Impact of the Acetyl Group on Cysteine: A Study of N-Acetyl-Cysteine through Rotational Spectroscopy.

Herein, we report a spectroscopic study of N-acetyl-L-cysteine, an important antioxidant drug, using Fourier-transform microwave techniques and in isolated conditions. Two conformers are observed, where most stable structure adopts a cis disposition, and the second conformer has a lower abundance and adopts a trans disposition. The rotational constants and the barriers to methyl internal rotation are determined for each conformer, allowing a precise conformation identification. The results show that the cis form adopts an identical structure in the crystal, solution, and gas phases. Additionally, the structures are contrasted against those of cysteine.

Bringing Machine-Learning Enhanced Quantum Chemistry and Microwave Spectroscopy to Conformational Landscape Exploration: the Paradigmatic Case of 4-Fluoro-Threonine.

A combined experimental and theoretical study has been carried out on 4-fluoro-threonine, the only naturally occurring fluorinated amino acid. Fluorination of the methyl group significantly increases the conformational complexity with respect to the parent amino acid threonine. The conformational landscape has been characterized in great detail, with special attention given to the inter-conversion pathways between different conformers. This led to the identification of 13 stable low-energy minima. The equilibrium population of so many conformers produces a very complicated and congested rotational spectrum that could be assigned through a strategy that combines several levels of quantum chemical calculations with the principles of machine learning. Twelve conformers out of 13 could be experimentally characterized. The results obtained from the analysis of the intra-molecular interactions can be exploited to accurately model fluorine-substitution effects in biomolecules.

Understanding the abundance of the rare sugar ß-D-allose.

The conformational landscape of ß-D-allose, a rare sugar, was investigated using laser ablation in combination with high-resolution rotational spectroscopy. Altogether, three species are identified, exhibiting a counter-clockwise intramolecular hydrogen bond network. The effect of epimerization on the main aldohexose is also studied and, despite the main conformers being very similar, the position of the hydroxyl groups in allose allows the formation of considerably stronger intramolecular hydrogen bonds than in glucose, and this could explain the low abundance of ß-D-allose in Nature.

Hereditary angioedema: 24 years of experience in a Portuguese Reference Center.

Summary: Hereditary angioedema (HAE) poses a high burden of disease, being its epidemiological and clinical data heterogeneous among countries, with no recent published studies concerning Portuguese patients. Therefore, we aimed to raise awareness of HAE and to contribute to clinical knowledge. An observational, descriptive, retrospective, and cross-sectional study was performed, that included a cohort of 126 patients followed in a single Portuguese Center. We observed a high prevalence of HAE-C1-INH type II (45.2% of patients). Most HAE patients (67.4%) presented the initial manifestations of the disease before adulthood, at a mean age of 12.6 ± 8.4 years. However, we found a long delay in HAE diagnosis, especially in those without family history (mean 20.7 ± 17.3 years). Stress was the most common trigger, followed by trauma and infection. Symptoms involving different systems were increasingly reported with increased disease duration. Cutaneous symptoms (95.0%) were more frequent, followed by gastrointestinal (80.7%), and respiratory symptoms (50.4%). HAE symptoms led to abdominal surgery in 22 (17.5%) patients and induced laryngeal edema requiring intubation/tracheostomy in 8 (6.3%) patients. Most patients were under long-term prophylaxis, mainly with attenuated androgens (62.7% of patients).The correct distinction between HAE and other common causes of angioedema is critical, allowing reduction of diagnostic delay, improvement of adequate management, and ultimately improving outcomes and quality of life of HAE patients.

[Recommendations for the management of critically ill patients with COVID-19 in Intensive Care Units]. / Recomendaciones para el manejo de los pacientes críticos con COVID-19 en las Unidades de Cuidados Intensivos.

The COVID-19 pandemic has led to the admission of a high number of patients to the ICU, generally due to severe respiratory failure. Since the appearance of the first cases of SARS-CoV-2 infection, at the end of 2019, in China, a huge number of treatment recommendations for this entity have been published, not always supported by sufficient scientific evidence or with methodological rigor necessary. Thanks to the efforts of different groups of researchers, we currently have the results of clinical trials, and other types of studies, of higher quality. We consider it necessary to create a document that includes recommendations that collect this evidence regarding the diagnosis and treatment of COVID-19, but also aspects that other guidelines have not considered and that we consider essential in the management of critical patients with COVID-19. For this, a drafting committee has been created, made up of members of the SEMICYUC Working Groups more directly related to different specific aspects of the management of these patients.

