Modern organic chemistry is a titan supporting and reinforcing pharmaceutical, agricultural, food and material science products. Over the past decades, the organic compounds market has been evolving ...to meet all the research demands. In this regard, medicinal chemistry is especially dependent on available chemical space as subtle tuning of the molecule structure is required to create a drug with relevant physicochemical properties and a remarkable activity profile. The recent rapid evolution of synthetic methodology to deploy fluorine has brought fluorinated compounds to the spotlight of MedChem community. And now unique properties of fluorine still keep fascinating more and more as its justified installation into a molecular framework has a beneficial impact on membrane permeability, lipophilicity, metabolic stability, pharmacokinetic properties, conformation, pKa, etc. The backward influence of medicinal chemistry on organic synthesis has also changed the landscape of the latter towards new fluorinated topologies as well. Such complex relationships create a flexible and ever‐changing ecosystem. Given that MedChem investigations strongly lean on the ability to reach suitable building blocks and the existence of reliable synthetic methods in this review we collected advances in the chemistry of respectful, but still enigmatic gem‐difluorinated aza‐heterocyclic building blocks.
Despite a long and fruitful history of fluorinated motifs in MedChem research, saturated scaffolds with CF2 group are still mysterious. Recently, the state of art has given a fresh impetus to investigations within aliphatic and alicyclic series. Meanwhile, nitrogen‐containing heterocycles with CF2 moiety being ubiquitous instruments in drug discovery process remain overlooked with no comprehensive understanding of even reachable chemical space. By means of this review we are willing to change such a disappointing status quo and compiled information concerning synthetic approaches, applications, peculiarities, drawbacks, advantages, and existing gaps within saturated aza‐heterocycles featuring in‐ring gem‐di‐F fragment.
Modern organic chemistry is a titan supporting and reinforcing pharmaceutical, agricultural, food and material science products. Over the past decades, the organic compounds market has been evolving ...to meet all the research demands. In this regard, medicinal chemistry is especially dependent on available chemical space as subtle tuning of the molecule structure is required to create a drug with relevant physicochemical properties and a remarkable activity profile. The recent rapid evolution of synthetic methodology to deploy fluorine has brought fluorinated compounds to the spotlight of MedChem community. And now unique properties of fluorine still keep fascinating more and more as its justified installation into a molecular framework has a beneficial impact on membrane permeability, lipophilicity, metabolic stability, pharmacokinetic properties, conformation, pK
, etc. The backward influence of medicinal chemistry on organic synthesis has also changed the landscape of the latter towards new fluorinated topologies as well. Such complex relationships create a flexible and ever-changing ecosystem. Given that MedChem investigations strongly lean on the ability to reach suitable building blocks and the existence of reliable synthetic methods in this review we collected advances in the chemistry of respectful, but still enigmatic gem-difluorinated aza-heterocyclic building blocks.
SETTING: Mawenzi Regional Hospital, northern Tanzania.OBJECTIVE: To determine the value of light-emitting diode (LED) microscopy in diagnosing tuberculosis (TB) on bleach-treated and direct sputum ...smears.DESIGN: Sputum samples were collected from patients suspected of pulmonary
TB who presented consecutively at the laboratory for smear evaluation between December 2009 and February 2010. Four smears were prepared from each specimen: conventional Ziehl-Neelsen (ZN), direct auramine, bleach centrifugation and bleach short sedimentation auramine smears. A light microscope
was used to examine ZN smears and an LED fluorescent microscope to examine auramine-stained smears.RESULTS: Of the 267 sputum samples examined, respectively 78 (29%), 62 (23%), 74 (28%) and 48 (18%) were acid-fast bacilli (AFB) positive by the bleach centrifugation, bleach short sedimentation,
direct auramine and ZN methods. Bleach centrifugation identified 30 (11%) more positives than ZN microscopy (P < 0.001), but was not superior to the direct auramine method (P = 0.46), which yielded 26 (10%) more positives than ZN microscopy (P < 0.001). Fluorescent
LED required a shorter smear reading time (1.5 min on average), while the light microscope took 4 min (P < 0.001).CONCLUSION: Fluorescent LED microscopy with direct smear preparation is rapid and effective. Further studies are needed to ascertain its performance under routine
conditions.
Data on survival and prognosis factors in incident cohorts are scarce in systemic sclerosis (SStc). To describe survival, standardized mortality ratio (SMR), and prognosis factors in systemic ...sclerosis (SSc), we analyzed a multicenter French cohort of incident patients and performed a systematic review of the literature and meta-analysis.
A multicenter, French cohort study was conducted between January 1, 2000, and December 31, 2013. Patients were followed-up until July 1, 2016. A systematic review of the literature was carried out in MEDLINE and EMBASE up to July 2017. Meta-analysis was performed using all available data on SMR and hazard ratios of prognosis factors.
