Hypervalent iodine mediated cyclization of bishomoallylamides to prolinols

A change in mechanism was observed in the hypervalent iodine mediated cyclization of N-alkenylamides when the carbon chain between the alkene and the amide increased from two to three atoms. In the latter case, cyclization at the amide nitrogen to form the pyrrolidine ring was favored over cyclization at the amide oxygen. A DFT study was undertaken to rationalize the change in mechanism of this cyclization process. In addition, reaction conditions were developed, and the scope of this cyclization studied

The regulator’s trilemma: On the limits of technocratic governance in digital markets

Policymakers increasingly recognise the need for regulatory intervention in the digital economy to promote competition, privacy and innovation, among other policy objectives. Much policy-focused literature presents regulation as a technical puzzle to be ‘solved’ through identification of the appropriate intervention in a particular context, though there is persistent disagreement among experts about what remedies are preferable in different digital markets. At the same time, many external observers emphasise the sheer multiplicity of public policy objectives that regulatory interventions might fulfil, claiming that conflicts between these objectives are inevitable and thus require political rather than technocratic solutions. This article attempts to bridge the gap between these perspectives through a novel theoretical analysis of digital markets characterised by strong network effects, conceptualising different markets in terms of common underlying structural characteristics. The resulting framework helps policymakers to anticipate which remedies will safeguard competition, privacy and innovation/efficiency under what circumstances, both in well-established digital markets and with respect to emerging technologies such as artificial intelligence. In so doing, it also highlights limits to the technocratic governance of digital markets, identifying circumstances in which conflicts between competing public values cannot be neatly resolved through technocratic regulatory intervention alone

Investigating the therapeutic potential of repurposed drugs that target central nervous system and peripheral pathologies in cellular and animal models of spinal muscular atrophy

Spinal muscular atrophy (SMA) is a neuromuscular disorder caused by the loss-of-function of the survival motor neuron (SMN) gene resulting in muscle atrophy and weakness. There are currently 3 gene-based therapies (Spinraza®, Zolgensma® and Evrysdi®) approved for the treatment of SMA. Although these treatments lead to significant life-changing and life-saving improvements, they have limitations. Moreover, going beyond neuronal pathologies in SMA, developmental and metabolic pathologies in many peripheral tissues have been found in both SMA mouse models and patients. Our previous research has demonstrated that prednisolone, a synthetic glucocorticoid (GC), has been found to alleviate the disease SMA genotype phenotype in Smn-/-;SMN2 and Smn2B/- SMA mice. To identify commercially available drugs predicted to ameliorate peripheral pathologies and possess similar effects to prednisolone via RNA sequencing. Combined in silico analysis were used to identify commercially available drugs predicted to restore the levels of differentially expressed genes in SMA muscle and similar activity potential with prednisolone. This comprehensive in silico approach identified strong pharmacological candidates, pioglitazone, melatonin, and insulin. Through combined in silico analyses, several target genes have been predicted: Thbs1 and Ppar-α, which could be regulated by pioglitazone; Per1, Bcl2, Sirt1, and Ror- α, potentially corrected by melatonin; and Igf1R, Rb1, and InsR, which may be regulated via insulin. First, we validated the abnormal expression of these predicted targeted genes in symptomatic skeletal muscle tissue in both SMA mouse models. Subsequent research has stated the safety and pharmacological impact of pioglitazone, melatonin and insulin on the C2C12s and LCHN-M2 cell line. Importantly, melatonin has been observed to improve weight, lifespan, and RR (righting reflex); pioglitazone has shown positive contributions to weight and survival; and insulin has demonstrated beneficial effects on weight in Smn2B/- mouse models. Post-treatment of these candidates caused a change in expression of all these genes compared to untreated counterparts both CNS and periphery. Pioglitazone and melatonin show promise in addressing metabolic disorders by potentially enhancing glucose uptake from circulation into skeletal muscle. They may also shift metabolism towards increased ATP production by supporting mitochondrial biogenesis and function. The perspective results highlights the complexity of SMA and the potential multifaceted approach required for effective treatment, underscoring the importance of targeting not just the primary symptoms but also the broader metabolic disturbances associated with the disease aiming to improve overall patient outcomes and quality of life

