENTS & METHODS: Exomes from eight capecitabine-treated patients with severe adverse reactions (grade >2), among a population of 319, were sequenced (Ion Proton). SNPs in genes classified as potentially damaging (Sorting Intolerant from Tolerant and Polymorphism Phenotyping v2) were tested for association with toxicity in a validation cohort of 319 capecitabine-treated patients. RESULTS: A total of 17 nonsynonymous genetic variants were identified. Of these, five putative damaging SNPs in DPYD, ABCC4 and MTHFR were genotyped in the validation cohort. DPYD rs1801160 was associated with the risk of toxicity (p = 0.029) and MTHFR rs1801133 with delayed administration of chemotherapy due to toxicity (p = 0.047). CONCLUSION: Exome sequencing revealed two specific biomarkers of the risk of toxicity to capecitabine.

Identification of new SNPs associated with severe toxicity to capecitabine.

Predicting individual risk of chemotherapy-induced severe adverse reaction is a critical issue when selecting the best treatment for cancer patients. SNPs have been identified in genes involved in the pharmacodynamics of fluoropyrimidines, and guidelines even recommend genotyping some DPYD variants in order to estimate the risk of toxicity. However, the predictive value of this approach remains insufficient, thus limiting its clinical implementation. The aim of the present study was to identify new genetic variants by selecting a group of tag SNPs in genes associated with the pharmacodynamics of fluoropyrimidines (CDA, DPYD, ENOSF1, CES1, TYMS, SLC22A7, TYMP, and UMPS). For this purpose, 23 selected SNPs were genotyped on an OpenArray™ platform in a cohort of 301 colorectal cancer patients receiving capecitabine-based chemotherapy. Univariate and multivariate statistical analysis by logistic regression revealed 10 SNPs associated with severe adverse reactions to capecitabine (P<0.05): rs1048977, rs12726436, and rs2072671 in CDA; rs12119882 in DPYD; rs2853741 in TYMS; rs699517 in TYMS/ENOSF1; rs2270860 and rs4149178 in SLC22A7; and rs2279199 and rs4678145 in UMPS. Except for rs2072671, no association had previously been reported between these SNPs and the risk of capecitabine-induced toxicity. The use of tag SNPs to find new polymorphisms related to adverse reactions to capecitabine was successful. These new variants could increase the predictive power of currently available tests and thus prevent severe adverse reactions to capecitabine.

Management of freezing rate and trehalose concentration to improve frozen dough properties and bread quality

Abstract Bread is one of the most consumed foods in the world, and alternatives have been sought to extend its shell life, and freezing is one of the most popular methods. The purpose of this study was to evaluate the effect of freezing rate and trehalose concentration on the fermentative and viscoelastic properties of dough and bread quality. Dough was prepared and trehalose was added at three concentrations (0, 400, 800 ppm); dough was pre fermented and frozen at two freezing rates then stored for 42 days. Frozen dough samples were thawed every two weeks. CO2 production and elastic and viscous modulus were determined. In addition, bread was elaborated and specific volume and firmness were evaluated. High trehalose concentrations (400 and 800 ppm) produced dough with the best viscoelastic and fermentative properties. Greater bread volume and less firmness were observed when a slow freezing rate (-.14 °C/min) was employed.