N-Methylation of Amines with Methanol Catalyzed by Iridium(I) Complexes Bearing an N, O-Functionalized NHC Ligand

A set of neutral IrBr(L-2)-(kappa C-(t)BuImCH(2)PyCH(2)OMe)] and cationic Ir(L-2)-(kappa C, N-tBuImCH(2)PyCH(2)OMe)]PF6 (L-2 = cod, (CO)(2)) Ir(I) compounds featuring a flexible lutidine-derived polydentate ligand having NHC and - OMe as donor functions have been evaluated as catalyst precursors for the N-methylation of aniline using methanol both as a reducing agent and a C1 source. The carbonyl complexes are somewhat more active than the related diene compounds with the neutral compound IrBr(CO)(2)(kappa C-(t)BuImCH(2)PyCH(2)OMe)] being the more active. A range of aromatic primary amines, including heterocyclic amines, have been selectively transformed into the corresponding N-methylamino derivatives using this catalyst at a low catalyst loading (0.1 mol %) and substoichiometric amounts of Cs2CO3 (half equiv) as a base, in methanol at 423 K. For aliphatic primary amines, selective N, N-dimethylation was achieved under the same catalytic conditions. The unselective deprotonation of the methylene linkers in IrBr(CO)(2)(kappa C-(t)BuImCH(2)PyCH(2)OMe)] affords two isomeric neutral complexes featuring a coordinated dearomatized pyridine core, which were converted into Ir(OMe)(CO)(2)(kappa C-(t)BuImCH(2)PyCH(2)OMe)] upon addition of methanol. This compound undergoes thermal activation of a C-H bond of the tert-butyl group to give the cyclometalated iridium(I) complex Ir(CO)(2){kappa C-2, C-(-CH2Me2C-ImCH(2)PyCH(2)OMe)}] featuring a bidentate C, C-coordinated NHC ligand. Mechanistic investigations support a borrowing hydrogen mechanism proceeding through iridium(I) intermediates with the methoxo complex as the catalytic active species and the cyclometalated complex as the catalyst resting state. Deuterium labeling experiments have demonstrated that both species are in equilibrium under catalytic conditions, which is consistent with the exhibited catalytic activity of the cyclometalated complex

Headache yesterday in Europe

BACKGROUND: Surveys enquiring about burden of headache over a prior period of time (eg, 3 months) are subject to recall bias. To eliminate this as far as possible, we focused on presence and impact of headache on the preceding day (“headache yesterday”). METHODS: Adults (18-65 years) were surveyed from the general populations of Germany, Italy, Lithuania, Luxembourg and the Netherlands, from a work-force population in Spain and from mostly non-headache patient populations of Austria, France and UK. A study of non-responders in some countries allowed detection of potential participation bias where initial participation rates were low. RESULTS: Participation rates varied between 11% and 59% (mean 27%). Non-responder studies suggested that, because of participation bias, headache prevalence might be overestimated in initial responders by up to 2% (absolute). Across all countries, 1,422 of 8,271 participants (15-17%, depending on correction for participation bias) had headache yesterday lasting on average for 6 hours. It was bad or very bad in 56% of cases and caused absence from work or school in 6%. Among those who worked despite headache, 20% reported productivity reduced by >50%. Social activities were lost by 24%. Women (21%) were more likely than men (12%) to have headache yesterday, but impact was similar in the two genders. CONCLUSIONS: With recall biases avoided, our findings indicate that headache costs at least 0.7% of working capacity in Europe. This calculation takes into account that most of those who missed work could make up for this later, which, however, means that leisure and social activities are even more influenced by headache

Cluster headache attack remission with sphenopalatine ganglion stimulation:experiences in chronic cluster headache patients through 24 months

BACKGROUND: Cluster headache (CH) is a debilitating headache disorder with severe consequences for patient quality of life. On-demand neuromodulation targeting the sphenopalatine ganglion (SPG) is effective in treating the acute pain and a subgroup of patients experience a decreased frequency of CH attacks. METHODS: We monitored self-reported attack frequency, headache disability, and medication intake in 33 patients with medically refractory, chronic CH (CCH) in an open label follow-up study of the original Pathway CH-1 study. Patients were followed for at least 24 months (average 750 ± 34 days, range 699-847) after insertion of an SPG microstimulator. Remission periods (attack-free periods exceeding one month, per the ICHD 3 (beta) definition) occurring during the 24-month study period were characterized. Attack frequency, acute effectiveness, medication usage, and questionnaire data were collected at regular clinic visits. The time point “after remission” was defined as the first visit after the end of the remission period. RESULTS: Thirty percent (10/33) of enrolled patients experienced at least one period of complete attack remission. All remission periods followed the start of SPG stimulation, with the first period beginning 134 ± 86 (range 21-272) days after initiation of stimulation. On average, each patient’s longest remission period lasted 149 ± 97 (range 62-322) days. The ability to treat acute attacks before and after remission was similar (37 % ± 25 % before, 49 % ± 32 % after; p = 0.2188). Post-remission headache disability (HIT-6) was significantly improved versus baseline (67.7 ± 6.0 before, 55.2 ± 11.4 after; p = 0.0118). Six of the 10 remission patients experienced clinical improvements in their preventive medication use. At 24 months post insertion headache disability improvements remained and patient satisfaction measures were positive in 100 % (10/10). CONCLUSIONS: In this population of 33 refractory CCH patients, in addition to providing the ability to treat acute attacks, neuromodulation of the SPG induced periods of remission from cluster attacks in a subset of these. Some patients experiencing remission were also able to reduce or stop their preventive medication and remissions were accompanied by an improvement in headache disability