TOI–757 b: an eccentric transiting mini–Neptune on a 17.5–d orbit

We report the spectroscopic confirmation and fundamental properties of TOI$-$757 b, a mini$-$Neptune on a 17.5$-$d orbit transiting a bright star ($V\, =\, 9.7$ mag) discovered by the TESS mission. We acquired high$-$precision radial velocity measurements with the HARPS, ESPRESSO, and PFS spectrographs to confirm the planet detection and determine its mass. We also acquired space$-$borne transit photometry with the CHEOPS space telescope to place stronger constraints on the planet radius, supported with ground$-$based LCOGT photometry. WASP and KELT photometry were used to help constrain the stellar rotation period. We also determined the fundamental parameters of the host star. We find that TOI$-$757 b has a radius of $R_{\mathrm{p}} = 2.5 \pm 0.1 R_{\oplus }$ and a mass of $M_{\mathrm{p}} = 10.5^{+2.2}_{-2.1} M_{\oplus }$, implying a bulk density of $\rho _{\text{p}} = 3.6 \pm 0.8$ g cm$^{-3}$. Our internal composition modelling was unable to constrain the composition of TOI$-$757 b, highlighting the importance of atmospheric observations for the system. We also find the planet to be highly eccentric with e = 0.39$^{+0.08}_{-0.07}$, making it one of the very few highly eccentric planets among precisely characterized mini$-$Neptunes. Based on comparisons to other similar eccentric systems, we find a likely scenario for TOI$-$757 b’s formation to be high eccentricity migration due to a distant outer companion. We additionally propose the possibility of a more intrinsic explanation for the high eccentricity due to star$-$star interactions during the earlier epoch of the Galactic disc formation, given the low metallicity and older age of TOI$-$757

Evaluation of chemometric software for analysis of complex mixtures for biologically derived samples analysed using liquid-chromatography mass spectrometry

There is a risk of losing important information when choosing the best metabolomic workflow for untargeted chemometric analysis. Choosing the best software for conducting this analysis is crucial as wrong parameters with the wrong software could lead to false negatives, as well as over-saturating the data analysis with false positives. Over the course of this study, the intention was to show how a robust untargeted liquid chromatography-mass spectrometry method, followed by deconvolution then performing statistical analysis can determine consistent, concise and accurate markers that explain differences between datasets. Different software packages were used throughout to determine whether the chosen software affects the results. Software packages for deconvolution and statistical analysis were compared over a range of different samples to evaluate the workflow over a range of sample types; plant samples, solid human products (hair samples) and liquid human products (blood samples) were used. The different deconvolution software packages used showed different results through the studies showing that the software used will affect the outcome. Though some markers were consistent in the statistical analysis performed with the same deconvolution, a lot of the results were different which shows that conducting the analysis in different types of software, results in different biomarker detection. This could lead to a potential oversight and loss of important information. The data showed that deconvolution worked best in Mass Profinder then statistical analysis in MPP gave the most reliable results whilst being the easiest to navigate. However, where possible, it was concluded that more than one type of software should be used for reliable biomarker detection to reduce the risk of losing important information through the software choice

The burden of cardiovascular disease in Asia from 2025 to 2050: a forecast analysis for East Asia, South Asia, South-East Asia, Central Asia, and high-income Asia Pacific regions