Gas-Phase Conformational Map of the Amino Acid Isovaline.

Four conformers of the non-proteinogenic α-amino acid isovaline, vaporized by laser ablation, are characterized by Fourier-transform microwave techniques in a supersonic expansion. The comparison between the experimental rotational and 14 N nuclear quadrupole coupling constants and the ab initio calculated ones provides conclusive evidence for the identification of the conformers. The most stable species is stabilized by an N-H⋅⋅⋅O =C intramolecular hydrogen bond and a cis-COOH interaction, whereas the higher-energy conformers exhibit an N⋅⋅⋅H-O intramolecular hydrogen bond and trans-COOH, as in other aliphatic amino acids. The spectroscopic data herein reported can be used for the astrophysical purpose in a possible detection of isovaline in space.

A rotational study of the AlaAla dipeptide.

Herein, we present the first rotational study of the AlaAla dipeptide, brought into the gas phase by laser ablation. Two different structures have been unveiled in the isolated environment of a supersonic expansion by Fourier transform microwave spectroscopy. These structures have been identified through their rotational and 14N quadrupole coupling constants. The flexibility of the -NH2 and -COOH ends allows the formation of strong intramolecular interactions giving rise to five- and seven-membered ring configurations.

Nodal staging in the rectal cancer follow-up MRI after chemoradiotherapy: use of morphology, size, and diffusion criteria.

AIM: To analyse changes in post-neoadjuvant follow-up magnetic resonance imaging (MRI) staging accuracy for malignant adenopathies in rectal cancer, by comparing size criteria with morphological criteria using high-resolution T2-weighted sequences, as well as variations when adding diffusion-weighted imaging. METHODS AND MATERIALS: The present study was a cross-sectional study of a database including 46 1.5-T MRI examinations (2011-2016) from patients with biopsy-proven rectal cancer and chemoradiotherapy treatment before surgery. All cases were reviewed by three radiologists individually, who were blinded to any clinical information. The radiologists were experienced in rectal cancer (3-6 years) and evaluated the presence of malignant nodes in each patient. Malignancy was determined using morphological, size (5 mm), and diffusion criteria separately, as well as morphology plus diffusion. Each case was assessed four times: (1) evaluation of morphological criteria; (2) size criteria; (3) evaluation only using diffusion (b-values 50, 400, and 800); and (4) diffusion plus morphological criteria. Histological staging of surgical specimens was the reference standard. Statistical analysis included accuracy (area under the receiver operating characteristic [ROC] curve [AUC]), sensitivity, specificity, and positive/negative predictive values (PPV/NPV) for each radiologist, and group agreement (Fleiss' kappa). RESULTS: Mean values using morphological criteria were: AUC 0.78, sensitivity 77.7%, specificity 73.8%, PPV 66.1%, NPV 85.2%. Using size criterion: AUC 0.75, sensitivity 62.9%, specificity 83.2%, PPV 74.1%, NPV 80%. Added diffusion yielded no improvement, and yielded worse results by itself. CONCLUSIONS: Although morphological criteria showed better results in accuracy, sensitivity, and NPV, size criterion yielded the best specificity and PPV. Adding diffusion did not demonstrate a clear advantage over the criteria by themselves. Thus, mixed size-morphology criteria could have the greatest diagnostic value for follow-up N-staging.

Elucidating the multiple structures of pipecolic acid by rotational spectroscopy.

The complex conformational space of the non-proteinogenic cyclic amino acid pipecolic acid has been explored in the gas phase for the first time. Solid pipecolic acid samples were vaporized by laser ablation and expanded in a supersonic jet where the rotational spectral signatures owing to nine different conformers were observed by Fourier transform microwave spectroscopy. All species were identified by comparison of the experimental rotational and nuclear quadrupole coupling constants with those predicted theoretically. Observation of type-III conformers, leading to a difference when compared against the conformational behavior of the analog amino acid proline, has been interpreted by an increment in steric hindrance when increasing the number of carbons present in the ring.

The last link of the x-aminobutyric acid series: the five conformers of ß-aminobutyric acid.

