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Although the nucleophilic alkylation of aromatics has recently been achieved with a variety of potent main group reagents, all of this reactivity is limited to a stoichiometric regime. We now report that the ytterbium(II) hydride, [BDI Dipp YbH] 2 (BDI Dipp  = CH[C(CH 3 )NDipp] 2 , Dipp = 2,6-diisopropylphenyl), reacts with ethene and propene to provide the ytterbium(II) n- alkyls, [BDI Dipp YbR] 2 (R = Et or Pr), both of which alkylate benzene at room temperature. Density functional theory (DFT) calculations indicate that this latter process operates through the nucleophilic (S N 2) displacement of hydride, while the resultant regeneration of [BDI Dipp YbH] 2 facilitates further reaction with ethene or propene and enables the direct catalytic (anti-Markovnikov) hydroarylation of both alkenes with a benzene C-H bond. Nucleophilic alkylation of aromatics with main group reagents was achieved, but it is limited to a stoichiometric regime. Here, the authors report that the ytterbium(II) hydride reacts with ethene and propene to afford ytterbium(II) n-alkyls, both of which can facilitate the catalytic alkylation of benzene at room temperature via an S N 2 mechanism.

Bile acid receptors have been identified as important targets for the development of new therapeutics to treat various metabolic and inflammatory diseases. The synthesis of new bile acid analogues can help elucidate structure–activity relationships and define compounds that activate these receptors selectively. Towards this, access to large quantities of a chenodeoxycholic acid derivative bearing a C-12 methyl and a C-13 to C-14 double bond provided an interesting scaffold to investigate the chemical manipulation of the C/D ring junction in bile acids. The reactivity of this alkene substrate with various zinc carbenoid species showed that those generated using the Furukawa methodology achieved selective α-cyclopropanation, whereas those generated using the Shi methodology reacted in an unexpected manner giving rise to a rearranged skeleton whereby the C ring has undergone contraction to form a novel spiro–furan ring system. Further derivatization of the cyclopropanated steroid included O-7 oxidation and epimerization to afford new bile acid derivatives for biological evaluation.

Parkinson’s Disease is the most common neurodegenerative movement disorder globally, with prevalence increasing. There is an urgent need for new therapeutics which are disease-modifying rather than symptomatic. Mitochondrial dysfunction is a well-documented mechanism in both sporadic and familial Parkinson’s Disease. Furthermore, ursodeoxycholic acid (UDCA) has been identified as a bile acid which leads to increased mitochondrial function in multiple in vitro and in vivo models of Parkinson’s Disease. Here, we describe the synthesis of novel C-nor-D-homo bile acid derivatives and the 12-hydroxy-methylated derivative of lagocholic acid (7) and their biological evaluation in fibroblasts from patients with either sporadic or LRRK2 mutant Parkinson’s Disease. These compounds boost mitochondrial function to a similar level or above that of UDCA in many assays; notable, however, is their ability to boost mitochondrial function to a higher level and at lower concentrations than UDCA specifically in the fibroblasts from LRRK2 patients. Our study indicates that novel bile acid chemistry could lead to the development of more efficacious bile acids which increase mitochondrial function and ultimately cellular health at lower concentrations proving attractive potential novel therapeutics for Parkinson’s Disease.

ObjectiveWe aimed to compare the severity of coronary artery abnormalities in Kawasaki disease between infants and older children.MethodsWe retrospectively reviewed and compared coronary artery dilation and aneurysm severity in infants <1 year of age with Kawasaki disease at our centre over a 10-year period with that observed in children ≥1 year of age in the Pediatric Heart Network Trial of Pulse Steroid Therapy in Kawasaki Disease. Coronary artery abnormalities were defined by z-scores according to American Heart Association guidelines.ResultsOf the 93 infants identified during the study period, 80 were treated with intravenous gamma globulin within the first 10 days of illness and were included for comparison to 170 children ≥1 year of age treated in the same time frame from the Pediatric Heart Network public database. The mean maximum z-score was significantly higher in infants compared with older children (3.37 vs 2.07, p<0.001). A higher incidence of medium and giant aneurysms was observed in infants compared with children ≥1 year of age (11% vs 3% for medium aneurysms, p=0.015; 8% vs <1% for giant aneurysms, p=0.005).ConclusionsInfants with Kawasaki disease have more severe coronary artery dilation compared with older children, and a higher prevalence of medium and giant aneurysms. Because adverse outcomes are closely linked to the maximal coronary artery diameter in Kawasaki disease, patients diagnosed as infants require very close long-term monitoring for cardiac complications.

