Precise glucose measurement in sodium fluoride-citrate plasma affects estimates of prevalence in diabetes and prediabetes.

OBJECTIVES: Estimates of glucose concentrations vary among types of blood samples, which impact on the assessment of diabetes prevalence. Guidelines recommend a conversion factor to calculate plasma glucose from measurements of glucose in whole blood. The American Diabetes Association recommends the use of blood drawing tubes containing sodium fluoride (NaF) and citrate, which have not yet been evaluated regarding possible differences in glucose concentration and conversion factors. Thus, we compared glucose measurements in NaF-citrate plasma and venous whole blood and estimated the impact of differences on diabetes and prediabetes prevalence. METHODS: Glucose differences were calculated by Bland-Altman analysis with pairwise comparison of glucose measurements from whole blood and NaF-citrate plasma (n=578) in clinical studies of the German Diabetes Center. Subsequently, we computed the impact of the glucose difference on diabetes and prediabetes prevalence in the population-based National Health and Nutrition Examination Survey (NHANES). RESULTS: Even upon conversion of whole blood to plasma glucose concentrations using the recommended conversion factor, mean glucose concentration difference remained 4.72 % higher in NaF-citrate plasma. Applying the higher glucose estimates, increases the population-based diabetes and prediabetes prevalence by 13.67 and 33.97 % or more than 7.2 and 13 million people in NHANES, respectively. Additional economic burden could be about 20 $ billion per year due to undiagnosed diabetes. CONCLUSIONS: The recommended conversion factor is not valid for NaF-citrate plasma. Systematic bias of glucose measurements due to sampling type leads to clinically relevant higher estimates of diabetes and prediabetes prevalence.

The Chameleonic Nature of the Nitro Group Applied to a Base-Promoted Cascade Reaction To Afford Indane-Fused Dihydrofurans.

We disclose a Michael/Conia-ene/SN2 cascade reaction for the synthesis of Indane-fused dihydrofurans from 1,3-dicarbonyl compounds and 2-alkynylnitrostyrenes promoted by potassium carbonate in DMSO at room temperature. In this reaction, the nitro group has a chameleonic role, first as an electron-withdrawing group for the Michael addition, then the nitronate behaves as a nucleophile, and finally, the allylic nitro acts as a leaving group. The product is obtained as a single diastereomer, affording up to 82% with 1,3-keto esters and 58% with 1,3-diketones. Furthermore, DFT calculations of the reaction mechanism explained the chemoselective addition of the nitronate over the enolate to the unactivated triple bond, with the enolate addition being highly endothermic.

Ventricular Arrhythmias and Sudden Death in Nonischemic Dilated Cardiomyopathy: Matter of Sex or Scar?

BACKGROUND: To evaluate the association between sex and ventricular arrhythmias (VA) or sudden death (SD) in nonischemic dilated cardiomyopathy, including analysis of potential confounders. METHODS AND RESULTS: Retrospective cohort study of consecutive patients with DCM referred for cardiac magnetic resonance at 2 tertiary hospitals. The primary combined end point encompassed sustained VA, appropriate implantable cardioverter defibrillator therapies, resuscitated cardiac arrest, and SD. We included 1165 patients with median follow-up of 36 months (interquartile range 20-58 months). The majority of patients (66%) were males. Males and females had similar left ventricular ejection fraction, but the prevalence of late gadolinium enhancement (LGE) at cardiac magnetic resonance was significantly higher among males (48% vs 30%, P < .001). Males had higher cumulative incidence of the primary end point (8% vs 4%, P = .02), and male sex was a significant predictor of the primary end point at univariate analysis (hazard ratio 1.93, P = .02). However, LGE had a major confounding effect in the association between sex and the primary outcome: the hazard ratio of male sex adjusted for LGE was 1.29 (P = .37). LGE+ females had significantly higher cumulative incidence of the primary end point than LGE- males (13% vs 1.8%, P < .001). CONCLUSIONS: In patients with DCM, the prevalence of LGE is significantly higher among males, implying a major confounding effect in the association between male sex and VA or SD. LGE+ females have significantly higher risk than LGE- males. These data do not support the inclusion of sex into risk stratification algorithms for VA or SD in DCM.

Multimodal meta-analysis of structural gray matter, neurocognitive and social cognitive fMRI findings in schizophrenia patients.