ß-Aminobutyric acid is a non-proteinogenic amino acid that is known to protect plants against various pathogens. Its structure is midway between α-aminobutyric acid and γ-aminobutyric acid. The structural differences in the position of the amino group in the conformational stabilization of ß-aminobutyric acid have been studied by laser ablation Fourier transform microwave spectroscopy. Five conformers have been detected, and their rotational and quadrupole coupling constants of the 14N nucleus determined. Three of the conformers, including the most stable structure, are stabilized by a non-bifurcated N-HO[double bond, length as m-dash]C intramolecular hydrogen bond. The other two conformers possess a NH-O intramolecular interaction. In this work we highlight that ß-aminobutyric acid shows the conformational peculiarities of α-aminobutyric acid and γ-aminobutyric acid completing the rotational spectroscopic study of the x-aminobutyric acid series.

The effect of N-methylation on the conformational landscape of alanine: the case of N-methyl-l-alanine.

The non-proteinogenic amino acid N-methyl-l-alanine has been brought into the gas phase using laser ablation techniques and studied by high resolution chirped pulse and molecular-beam Fourier transform microwave spectroscopies coupled to supersonic expansion. Four conformers showing the three types of hydrogen bond interactions I (NHO[double bond, length as m-dash]C), II (OHN) and III (N-HO-H) have been unambiguously identified, based on the comparison of the experimental rotational and 14N nuclear quadrupole constants with the calculated ab initio values. The observation of a type III conformer evidences the role of methyl groups in both sides to impose the steric hindrance, precluding the relaxation from type III to type I conformers and explains the responsibility for the unique conformational landscape observed in the case of NMA.

Omalizumab in chronic spontaneous and inducible urticaria: a 9 year retrospective study in Portugal.

Summary: Objective. Describe the safety and long-term use of omalizumab in chronic urticaria (CU), both spontaneous (CSU) and inducible (CIndU). Methods. Retrospective chart-review (2006-15) of CU patients treated with omalizumab for ≥ 6 months. Statistical analyses: descriptive statistics, Mann-Whitney, generalized linear models. Results. 23 patients with CSU (3 men), 3 with CIndU (2 men). Generalized linear models showed UAS reduction per omalizumab administration of 16% in CIndU and CSU and UAS7, of 15% in CIndU, and 20% in CSU. DLQI score at baseline had a median of 19 (CIndU and CSU) and after omalizumab a median of 0 (in both). Seven CSU patients stopped omalizumab and remain asymptomatic. No side-effects were observed. Conclusion. Omalizumab is safe and efficacious in CU. Stopping omalizumab can be tried, as some patients achieve remission.

The Medication Level Variability Index (MLVI) Predicts Poor Liver Transplant Outcomes: A Prospective Multi-Site Study.

Nonadherence to immunosuppressant medications is a leading cause of poor long-term outcomes in transplant recipients. The Medication Level Variability Index (MLVI) provides a vehicle for transplant outcome risk-stratification through continuous assessment of adherence. The MALT (Medication Adherence in children who had a Liver Transplant) prospective multi-site study evaluated whether MLVI predicts late acute rejection (LAR). Four hundred pediatric (1-17-year-old) liver transplant recipients were enrolled and followed for 2 years. The a-priori hypothesis was that a higher MLVI predicts LAR. Predefined secondary analyses evaluated other outcomes such as liver enzyme levels, and sensitivity analyses compared adolescents to pre-adolescents. In the primary analysis sample of 379 participants, a higher prerejection MLVI predicted LAR (mean prerejection MLVI with LAR: 2.4 [3.6 standard deviation] versus without LAR, 1.6 [1.1]; p = 0.026). Fifty-three percent of the adolescents with MLVI>2 in year 1 had LAR by the end of year 2, as compared with 6% of those with year 1 MLVI≤2. A higher MLVI was significantly associated with all secondary outcomes. MLVI, a marker of medication adherence that uses clinically derived information, predicts LAR in pediatric liver transplant recipients.

Environmental sampling coupled with real-time PCR and genotyping to investigate the source of a Q fever outbreak in a work setting.