Recent therapeutic advances in urothelial carcinoma : A paradigm shift in disease management

Altres ajuts: Pfizer.Management of first-line advanced urothelial carcinoma (UC) has consisted during the past three decades in the administration of platinum-based chemotherapy followed by observation. Despite moderate to high response rates to first-line treatment, most patients will relapse shortly after and the outcomes with subsequent therapies are poor with 5-year overall survival rates of 5% in the pre-immunotherapy era. Nonetheless, recent therapeutic developments including the paradigm shift of first-line maintenance therapy with avelumab after response or stabilization on platinum-based chemotherapy, along with the incorporation of new drug classes in further lines of treatment such as antibody drug-conjugates and fibroblast growth factor receptor inhibitors have reshaped the field leading to better outcomes in this patient population. This article reviews the current state of the art with an overview on UC management, recent advances, and the upcoming strategies currently in development in advanced UC with an insight into the biology of this disease

¿Va a cambiar la neurología tras la pandemia de COVID-19 en los próximos 5 años?: estudio de enfoque mediante informadores clave

Review[Abstract] Introduction. The COVID-19 pandemic will give rise to long-term changes in neurological care, which are not easily predictable. Material and methods. A key informant survey was used to enquire about the changes expected in the specialty over the next 5 years. The survey was completed by heads of neurology departments with broad knowledge of the situation, having been active during the pandemic. Results. Despite a low level of consensus between participants, there was strong (85%) and moderate consensus (70%) about certain subjects, mainly the increase in precautions to be taken, the use of telemedicine and teleconsultations, the reduction of care provided in in-person consultations to avoid the presence of large numbers of people in waiting rooms, the development of remote training solutions, and the changes in monitoring visits during clinical trials. There was consensus that there would be no changes to the indication of complementary testing or neurological examination. Conclusion. The key informant survey identified the foreseeable changes in neurological care after the pandemic.[Resumen] Introducción. La pandemia de COVID-19 va a conllevar cambios en la asistencia neurológica, que no se pueden prever fácilmente a largo plazo. Material y métodos. A través de un modelo de informadores clave se busca el consenso de cómo va a ser la especialidad en un plazo de 5 años, siendo los encuestados jefes de servicio de neurología con conocimiento amplio de la situación al haber actuado durante la pandemia. Resultados. Aunque se obtiene un grado de acuerdo bajo entre los encuestados, sí se describen acuerdos por consenso a nivel mayor (85%) y menor (70%). Los principales acuerdos se refieren al incremento de precauciones, al uso de la telemedicina, al mantenimiento de las consultas telefónicas, a la reducción de asistencia a las consultas evitando que hayan salas de espera con un número alto de personas, al desarrollo de técnicas docentes no presenciales y a la adaptación en el desarrollo de ensayos clínicos en relación con la visita de los monitores. Sin embargo, no se acuerda que haya cambios en la indicación de exploraciones complementarias, ni en la propia exploración neurológica. Conclusión. El método de informadores clave ha permitido conocer qué cambios se pueden prever tras la pandemia

Prognostic significance of FLT3-ITD length in AML patients treated with intensive regimens

FLT3-ITD mutations are detected in approximately 25% of newly diagnosed adult acute myeloid leukemia (AML) patients and confer an adverse prognosis. The FLT3-ITD allelic ratio has clear prognostic value. Nevertheless, there are numerous manuscripts with contradictory results regarding the prognostic relevance of the length and insertion site (IS) of the FLT3-ITD fragment. We aimed to assess the prognostic impact of these variables on the complete remission (CR) rates, overall survival (OS) and relapse-free survival (RFS) of AML patients with FLT3-ITDmutations. We studied the FLT3-ITD length of 362 adult AML patients included in the PETHEMA AML registry. We tried to validate the thresholds of ITD length previously published (i.e., 39 bp and 70 bp) in intensively treated AML patients (n = 161). We also analyzed the mutational profile of 118 FLT3-ITD AML patients with an NGS panel of 39 genes and correlated mutational status with the length and IS of ITD. The AUC of the ROC curve of the ITD length for OS prediction was 0.504, and no differences were found when applying any of the thresholds for OS, RFS or CR rate. Only four out of 106 patients had ITD IS in the TKD1 domain. Our results, alongside previous publications, confirm that FLT3-ITD length lacks prognostic value and clinical applicability. © 2021, The Author(s)