A total of 625 patients (493 females, 446 lcSSc) were included. During the study period, 104 deaths (16.6%) were recorded and 133 patients were lost to follow-up. Overall survival rates at 1, 3, 5, and 10 years from diagnosis were 98.0%, 92.5%, 85.9%, and 71.7% respectively in the French cohort. Overall SMR was 5.73 (95% CI 4.68-6.94). Age at diagnosis > 60 years, diffuse cutaneous SSc, scleroderma renal crisis, dyspnea, 6-min walking distance (6MWD), forced vital capacity < 70%, diffusing capacity of the lungs for carbon monoxide < 70%, pulmonary hypertension (PH), telangiectasia, valvular disease, malignancy, anemia, and CRP > 8 mg/l were associated with a poorer survival after adjustment. Eighteen studies (11,719 patients) were included in the SMR meta-analysis and 36 studies (26,187 patients) in the prognosis factor analysis. Pooled SMR was 3.45 (95%CI 3.03-3.94). Age at disease onset, male sex, African origin, diffuse cutaneous SSc, anti-Scl70 antibodies, cardiac and renal involvement, interstitial lung disease, PH, and malignancy were significantly associated with a worse prognosis. Anti-centromere antibodies were associated with a better survival.
Overall, our study highlights a high mortality rate in SSc patients and confirms previously described prognosis factors related to skin extension and organ involvement while identifying additional prognosis factors such as autoantibody status, telangiectasia, 6MWD, and valvular disease.
Functional differences in the anterior and posterior hippocampus during episodic memory processing have not been examined in human electrophysiological data. This is in spite of strong evidence for ...such differences in rodent data, including greater place cell specificity in the dorsal hippocampus, greater sensitivity to the aversive or motivational content of memories in ventral regions, connectivity analyses identifying preferential ventral hippocampal connections with the amygdala, and gene expression analyses identifying a dorsal–ventral gradient. We asked if memory‐related oscillatory patterns observed in human hippocampal recordings, including the gamma band and slow‐theta (2.5–5 Hz) subsequent memory effects, would exhibit differences along the longitudinal axis and between hemispheres. We took advantage of a new dataset of stereo electroencephalography patients with simultaneous, robotically targeted anterior, and posterior hippocampal electrodes to directly compare oscillatory subsequent memory effects during item encoding. This same data set allowed us to examine left–right connectivity and hemispheric differences in hippocampal oscillatory patterns. Our data suggest that a power increase during successful item encoding in the 2.5–5 Hz slow‐theta frequency range preferentially occurs in the posterior hippocampus during the first 1,000 ms after item presentation, while a gamma band power increase is stronger in the dominant hemisphere. This dominant–nondominant pattern in the gamma range appears to reverse during item retrieval, however. Intrahippocampal phase coherence was found to be stronger during successful item encoding. Our phase coherence data are also consistent with existing reports of a traveling wave for theta oscillations propagating along the septotemporal (longitudinal) axis of the human hippocampus. We examine how our findings fit with theories of functional specialization along the hippocampal axis.
Models of memory formation posit that episodic memory formation depends critically on the hippocampus, which binds features of an event to its context. For this reason, the contrast between study ...items that are later recollected with their associative pair versus those for which no association is made fails should reveal electrophysiological patterns in the hippocampus selectively involved in associative memory encoding. Extensive data from studies in rodents support a model in which theta oscillations fulfill this role, but results in humans have not been as clear. Here, we used an associative recognition memory procedure to identify hippocampal correlates of successful associative memory encoding and retrieval in patients (10 females and 9 males) undergoing intracranial EEG monitoring. We identified a dissociation between 2-5 Hz and 5-9 Hz theta oscillations, by which power increases in 2-5 Hz oscillations were uniquely linked with successful associative memory in both the anterior and posterior hippocampus. These oscillations exhibited a significant phase reset that also predicted successful associative encoding and distinguished recollected from nonrecollected items at retrieval, as well as contributing to relatively greater reinstatement of encoding-related patterns for recollected versus nonrecollected items. Our results provide direct electrophysiological evidence that 2-5 Hz hippocampal theta oscillations preferentially support the formation of associative memories, although we also observed memory-related effects in the 5-9 Hz frequency range using measures such as phase reset and reinstatement of oscillatory activity.
Models of episodic memory encoding predict that theta oscillations support the formation of interitem associations. We used an associative recognition task designed to elicit strong hippocampal activation to test this prediction in human neurosurgical patients implanted with intracranial electrodes. The findings suggest that 2-5 Hz theta oscillatory power and phase reset in the hippocampus are selectively associated with associative memory judgments. Furthermore, reinstatement of oscillatory patterns in the hippocampus was stronger for successful recollection. Collectively, the findings support a role for hippocampal theta oscillations in human associative memory.
Several randomised controlled studies and a previous meta-analysis have reported conflicting results regarding the effect of combined targeted therapy compared with monotherapy for pulmonary arterial ...hypertension (PAH). We did a systematic review and meta-analysis to assess the effects of a combination of PAH-specific therapies compared with monotherapy on predefined clinical worsening in PAH.