Neuroimaging research has shown that patients with schizophrenia (SCZ) present brain structural and functional alterations, but the results across imaging modalities and task paradigms are difficult to reconcile. Specifically, no meta-analyses have tested whether the same brain systems that are structurally different in SCZ patients are also involved in neurocognitive and social cognitive tasks. To answer this, we conducted separate meta-analyses of voxel-based morphometry, neurocognitive functional magnetic resonance imaging (fMRI), and social cognitive fMRI studies. Next, with a multimodal approach, we identified the common alterations across meta-analyses. Further exploratory meta-analyses were performed taking into account several clinical variables (illness duration, medication status, and symptom severity). A cluster covering the dorsomedial prefrontal cortex (dmPFC) and the supplementary motor area (SMA), and the right inferior frontal gyrus (IFG), presented shared structural and neurocognitive-related activation decreases, while the right angular gyrus presented shared decreases between structural and social cognitive-related activation. The exploratory meta-analyses replicated to some extent these findings, while new regions of alterations appeared in patient subgroups with specific clinical features. In conclusion, we found task-specific correlates of brain structure and function in SCZ, which help summarize and integrate a growing literature.

Combination therapy of specific aeroallergens immunotherapy and omalizumab, in children with severe asthma.

BACKGROUND: In most cases, severe asthma in children has an allergic etiology, but allergen-specific immunotherapy (AIT) is contraindicated. OBJECTIVE: This study aimed at analyzing the safety and efficacy of AIT in patients with severe asthma treated with omalizumab (OM). METHODS: A descriptive real-life study was carried out by reviewing medical records. Effectiveness was measured by the degree of control (CAN questionnaire), number of hospitalizations per year, number of exacerbations per year, and maintenance treatment and lung function (FEV1). Some adverse reactions occurred (AAI-EAACI-WAO guidelines). RESULTS: The retrospective study included 29 patients up to 18 years of age with severe asthma with OM plus AIT treatment. AIT treatment was started in a cluster schedule when patients treated with OM achieved disease control. Before starting AIT, patients were treated with OM for 1 year for achieving asthmatic control. AIT to mites (51%), Alternaria (37.9%), or pollens (10.3%) was administered. After one year with OM plus AIT,statistically significant differences in CAN scores and FEV1 measures were observed (P < 0.001). No patients under treatment with OM plus AIT required hospital admission. During the clustering schedule, only 3/64 doses showed systemic adverse reactions. During the AIT maintenance treatment, 348 doses were administered, with no significant adverse reactions. CONCLUSION: In this population-based study in children with severe asthma, the combined treatment with OM plus AIT was safe and effective. This strategy allows these pediatric patients to be safely treated with AIT.

Stereocontrolled Synthesis of Enantiopure cis-Fused Octahydroisoindolones via Chiral Oxazoloisoindolone Lactams.

Kinetically controlled cyclocondensation of stereoisomeric and ring-chain tautomeric mixture of (±)-hydroxylactone 1 and 0.5 equiv of (R)-phenylglycinol provided tricyclic oxazoloisoindolone lactam (3R,5aS,9aR,9bS)-2a, a versatile intermediate for further stereocontrolled transformations to access enantiopure cis-fused octahydroisoindolones. An extension of this methodology was successfully applied to the synthesis of the 5,6-dihydroxy derivative (3aR,5R,6S,7aS)-17.

Incidence, clinical characteristics, risk factors and outcomes of meningoencephalitis in patients with COVID-19.