Benzene reduction by molecular complexes remains an important synthetic challenge, requiring harsh reaction conditions involving group I metals. Reductions of benzene, to date, typically result in a loss of aromaticity, although the benzene tetra-anion, a 10π-electron system, has been calculated to be stable and aromatic. Due to the lack of sufficiently potent reductants, four-electron reduction of benzene usually requires the use of group I metals. Here we demonstrate the four-electron reduction of benzene and some of its derivatives using a samarium( ii ) alkyl reagent, with no requirement for group I metals. Whereas organosamarium( ii ) typically reacts through one-electron processes, the compounds reported here feature a rare two-electron process. Combined experimental and computational results implicate a transient samarium( i ) intermediate involved in this reduction process, which ultimately provides the benzene tetra-anion. The remarkably strong reducing power of this samarium( ii ) alkyl implies a rich reactivity, providing scope for its application as a reducing agent. Benzene reduction by molecular complexes remains a considerable synthetic challenge, and typically requires harsh reaction conditions involving group I metals. Now it has been shown that a highly polar organometallic samarium alkyl complex enables the reduction of benzene to its tetra-anion without the need for a group I metal.

We consider estimating the marginal likelihood in settings with independent and identically distributed (i.i.d.) data. We propose estimating the predictive distributions in a sequential factorization of the marginal likelihood in such settings by using stochastic gradient Markov Chain Monte Carlo techniques. This approach is far more efficient than traditional marginal likelihood estimation techniques such as nested sampling and annealed importance sampling due to its use of mini-batches to approximate the likelihood. Stability of the estimates is provided by an adaptive annealing schedule. The resulting stochastic gradient annealed importance sampling (SGAIS) technique, which is the key contribution of our paper, enables us to estimate the marginal likelihood of a number of models considerably faster than traditional approaches, with no noticeable loss of accuracy. An important benefit of our approach is that the marginal likelihood is calculated in an online fashion as data becomes available, allowing the estimates to be used for applications such as online weighted model combination.

Background: Anecdotal report suggests that provocation of pain during epidural steroid injection (ESI) that is concordant with typical radicular symptoms predicts pain outcome following injection. However, limited evidence exists that substantiates this theory. Additionally, there is a paucity of literature investigating factors associated with the provocation of pain during ESI. Objectives: The goal of this study was to determine whether provocation of concordant radicular pain during transforaminal ESI predicts pain relief immediately after injection and at short-term follow-up. Demographic, radiologic, and procedural factors associated with the pain provocation and pain outcomes at immediate and short-term follow-up were also investigated. Study Design: Longitudinal cohort study. Setting: Urban academic outpatient interventional spine clinics. Methods: Adults who underwent a fluoroscopically guided transforaminal ESI without sedation between January 1, 2006, and October 29, 2007, for the treatment of lumbosacral radicular pain were included in this study. The relationships between provocation of concordant pain, immediate post-injection, and follow-up visual analogue scale (VAS) pain scores, as well as with demographic, radiologic, and procedural factors were determined using chi-square/Fisher’s exact tests for categorical variables and t-tests or ANOVA for numerical variables. Results: One thousand twenty one patients, 42.4% (433) male/57.6% (588) female, with a mean (SD) age of 54.1 (16.7) years were included in the study. Concordant pain provocation did not predict the magnitude of pain reduction (P = 0.9255) or the frequency of achieving > 50% pain relief (P = 0.7449) at short-term follow-up. Radiologic evidence of foraminal stenosis or nerve root impingement (P < 0.0001) and the lack of a medial-superior contrast flow pattern (P = 0.0199) were associated with a greater frequency of pain provocation during transforaminal ESI. Limitations: This study is primarily limited by possible selection bias given that patients who did not follow-up in the clinic could not be studied, and an incomplete follow-up rate (66%). Conclusions regarding subacute and long-term pain outcomes cannot be determined from this study as only short-term data were available. Conclusions: Provocation of concordant radicular pain does not predict pain relief at short-term follow-up after a transforaminal ESI. Foraminal stenosis, nerve root impingement, and lack of a medial-superior contrast flow pattern are associated with pain during the transforaminal ESI. Thus, clinicians should be aware of these radiologic and procedural risk factors for inciting pain during transforaminal ESI. Key words: Epidural steroid injection, lumbar, radicular pain, outcomes, prognostic

