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The Amaryllidaceae alkaloid (−)-galanthamine (1) is a reversible, competitive acetylcholinesterase inhibitor deployed clinically to treat the dementia associated with Alzheimer’s disease. Here, we describe a six-step synthesis of this natural product from simple, readily accessible starting materials. Enantioselective 1,2-reduction, Mitsunobu coupling, Heck cyclization and diastereoselective allylic oxidation reactions are used in our approach, which provides the shortest synthetic route to compound 1 reported to date. A simple modification to the closing stages of the sequence allows equally facile access to (−)-N-norgalanthamine (2), a compound with a range of distinctive biological properties. The concise and operationally simple synthetic protocols reported here could obviate the need to manipulate naturally sourced galanthamine in the pursuit of analogues required for pharmacological studies.

A formal total synthesis of (-)-aspidophytine (

The naturally abundant, enantiomerically pure cyclitol quinic acid has been converted into a synthetically useful enone in nearly quantitative yield using the operationally straightforward and reproducible protocols reported herein. The latter compound, which was obtained in multigram quantities, engages in a diastereoselective 1,2-addition reaction with a hydrazone-based nucleophile. Furthermore, a readily derived α-iodoenone participates in both cross-coupling and α,β-annulation reactions. The results reported here emphasize that the now practically accessible cyclohexenones are useful, enantiomerically pure building blocks for organic synthesis.

The morphinan alkaloid (–)-thebaine is an industrially important chemical intermediate deployed in the semi-synthesis of various opioid medicines. Here, a seven-step total synthesis of this natural product is reported from simple, commercially available starting materials. The pivotal aryl allyl ether substrate, which is obtained through successive Suzuki-Miyaura cross-coupling and Mitsunobu substitution reactions, was engaged in a double-Heck cyclization sequence. The tetracyclic product of these processes was subjected to a photochemical hydroamination reaction that generated a N-Boc piperidine derivative embodying the full pentacyclic morphinan framework. Over a further three simple steps, this last compound was converted into (–)-thebaine.

The readily prepared and vinylated β-carboline

Communication skills training can enhance health professionals’ knowledge and repertoire of effective communication practices. This paper describes the conceptual model underlying a 3-day retreat communication skills training program, methods used for training, and participant perception of outcomes from the training using qualitative interviews. Repeated qualitative telephone interviews (approximately 6 months apart) with participants of a 3-day Clinical Consultation Skills Retreat. Fourteen participants (70% response, 57% doctors) took part at Time 1, with 12 participating at Time 2. Semi-structured interviews were recorded and transcribed, and directional content analysis was conducted to assess themes in areas of key learnings, implementation of skills, and barriers. The training was received very positively with participants valuing the small group learning, role play, and facilitator skills. Key learnings were grouped into two themes: (i) tips and strategies to use in clinical practice and (ii) communication frameworks/methods, with the second theme reflecting an awareness of different communication styles. Most participants had tried to implement their new skills, with implementation reported as a more deliberate activity at T1 than at T2. Those implementing the new skills noted more open conversations with patients. Practical barriers of lack of time and expectations of others were mentioned more often at T2. A 3-day retreat-based communication training program was positively received and had a positive impact on the use of new communication skills. While further work is needed to determine whether effects of training are evidenced in objective clinical behaviors, the positive longer-term benefits found suggest this work would be worthwhile.

Since the early sixties, our view of radio galaxies and quasars has been drastically shaped by discoveries made thanks to observations of radio sources listed in the Third Cambridge Catalog and its revised version (3CR). However, the largest fraction of data collected to date on 3CR sources was performed with relatively old instruments, rarely repeated and/or updated. Importantly, the 3CR contains only objects located in the Northern Hemisphere, thus having limited access to new and innovative astronomical facilities. To mitigate these limitations, we present a new catalog of powerful radio sources visible from the Southern Hemisphere, extracted from the GLEAM 4 Jy (G4Jy) catalog and based on equivalent selection criteria as the 3CR. This new catalog, named G4Jy- 3CRE, where the E stands for “equivalent,” lists a total of 264 sources at decl. below −5° and with 9 Jy limiting sensitivity at ∼178 MHz. We explored archival radio maps obtained with different surveys and compared them with optical images available in the Pan-STARRS, DES, and DSS databases to search for optical counterparts of their radio cores. We compared mid-infrared counterparts, originally associated in the G4Jy, with the optical ones identified here, and we present results of a vast literature search carried out to collect redshift estimates for all G4Jy-3CRE sources resulting in a total of 145 reliable z measurements., Instituto Argentino de Radioastronomía, Instituto de Astrofísica de La Plata

Pyrethroids are commonly used in barrier treatments but less is known about how mosquitoes are affected by the simultaneous application of an insect growth regulator (i.e., pyriproxyfen) used in barrier treatments. This field study, conducted from May 14 – October 16, 2018, evaluated the effect of lambda-cyhalothrin (pyrethroid adulticide) and pyriproxyfen on the reproduction (measured by fecundity and adult emergence) and abundance of Aedes albopictus. Nine properties were treated with Demand®CS 0.06% + Archer® 0.010% (every 60 days) and three control properties received no treatment (N=12 total properties). No significant (P>0.05) differences were observed between abundance of Ae. albopictus in treatment compared to control groups. However, significant differences were observed in abundance of Ae. albopictus adults between weeks at both control (P = 0.003) and treatment (P < 0.0001) properties. Results from our research show that continued studies are needed to determine the efficacy of barrier treatments for this species.