We investigated the incidence, clinical characteristics, risk factors, and outcome of meningoencephalitis (ME) in patients with COVID-19 attending emergency departments (ED), before hospitalization. We retrospectively reviewed all COVID patients diagnosed with ME in 61 Spanish EDs (20% of Spanish EDs, COVID-ME) during the COVID pandemic. We formed two control groups: non-COVID patients with ME (non-COVID-ME) and COVID patients without ME (COVID-non-ME). Unadjusted comparisons between cases and controls were performed regarding 57 baseline and clinical characteristics and 4 outcomes. Cerebrospinal fluid (CSF) biochemical and serologic findings of COVID-ME and non-COVID-ME were also investigated. We identified 29 ME in 71,904 patients with COVID-19 attending EDs (0.40‰, 95%CI=0.27-0.58). This incidence was higher than that observed in non-COVID patients (150/1,358,134, 0.11‰, 95%CI=0.09-0.13; OR=3.65, 95%CI=2.45-5.44). With respect to non-COVID-ME, COVID-ME more frequently had dyspnea and chest X-ray abnormalities, and neck stiffness was less frequent (OR=0.3, 95%CI=0.1-0.9). In 69.0% of COVID-ME, CSF cells were predominantly lymphocytes, and SARS-CoV-2 antigen was detected by RT-PCR in 1 patient. The clinical characteristics associated with a higher risk of presenting ME in COVID patients were vomiting (OR=3.7, 95%CI=1.4-10.2), headache (OR=24.7, 95%CI=10.2-60.1), and altered mental status (OR=12.9, 95%CI=6.6-25.0). COVID-ME patients had a higher in-hospital mortality than non-COVID-ME patients (OR=2.26; 95%CI=1.04-4.48), and a higher need for hospitalization (OR=8.02; 95%CI=1.19-66.7) and intensive care admission (OR=5.89; 95%CI=3.12-11.14) than COVID-non-ME patients. ME is an unusual form of COVID presentation (<0.5‰ cases), but is more than 4-fold more frequent than in non-COVID patients attending the ED. As the majority of these MEs had lymphocytic predominance and in one patient SARS-CoV-2 antigen was detected in CSF, SARS-CoV-2 could be the cause of most of the cases observed. COVID-ME patients had a higher unadjusted in-hospital mortality than non-COVID-ME patients.

Water clusters as bifunctional catalysts in organic chemistry: the hydrolysis of oxirane and its methyl derivatives.

This contribution explores the bifunctional catalytic activity of water clusters ((H2O)n with n = 1-5) in organic chemistry similar to that observed in the formation of H2SO4 in acid rain (Chem. Commun., 53, 3516, (2017)). We considered for this purpose the Hydrolysis of Epoxides (HE), in particular, that of oxirane and its methyl derivatives. Surrounding water molecules with H-bond cooperative effects decrease the activation energy of the rate-limiting step of HE in condensed phase, especially when they lead to an anti-periplanar attack on the alkoxide leaving group. Furthermore, the water molecules have a bifunctional catalytic role in HE by (i) increasing the nucleophilic and electrophilic character of the attacking oxygen atom and the leaving group of the reaction, respectively, and (ii) placing the reactants in a suitable disposition for the substitution to occur. Overall, this investigation provides relevant insights into the collective action of water molecules on organic reactions in neutral, basic and acid media.

Automated Extraction of Skin Wound Healing Biomarkers From In Vivo Label-Free Multiphoton Microscopy Using Convolutional Neural Networks.

BACKGROUND AND OBJECTIVES: Histological analysis is a gold standard technique for studying impaired skin wound healing. Label-free multiphoton microscopy (MPM) can provide natural image contrast similar to histological sections and quantitative metabolic information using NADH and FAD autofluorescence. However, MPM analysis requires time-intensive manual segmentation of specific wound tissue regions limiting the practicality and usage of the technology for monitoring wounds. The goal of this study was to train a series of convolutional neural networks (CNNs) to segment MPM images of skin wounds to automate image processing and quantification of wound geometry and metabolism. STUDY DESIGN/MATERIALS AND METHODS: Two CNNs with a 4-layer U-Net architecture were trained to segment unstained skin wound tissue sections and in vivo z-stacks of the wound edge. The wound section CNN used 380 distinct MPM images while the in vivo CNN used 5,848 with both image sets being randomly distributed to training, validation, and test sets following a 70%, 20%, and 10% split. The accuracy of each network was evaluated on the test set of images, and the effectiveness of automated measurement of wound geometry and optical redox ratio were compared with hand traced outputs of six unstained wound sections and 69 wound edge z-stacks from eight mice. RESULTS: The MPM wound section CNN had an overall accuracy of 92.83%. Measurements of epidermal/dermal thickness, wound depth, wound width, and % re-epithelialization were within 10% error when evaluated on six full wound sections from days 3, 5, and 10 post-wounding that were not included in the training set. The in vivo wound z-stack CNN had an overall accuracy of 89.66% and was able to isolate the wound edge epithelium in z-stacks from eight mice across post-wound time points to quantify the optical redox ratio within 5% of what was recorded by manual segmentations. CONCLUSION: The CNNs trained and presented in this study can accurately segment MPM imaged wound sections and in vivo z-stacks to enable automated and rapid calculation of wound geometry and metabolism. Although MPM is a noninvasive imaging modality well suited to imaging living wound tissue, its use has been limited by time-intensive user segmentation. The use of CNNs for automated image segmentation demonstrate that it is possible for MPM to deliver near real-time quantitative readouts of tissue structure and function. Lasers Surg. Med. © 2021 Wiley Periodicals LLC.