Objectives Measles was endemic in England during the early 1800s; however, it did not arrive in Australia until 1850 whereas other infectious diseases were known to have arrived much earlier—many with the First Fleet in 1788—leading to the question of why there was a difference. Design Ships surgeons’ logbooks from historical archives, 1829–1882, were retrospectively reviewed for measles outbreak data. Infectious disease modelling techniques were applied to determine whether ships would reach Australia with infectious measles cases. Setting Historical ship surgeon logbooks of measles outbreaks occurring on journeys from Britain to Australia were examined to provide new insights into measles epidemiology. Primary and secondary outcome measures Serial intervals and basic reproduction numbers (R0), immunity, outbreak generations, age-distribution, within-family transmission and outbreak lengths for measles within these closed cohorts. Results Five measles outbreaks were identified (163 cases). The mean serial interval (101 cases) was 12.3 days (95% CI 12.1 to 12.5). Measles R0 (95 cases) ranged from 7.7–10.9. Immunity to measles was lowest among children ≤10 years old (range 37–42%), whereas 94–97% of adults appeared immune. Outbreaks ranged from 4–6 generations and, before 1850, were 41 and 38 days in duration. Two outbreaks after 1850 lasted longer than 70 days and one lasted 32 days. Conclusions Measles syndrome reporting in a ship surgeon's logs provided remarkable detail on prevaccination measles epidemiology in the closed environment of ship voyages. This study found lower measles R0 and a shorter mean clinical serial interval than is generally reported. Archival ship surgeon log books indicate it was unlikely that measles was introduced into Australia before 1850, owing to high levels of pre-existing immunity in ship passengers, low numbers of travelling children and the journey's length from England to Australia.

A new potentially octadentate N 2 O 6 Schiff base ligand, H 2 L derived from the condensation of 2,2′-(1,1′-binaphthyl-2,2′-diylbis(oxy))dianiline and o-vanillin, along with its copper(II) and zinc(II) complexes, is synthesized and has been characterized by elemental analyses, IR, UV–vis, 1 H and 13 C NMR spectra, as well as conductivity measurements. H 2 L forms mononuclear complexes of 1:1 (metal:ligand) stoichiometry with Cu(II) and Zn(II), and conductivity data confirm the non-electrolyte nature of these complexes. The [ZnL] and [CuL] complexes display very different solid-state structures, as determined by X-ray crystallography. While the [ZnL] complex has a distorted octahedral geometry about the metal, the [CuL] complex displays a distorted square planar geometry about the copper, with long Cu–O(ether) distances of 2.667 Å.

A new potentially octadentate N2O^sub 6^ Schiff base ligand, H2L derived from the condensation of 2,2'-(1,1'-binaphthyl-2,2'-diylbis(oxy))dianiline and o-vanillin, along with its copper(II) and zinc(II) complexes, is synthesized and has been characterized by elemental analyses, IR, UV-vis, ^sup 1^H and ^sup 13^C NMR spectra, as well as conductivity measurements. H2L forms mononuclear complexes of 1:1 (metal:ligand) stoichiometry with Cu(II) and Zn(II), and conductivity data confirm the non-electrolyte nature of these complexes. The [ZnL] and [CuL] complexes display very different solid-state structures, as determined by X-ray crystallography. While the [ZnL] complex has a distorted octahedral geometry about the metal, the [CuL] complex displays a distorted square planar geometry about the copper, with long Cu-O(ether) distances of 2.667 .[PUBLICATION ABSTRACT]