New uses of the Migraine Screen Questionnaire (MS-Q): validation in the Primary Care setting and ability to detect hidden migraine. MS-Q in Primary Care

<p>Abstract</p> <p>Background</p> <p>PC plays an important role in early diagnosis of health disorders, particularly migraine, due to the financial impact of this disease for the society and its impact on patients' quality of life. The aim of the study was to validate the self-administered MS-Q questionnaire for detection of hidden migraine in the field of primary care (PC), and to explore its use in this setting.</p> <p>Methods</p> <p>Cross-sectional, observational, and multicentre study in subjects above 18 years of age patients attending PC centers (regardless of the reason for consultation). A MS-Q score ≥ 4 was considered possible migraine. Level of agreement with IHS criteria clinical diagnosis (kappa coefficient), and instrument's validity properties: sensitivity, specificity, positive (PPV) and negative (NPV) predictive values were determined. The ability of the instrument to identify possible new cases of migraine was calculated, as well as the ratio of hidden disease compared to the ratio obtained by IHS criteria.</p> <p>Results</p> <p>A total of 9,670 patients were included [48.9 ± 17.2 years (mean ± SD); 61.9% women], from 410 PC centers representative of the whole national territory. The clinical prevalence of migraine according to the IHS criteria was 24.7%, and 20.4% according to MS-Q: Kappa index of agreement 0.82 (p < 0.05). MS-Q sensitivity was 0.82 (95% CI, 0.81 - 0.84), specificity 0.97 (95% CI, 0.98 - 0.99), PPV 0.95 (95% CI, 0.94 - 0.96), and NPV 0.94 (95% CI, 0.93 - 0.95). No statistically significant differences were found in the percentages of patients with <it>de novo </it>and hidden migraine identified by MS-Q and by IHS criteria: 5.7% vs. 6.1% and 26.6% vs. 24.1%, respectively.</p> <p>Conclusions</p> <p>The results of the present study confirm the usefulness of the MS-Q questionnaire for the early detection and assessment of migraine in PC settings, and its ability to detect hidden migraine.</p

Joint Observation of the Galactic Center with MAGIC and CTA-LST-1

MAGIC is a system of two Imaging Atmospheric Cherenkov Telescopes (IACTs), designed to detect very-high-energy gamma rays, and is operating in stereoscopic mode since 2009 at the Observatorio del Roque de Los Muchachos in La Palma, Spain. In 2018, the prototype IACT of the Large-Sized Telescope (LST-1) for the Cherenkov Telescope Array, a next-generation ground-based gamma-ray observatory, was inaugurated at the same site, at a distance of approximately 100 meters from the MAGIC telescopes. Using joint observations between MAGIC and LST-1, we developed a dedicated analysis pipeline and established the threefold telescope system via software, achieving the highest sensitivity in the northern hemisphere. Based on this enhanced performance, MAGIC and LST-1 have been jointly and regularly observing the Galactic Center, a region of paramount importance and complexity for IACTs. In particular, the gamma-ray emission from the dynamical center of the Milky Way is under debate. Although previous measurements suggested that a supermassive black hole Sagittarius A* plays a primary role, its radiation mechanism remains unclear, mainly due to limited angular resolution and sensitivity. The enhanced sensitivity in our novel approach is thus expected to provide new insights into the question. We here present the current status of the data analysis for the Galactic Center joint MAGIC and LST-1 observations

Effective N-methylation of nitroarenes with methanol catalyzed by a functionalized NHC-based iridium catalyst: a green approach to N-methyl amines

Compound [IrBr(CO)2(κC-tBuImCH2PyCH2OMe)] featuring a flexible pyridine/OMe functionalized NHC ligand κ1C coordinated efficiently catalyzes the selective N-monomethylation of nitroarenes using methanol as both the reducing agent and the C1 source. A range of functionalized nitroarenes including heterocyclic or sterically hindered derivatives have been efficiently converted to the corresponding N-monomethyl amines in good yields at low catalyst loadings using sub-stoichiometric amounts of Cs2CO3 as a base. Mechanistic investigations support a borrowing-hydrogen mechanism in which methanol acts as the hydrogen source and methylating agent. Further, the hydrogen transfer reduction of nitrobenzene to aniline under optimized reaction conditions should proceed through a direct mechanism involving nitrosobenzene and N-phenylhydroxylamine intermediates.Financial support from the Ministerio de Ciencia e Innovación (MICINN/FEDER) under the Project CTQ2016-75884-P and the Regional Government of Aragón/FEDER 2014-2020 “Building Europe from Aragón” (group E42_17R) is gratefully acknowledged. M. G.-L. thanks MINECO for a predoctoral fellowship (BES-2014-069624).Peer reviewe