Dysidealactams E and F and dysidealactone B are recently reported marine natural products. Their syntheses from β-cyclocitral are detailed here. The preparation of certain derivatives and analogues of these compounds is also described and single-crystal X-ray analyses of two of these, as well as that of (±)-dysidealactam F, are reported.

Abdominal aortic aneurism (AAA) is a complex immunological disease with a strong genetic component, and one of the ten leading causes of death of individuals 55-74 years old worldwide. Strong evidence has been accumulated suggesting that AAA is an autoimmune specific antigen-driven disease. Mononuclear cells infiltrating AAA lesions comprised of T and B lymphocytes and other cells expressing early-, intermediate- and late-activation antigens, and the presence of antigen-presenting cells have been documented, demonstrating an ongoing immune response. The three components of the trimolecular complex, T-cell receptor (TCR)/peptide (antigen)/HLA have been identified in AAA, and specifically: (i) clonal expansions of T-cell clones in AAA lesions; (ii) the association of AAA with particular HLA Class I and Class II; and (iii) self or nonself putative AAA-associated antigens. IgG autoantibodies recognizing proteins present in normal aortic tissue have been reported in patients with AAA. Molecular mimicry, defined as the sharing of antigenic epitopes between microorganisms (bacteria, viruses) and self antigens, maybe is responsible for T-cell responses and antibody production in AAA. Also, the frequency and the suppressor activity of CD4+ CD25+ FOXP3+ Tregs and the expression of FOXP3 transcripts and protein have been reported to be significantly impaired in AAA patients vs normal donors.

Introduction: Spontaneous aortic thrombosis causing distal embolization and acute limb ischemia is an ominous medical condition with a poor prognosis. Herein are reported the clinical courses of two women who presented with severe lower extremity ischemia caused by distal embolization of spontaneous aortic thrombus without obvious antecedent arterial disease. This unusual diagnosis should be expected in patients presenting with persistent lower extremity pain and numbness even in the absence of overt physical findings. Case 1: A 42 year-old woman with mild hyperlipidemia complained of left leg numbness and weakness. She was treated with analgesia but her symptoms worsened. Lower extremity ultrasound revealed a significant infra-inguinal perfusion defect; computed tomography revealed mural thrombus in a normal aorta along with extensive thrombotic occlusion of the left popliteal and tibial arteries. Attempts at endovascular recanalization were unsuccessful; the patient underwent successful left popliteal-to-plantar artery bypass with autologous vein. Case 2: A 57 year-old woman without medical history presented to a local Emergency Room with a five-day history of numbness in the right lower extremity. Computed tomographic angiography revealed complete infrarenal aortic occlusion in a 3 cm diameter area of mild aortic ectasia along with iliac and distal right infrainguinal thromboembolism. The patient was treated with aortobifemoral bypass grafting with right leg fasciotomy, which restored perfusion and function. Conclusion: Spontaneous aortic thrombosis causing distal embolization and acute limb ischemia is an ominous medical condition with a poor prognosis. Episodes of embolization may be intermittent and asymptomatic such that, when symptoms finally occur, the distal thrombus is often chronic and inaccessible. The diagnosis should be suspected in patients with unexplained lower extremity symptoms and pulse deficits; it can be readily established with computed tomography.

We report here the application of silyl enol ether moieties as efficient alkene coupling partners within cobalt-mediated intramolecular Pauson-Khand reactions. This cyclization strategy delivers synthetically valuable oxygenated cyclopentenone products in yields of ≤93% from both ketone- and aldehyde-derived silyl enol ethers, incorporates both terminal and internal alkyne partners, and delivers a variety of decorated systems, including more complex tricyclic structures. Facile removal of the silyl protecting group reveals oxygenated sites for potential further elaboration.

The recent detection of the quasi-stellar object (QSO) VIKING J231818.3$-$311346 (hereafter VIK J2318$-$3113) at redshift $z=6.44$ in the Rapid ASKAP Continuum Survey (RACS) uncovered its radio-loud nature, making it one of the most distant known to date in this class. By using data from several radio surveys of the Galaxy and Mass Assembly 23$^\mathrm{h}$ field and from dedicated follow-up, we were able to constrain the radio spectrum of VIK J2318$-$3113 in the observed range $\sim$0.1--10 GHz. At high frequencies (0.888--5.5 GHz in the observed frame) the QSO presents a steep spectrum ($\alpha_{\rm r}$=1.24, with $S_\nu\propto \nu^{-\alpha_{\rm r}}$), while at lower frequencies (0.4--0.888 GHz in the observed frame) it is nearly flat. The overall spectrum can be modelled by either a curved function with a rest-frame turnover around 5 GHz, or with a smoothly varying double power law that is flat below a rest-frame break frequency of about 20 GHz and which significantly steepens above it. Based on the model adopted, we estimated that the radio jets of VIK J2318$-$3113 must be a few hundred years old, in the case of a turnover, or less than few$\times$10$^4$ years, in the case of a break in the spectrum. Having multiple observations at two frequencies (888 MHz and 5.5 GHz), we further investigated the radio variability previously reported for this source. We found that the marginally significant flux density variations are consistent with the expectations from refractive interstellar scintillation, even though relativistic effects related to the orientation of the source may still play a non-negligible role. Further radio and X-ray observations are required to conclusively discern the nature of this variation., Comment: Accepted for publication in A&A