Lupus miliaris disseminatus faciei with complete response to isotretinoin.

Lupus miliaris disseminatus faciei is an uncommon type of granulomatous rosacea characterized by a papular eruption in the central regions of the face. A 43-year-old woman presented with an asymptomatic papular eruption on the face that had developed over a period of five months. Physical examination revealed multiple, small, reddish-brown papules, distributed symmetrically on the central area of the face. A biopsy was taken, showing dermal epithelioid cell granulomas with central necrosis and surrounding lymphocytic infiltrate with multinucleate giant cells. No foreign bodies were found in granulomas and no mycobacterial or fungal components were detected. On the basis of these findings, the diagnosis of lupus miliaris disseminatus faciei was made. The patient was given oral isotretinoin 20mg/day with initial slow response. After 6 months' treatment the lesions completely disappeared. Many authors consider this entity to be a variant of granulomatous rosacea. It is a chronic condition that primarily affects young adults. Treatment is usually unsatisfactory. Therapies with corticosterois, tetracyclines, retinoids, clofazimine or topical tacrolimus have been described but there is a lack of controlled studies and convincing results. Our success with a 6-month course of low dose isotretinoin suggests consideration of a longer trial prior to abandoning this as treatment.

The effect of chiral N-substituents with methyl or trifluoromethyl groups on the catalytic performance of mono- and bifunctional thioureas.

We evaluated thiourea organocatalysts that incorporate a chiral group which includes a trifluoromethyl moiety and contrasted their performance with non-fluorinated analogs. The comparison between such systems allows the direct study of the NH acidity of a thiourea bonded to an aliphatic substituent. In principle, -CF3 systems feature an enhanced hydrogen bond (HB) donor capacity that is undoubtedly beneficial for HB-catalysis applied to the Baylis-Hillman reaction. We found that the thiourea substituted on both nitrogens with this group accelerates this reaction like Schreiner's thiourea. On the other hand, we observed a different behavior in reactions promoted by bifunctional catalysts (thiourea-primary amine). In the Michael addition of isobutyraldehyde to methyl benzylidenepyruvate, the -CF3 containing catalysts were better than the -CH3 systems, whereas the conjugate addition to N-phenylmaleimide showed the opposite behavior. Theoretical calculations of the transition states indicated that the phenylethyl group in fluorinated and non-fluorinated compounds have different kinds of interactions with the electrophile. These interactions are responsible for a different arrangement of the electrophile and thereby the selectivity of the catalyst. Therefore, it cannot be generalized that in all cases NH acidity correlates with the performance of the catalyst, particularly, with aliphatic substituents that unlike the aromatic ones possess groups that are outside the plane of the thiourea.

Thousand-fold Conductivity Increase in 2D Perovskites by Polydiacetylene Incorporation and Doping.

Two-dimensional (2D) organic-inorganic perovskites have rapidly become an attractive alternative to traditional three-dimensional (3D) perovskite solar-cell absorbers owing to their improved stability and processability. Despite their advantages, the insulating nature of the organic cations and diminished light absorption limit their overall performance. Herein, it is demonstrated that the incorporation of conjugated diynes in hybrid 2D perovskites, and subsequent thermal treatment results in the formation of 2D perovskites that incorporate polydiacetylenes in their structure. Furthermore, it is shown that oxygen or iodine doping results in the formation of stable radicals within the material alongside a drastic shift of the band gap from 3.0 to 1.4 eV and in-plane conductivity improvements of up to three orders of magnitude, which lead to record conductivities for 2D halide perovskites (n=1).

Hydrogen-Bond Weakening through π Systems: Resonance-Impaired Hydrogen Bonds (RIHB).

Redefining interactions: The concept of the resonance-impaired hydrogen bond (RIHB) as an interaction in which a conjugated π system strongly impairs the formation of a hydrogen bond (HB) is introduced. A typical HB involving charged species can have a formation energy of tens of kcal mol-1 , whereas the corresponding value for the examined RIHB is only 2.6 kcal mol-1 . Quantum chemical topology tools are used to analyse the low formation energy of the studied RIHBs.

Stereocontrolled Nucleophilic Addition to Five-Membered Oxocarbenium Ions Directed by the Protecting Groups. Application to the Total Synthesis of (+)-Varitriol and of Two Diastereoisomers Thereof.