A Q fever outbreak was declared in February 2016 in a company that manufactures hoists and chains and therefore with no apparent occupational-associated risk. Coxiella burnetii infection was diagnosed by serology in eight of the 29 workers of the company; seven of them had fever or flu-like signs and five had pneumonia, one requiring hospitalisation. A further case of C. burnetii pneumonia was diagnosed in a local resident. Real-time PCR (RTi-PCR) showed a widespread distribution of C. burnetii DNA in dust samples collected from the plant facilities, thus confirming the exposure of workers to the infection inside the factory. Epidemiological investigations identified a goat flock with high C. burnetii seroprevalence and active shedding which was owned and managed by one of the workers of the company as possible source of infection. Genotyping by multispacer sequence typing (MST) and a 10-loci single-nucleotide polymorphism (SNP) discrimination using RTi-PCR identified the same genotype (MST18 and SNP type 8, respectively) in the farm and the factory. These results confirmed the link between the goat farm and the outbreak and allowed the identification of the source of infection. The circumstances and possible vehicles for the bacteria entering the factory are discussed.

The role of amino acid side chains in stabilizing dipeptides: the laser ablation Fourier transform microwave spectrum of Ac-Val-NH2.

The steric effects imposed by the isopropyl group of valine in the conformational stabilization of the capped dipeptide N-acetyl-l-valinamide (Ac-Val-NH2) have been studied by laser ablation molecular beam Fourier transform microwave (LA-MB-FTMW) spectroscopy. The rotational and quadrupole coupling constants of the two 14N nuclei determined in this work show that this dipeptide exists as a mixture of C7 and C5 conformers in the supersonic expansion. The conformers are stabilized by a C[double bond, length as m-dash]OH-N intramolecular hydrogen bond closing a seven- or a five-membered ring, respectively. The observation of both conformers is in good agreement with previous results on the related dipeptides containing different residues, confirming that the polarity/non-polarity of the side chains of the amino acid is responsible for the conformational locking/unlocking. The voluminous isopropyl group is not able to prevent the less stable C5 conformer from forming but it destabilizes the C[double bond, length as m-dash]OH-N interaction.

Oral Immunotherapy for Food Allergy: A Spanish Guideline. Immunotherapy Egg and Milk Spanish Guide (ITEMS Guide). Part I: Cow Milk and Egg Oral Immunotherapy: Introduction, Methodology, Rationale, Current State, Indications, Contraindications, and Oral Immunotherapy Build-up Phase.

BACKGROUND AND OBJECTIVE: Cow milk and egg are the most frequent causes of food allergy in the first years of life. Oral immunotherapy (OIT) has been investigated as an alternative to avoidance diets. No clinical practice guidelines on the management of OIT with milk and egg are currently available. Objectives: To develop clinical guidelines for OIT based on available scientific evidence and the opinions of experts. METHODS: A review was made of studies published between 1984 and June 2016, doctoral theses published in Spain, summaries of communications at scientific meetings (SEAIC, SEICAP, EAACI, and AAAAI), and the consensus of opinion established by a group of experts from the scientific societies SEICAP and SEAIC. RESULTS: Recommendations were established regarding the indications, requirements and practical aspects of the different phases of OIT, as well as special protocols for patients at high risk of adverse reactions. CONCLUSIONS: Clinical practice guidelines based on the consensus reached between Spanish experts are presented for the management of OIT with milk and egg.

Oral Immunotherapy for Food Allergy: A Spanish Guideline. Egg and Milk Immunotherapy Spanish Guide (ITEMS GUIDE). Part II: Maintenance Phase of Cow Milk (CM) and Egg Oral Immunotherapy (OIT), Special Treatment Dosing Schedules. Models of Dosing Schedules of OIT With CM and Egg.

BACKGROUND AND OBJECTIVE: Cow milk and egg are the most frequent causes of food allergy in the first years of life. Oral immunotherapy (OIT) has been investigated as an alternative to avoidance diets. No clinical practice guidelines on the management of OIT with milk and egg are currently available. Objectives: To develop clinical guidelines for OIT based on available scientific evidence and the opinions of experts. METHODS: A review was made of studies published between 1984 and June 2016, doctoral theses published in Spain, summaries of communications at scientific meetings (SEAIC, SEICAP, EAACI, and AAAAI), and the consensus of opinion established by a group of experts from the scientific societies SEICAP and SEAIC. RESULTS: Recommendations were established regarding the indications, requirements and practical aspects of the different phases of OIT, as well as special protocols for patients at high risk of adverse reactions. CONCLUSIONS: Clinical practice guidelines based on the consensus reached between Spanish experts are presented for the management of OIT with milk and egg.