We searched MEDLINE, Embase, and the Cochrane Library for reports published from Jan 1, 1990, to May 31, 2015, of prospective randomised controlled trials of at least 12 weeks that assessed a combination of PAH-specific therapies (upfront and sequential add-on) compared with background PAH-specific monotherapy in patients older than 12 years. We extracted data from the reports, and assessed the primary outcome of risk of clinical worsening, as defined a priori in each trial, using the Mantel-Haenszel method based on a fixed-effects model.
Of 2017 studies that we identified from our search, we included 17 (4095 patients) in our analysis. 15 studies assessed clinical worsening and were included in the primary analysis. Combined therapy was associated with significant risk reduction for clinical worsening compared with monotherapy (combined therapy 17% 332 of 1940 patients vs monotherapy 28% 517 of 1862 patients, risk ratio RR 0·65 95% CI 0·58-0·72, p<0·00001). We noted no heterogeneity between the studies (I(2)=18%, phomogeneity=0·25). A publication bias was suggested by the results of an Egger test (t=-2·3982, p=0·031), but when we excluded the four studies with the highest SEs, the RR for clinical worsening was identical (0·65 95% CI 0·58-0·73, p<0·00001).
In our analysis, combined therapy for PAH was associated with a significant reduction in clinical worsening compared with monotherapy. However, our study was limited by the variable definition of clinical worsening among the trials and possible publication bias. Because many patients still had clinical worsening with combination therapy, identification of innovative therapeutic targets for PAH is thus urgently needed.
None.
Since echinocandins are recommended as first line therapy for invasive candidiasis, detection of resistance, mainly due to alteration in FKS protein, is of main interest. EUCAST AFST recommends ...testing both MIC of anidulafungin and micafungin, and breakpoints (BPs) have been proposed to detect echinocandin-resistant isolates. We analyzed MIC distribution for all three available echinocandins of 2,787 clinical yeast isolates corresponding to 5 common and 16 rare yeast species, using the standardized EUCAST method for anidulafungin and modified for caspofungin and micafungin (AM3-MIC). In our database, 64 isolates of common pathogenic species were resistant to anidulafungin, according to the EUCAST BP, and/or to caspofungin, using our previously published threshold (AM3-MIC ≥ 0.5 mg/L). Among these 64 isolates, 50 exhibited 21 different FKS mutations. We analyzed the capacity of caspofungin AM3-MIC and anidulafungin MIC determination in detecting isolates with FKS mutation. They were always identified using caspofungin AM3-MIC and the local threshold while some isolates were misclassified using anidulafungin MIC and EUCAST threshold. However, both methods misclassified four wild-type C. glabrata as resistant. Based on a large data set from a single center, the use of AM3-MIC testing for caspofungin looks promising in identifying non-wild-type C. albicans, C. tropicalis and P. kudiravzevii isolates, but additional multicenter comparison is mandatory to conclude on the possible superiority of AM3-MIC testing compared to the EUCAST method.
Memory failures are frustrating and often the result of ineffective encoding. One approach to improving memory outcomes is through direct modulation of brain activity with electrical stimulation. ...Previous efforts, however, have reported inconsistent effects when using open-loop stimulation and often target the hippocampus and medial temporal lobes. Here we use a closed-loop system to monitor and decode neural activity from direct brain recordings in humans. We apply targeted stimulation to lateral temporal cortex and report that this stimulation rescues periods of poor memory encoding. This system also improves later recall, revealing that the lateral temporal cortex is a reliable target for memory enhancement. Taken together, our results suggest that such systems may provide a therapeutic approach for treating memory dysfunction.
The observed wide eccentricity distribution of extrasolar giant planets is thought to be the result of dynamical instabilities and gravitational scattering among planets. Previously, it has been ...assumed that the orbits in giant planet systems become gravitationally unstable after the gas nebula dispersal. It was not well understood, however, how these unstable conditions were established in the first place.
In this work, we numerically simulate the evolution of systems of three planets as the planets sequentially grow to Jupiter's mass, and dynamically interact among themselves and with the gas disk. We use the hydrodynamical code fargo that we modified by implementing the N-body integrator symba. The new code can handle close encounters and collisions between planets. To test their stability, the planetary systems were followed with symba for up to 108 yr after the gas disc dispersal.
We find that dynamics of the growing planets is complex, because migration and resonances raise their orbital eccentricities, and cause dynamical instabilities when gas is still around. If the dynamical instabilities occur early, planets can be removed by collisions and ejections, and the system rearranges into a new, more stable configuration. In this case, the planetary systems emerging from the gas discs are expected to be stable, and would need to be destabilized by other means (low-mass planets, planetesimal discs, etc.). Alternatively, for the giant planet system to be intrinsically unstable upon the gas disc dispersal, a special timing would be required with the growth of (at least some of) the giant planets having to occur near the end of the gas disc lifetime.
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