Chronic limb-threatening (CLTI) is associated with 25% limb loss and 25% mortality at 1-year. Its lethality increases to 45% in patients subjected to a major amputation. Percutaneous peripheral intervention (PPI) constitutes an attractive and less morbid treatment option for patients with CLTI. The purpose of this study was to assess amputation-free survival (AFS) in a contemporary cohort treated with endovascular recanalization and assess its predictors.Patients with CLTI undergoing endovascular revascularization at a single regional hospital between 2015-2019 were reviewed. Baseline demographic characteristics, Wound, Ischemia, and foot Infection (WIfI) stage, technical details, and clinical outcomes were tabulated. The primary endpoint was AFS; a P-value0.05 was used for univariate screening and inclusion in a multivariable model.A total of 137 limbs in 111 patients were studied. Comorbidities were prevalent and included diabetes (65%), congestive heart failure (21%), and dialysis dependence (18%). The majority of revascularized limbs presented with advanced wounds (66% WIfI stages 3-4; 47% Rutherford category 6). Presenting WIfI stages were similar across races (P = 0.26). Peripheral interventions most commonly targeted femoropopliteal disease (69%), although 26% were multilevel. Percutaneous atherectomy, stenting, and paclitaxel-coated or eluting devices were utilized in 68%, 28%, and 15% of cases, respectively. After a median follow-up of 16 months (interquartile range IQR = 4-29 months), significant independent predictors of reduced AFS included nonWhite race (HR = 2.96 [1.42-6.17]; P = 0.004) and WIfI stage 4 wounds (HR = 2.23 [1.10-4.52]; P = 0.026). At one year following successful revascularization, only 59% ± 1% of patients were alive with their limb intact.Despite considerable and consistent advances in urban health care delivery and the techniques of PPI, CLTI remains a morbid and deadly disease. Even in the endovascular era, nearly half of all patients presenting with CLTI will lose their limb and/or life within the first year. Unfortunately, late-stage presentation continues to be commonplace. Although endovascular intervention can reliably restore patency to affected arteries, this appears insufficient to restore most patients to health.

Morphinans are essential medicines derived entirely from poppy supply chains rendered increasingly volatile by climate change. Here, we report a seven-step, asymmetric chemical synthesis of (-)-codeine from simple materials that requires a total combined reaction time of fewer than 24 hours. The efficiency of our approach arises from a double-Heck cyclization reaction that generates two rings and two contiguous stereogenic carbon centres in the one pot. A subsequent photo-redox hydroamination protocol provides a novel, atom-economical means for assembling the piperidine D-ring of codeine. Simple modifications to the closing stages of our sequence offer effective access to pharmacologically valuable derivatives of N-demethyl codeine. Our work highlights the capacity for contemporary, stand-alone chemical synthesis regimes to diversify access to essential opiate medicines.

BACKGROUND: Bardet-Biedl syndrome (BBS) is a rare, autosomal recessive ciliopathy characterized by early onset retinal dystrophy, renal anomalies, postaxial polydactyly, and cognitive impairment with considerable phenotypic heterogeneity. BBS results from biallelic pathogenic variants in over 20 genes that encode key proteins required for the assembly or primary ciliary functions of the BBSome, a heterooctameric protein complex critical for homeostasis of primary cilia. While variants in BBS1 are most frequently identified in affected individuals, the renal and pulmonary phenotypes associated with BBS1 variants are reportedly less severe than those seen in affected individuals with pathogenic variants in the other BBS-associated genes. CASE-DIAGNOSIS: We report an infant with severe renal dysplasia and lethal pulmonary hypoplasia who was homozygous for the most common BBS1 pathogenic variant (c.1169 T > G; p.M390R) and also carried a predicted pathogenic variant in TTC21B (c.1846C > T; p.R616C), a genetic modifier of disease severity of ciliopathies associated with renal dysplasia and pulmonary hypoplasia. CONCLUSIONS: This report expands the phenotypic spectrum of BBS with the first infant with lethal neonatal respiratory failure associated with biallelic, pathogenic variants in BBS1 and a monoallelic, predicted pathogenic variant in TTC21B. BBS should be considered among the ciliopathies in the differential diagnosis of neonates with renal dysplasia and severe respiratory failure.