A stereodivergent C-glycosidation of carbohydrate-derived lactones can be mediated by the protecting groups and applied to the total synthesis of (+)-varitriol and of two diastereoisomers thereof, which represent an unprecedent use of the protecting groups in the synthesis of a naturally occurring compound. In particular, the stereoselective nucleophile attack for 2,3-trans-substituted five-membered ring oxocarbenium ions is strongly influenced by the presence of aromatic rings in the protecting groups. According to quantum chemical calculations, the stereoselectvity depends on the π-π interactions between the aromatic ring of the C-2 protecting group with the exocyclic triple bond and the oxocarbenium ion. These interactions account for the stabilization of the conformer in which the C-2 and C-3 substituents adopt pseudoaxial orientations. When protecting groups do not contain an aromatic ring, the sterochemical outcome is dictated by stereoelectronic factors established by the Woerpel's model. Based on these findings, a concise total synthesis of the natural product (+)-varitriol and of two diastereoisomers was acomplished.

Stereodivergent Mannich reaction of bis(trimethylsilyl)ketene acetals with N-tert-butanesulfinyl imines by Lewis acid or Lewis base activation, a one-pot protocol to obtain chiral ß-amino acids.

We report a one-pot synthesis of chiral ß2,2,3-amino acids by the Mannich addition of bistrimethylsilyl ketene acetals to N-tert-butanesulfinyl imines followed by the removal of the chiral auxiliary. The synthesis and isolation of pure ß-amino acid hydrochlorides were conducted under mild conditions, without strong bases and this method is operationally simple. The stereoselective reaction was promoted by two different activation methods that lead to different stereoisomers: (1) Lewis Acid (LA) catalysis with boron trifluoride diethyl etherate and (2) Lewis Base (LB) catalysis with tetrabutylammonium difluorotriphenylsilicate. The reaction presented good diastereoselectivity with LB activation and moderate to good dr with LA catalysis. The exceptions in both protocols were imines with electron donating groups in the aromatic ring.

Bifunctional Thioureas with α-Trifluoromethyl or Methyl Groups: Comparison of Catalytic Performance in Michael Additions.

Thioureas are an important scaffold in organocatalysis because of their ability to form hydrogen bonds that activate substrates and fix them in a defined position, which allows a given reaction to occur. Structures that enhance the acidity of the thiourea are usually used to increase the hydrogen-bonding properties, such as 3,5-bis(trifluoromethyl)phenyl and boronate ureas. Herein, we report the synthesis of bifunctional thioureas with a chiral moiety that include either a trifluoromethyl or methyl group. Their catalytic performance in representative Michael addition reactions was used in an effort to compare the electronic effects of the fluorination at the methyl group. The observed differences concerning yields and ee values cannot be attributed solely to the different steric environments; theoretical results indicate distinct interactions within the corresponding transition states. The calculated transition states show that the fluorinated catalysts have stronger N-H···O and C-H···F hydrogen bonds, while the nonfluorinated systems have C-H···π contacts. These results have shown that a variety of hydrogen-bonding interactions are important in determining the yield and selectivity of thiourea organocatalysis. These details can be further exploited in catalyst design.

Safety and outcomes of decompressive craniectomy after intravenous tissue plasminogen activator administration for malignant cerebral infarction.

OBJECTIVE: The aim of this study was to evaluate the safety and outcomes of decompressive craniectomy (DC) after intravenous tissue plasminogen activator (IV tPA) administration for malignant cerebral infarction. METHODS: We retrospectively reviewed patients who underwent DC for malignant cerebral infarction. We compared fourteen patients who underwent DC after IV tPA administration with another nine patients who underwent DC without prior IV tPA administration. RESULTS: Twenty-three patients underwent DC for malignant hemispheric cerebral infarction in our hospital for five years. Fibrinolysis was performed prior to the DC in fourteen patients (60,9%). The patients characteristics did not differ between the DC patients with and without prior IV tPA administration. The complications that developed after DC were similar in both groups: in patients who underwent DC after IV tPA administration, 9 (64.3%) developed haemorrhagic transformation and 6 (42.9%) developed hydrocephalus. The functional outcome, as the 6-month GOS, was similar in both groups (p = 0.762). ICU mortality (p = 0.329) and hospital mortality after ICU (p= 0.634) were also similar between the two groups. CONCLUSION: Although the main limitation is that the number of patients in our serie was small, which reduced the statistical power, our study suggest that DC after failure of IV tPA administration for malignant cerebral infarction is safe and did not cause an excess of complications arising from the use of fibrinolytic.