Background Given the rapidly growing burden of cardiovascular disease (CVD) in Asia, this study forecasts the CVD burden and associated risk factors in Asia from 2025 to 2050. Methods Data from the Global Burden of Disease 2019 study was used to construct regression models predicting prevalence, mortality, and disability-adjusted life years (DALYs) attributed to CVD and risk factors in Asia in the coming decades. Findings Between 2025 and 2050, crude cardiovascular mortality is expected to rise 91.2% despite a 23.0% decrease in the age-standardised cardiovascular mortality rate (ASMR). Ischaemic heart disease (115 deaths per 100,000 population) and stroke (63 deaths per 100,000 population) will remain leading drivers of ASMR in 2050. Central Asia will have the highest ASMR (676 deaths per 100,000 population), more than three-fold that of Asia overall (186 deaths per 100,000 population), while high-income Asia sub-regions will incur an ASMR of 22 deaths per 100,000 in 2050. High systolic blood pressure will contribute the highest ASMR throughout Asia (105 deaths per 100,000 population), except in Central Asia where high fasting plasma glucose will dominate (546 deaths per 100,000 population). Interpretation This forecast forewarns an almost doubling in crude cardiovascular mortality by 2050 in Asia, with marked heterogeneity across sub-regions. Atherosclerotic diseases will continue to dominate, while high systolic blood pressure will be the leading risk factor. Funding This was supported by the NUHS Seed Fund (NUHSRO/2022/058/RO5+6/Seed-Mar/03), National Medical Research Council Research Training Fellowship (MH 095:003/008-303), National University of Singapore Yong Loo Lin School of Medicine's Junior Academic Fellowship Scheme, NUHS Clinician Scientist Program (NCSP2.0/2024/NUHS/NCWS) and the CArdiovascular DiseasE National Collaborative Enterprise (CADENCE) National Clinical Translational Program (MOH-001277-01)

Healthcare practitioners' views of self‐harm management practices in older adults in Ireland: A qualitative study

ObjectivesTo explore healthcare practitioners' views on management practices of self-harm in older adults.MethodsSemi-structured interviews were conducted with healthcare practitioners, including consultant psychiatrists, general practitioners, clinical psychologists, psychotherapists, clinical nurse specialists and social workers. Purposeful sampling was used to recruit participants in the Republic of Ireland ensuring diverse perspectives of healthcare practitioners were included. Healthcare practitioners were recruited advertising via professional and clinical research networks, social media, and snowballing methods. Interviews were audio-recorded, transcribed verbatim, and analysed using reflexive thematic analysis.ResultsWe conducted interviews with 20 healthcare practitioners from April to July 2023. Three main themes were generated: first, a perceived greater risk of suicide, and increased awareness of complexity in older adults' self-harm presentations. Second, integrated care as an avenue for improving the management of self-harm in older adults. Third, the importance of safety planning in risk assessments of older adults.ConclusionsHealthcare practitioners viewed self-harm in older adults as complex, challenging, and associated with high suicide risk, approaching patients with care and caution. The need for integrated support and improved collaboration between relevant healthcare practitioners was identified. Suggestions were made for primary care having a lead role in identifying and managing older adults after self-harm. Increased mental health promotion and awareness of mental health and self-harm in this age group would help address current stigma and shame

Effectiveness of pneumococcal vaccination in adults with common immune-mediated inflammatory diseases in the UK: a case-control study.

People with immune-mediated inflammatory disease are at increased risk of pneumococcal pneumonia. The effectiveness of pneumococcal vaccination in people with immune-mediated inflammatory diseases has not been evaluated. We investigated the effectiveness of pneumococcal vaccination in preventing morbidity and mortality associated with pneumonia in patients with immune-mediated inflammatory diseases. In this matched case-control study, we used primary-care electronic health record data from the Clinical Practice Research Datalink Gold database in the UK, with linked hospitalisation and mortality data. Adults with incident common immune-mediated inflammatory diseases diagnosed between April 1, 1997, and Dec 31, 2019, were followed up from the first diagnosis date to the occurrence of an outcome or date of last follow-up. Cases (ie, those with an outcome of interest) were age-matched and sex-matched to up to ten contemporaneous controls by use of incidence density sampling. Outcomes were hospitalisation due to pneumonia, death due to pneumonia, or primary-care consultation for lower respiratory tract infection requiring antibiotics. We defined hospital admission for pneumonia using hospital discharge diagnoses, death due to pneumonia using death certification data, and lower respiratory tract infection as present when primary-care consultation and antibiotic prescription occurred on the same date. We used multivariable, unconditional, logistical regression and constructed three models to examine the association between pneumococcal vaccination as an exposure and each of the three outcomes. The first nested case-control analysis included 12 360 patients (7326 [59·3%] women and 5034 [40·7%] men): 1884 (15·2%) who were hospitalised due to pneumonia and 10 476 (84·8%) who were not admitted to hospital due to pneumonia. The second analysis included 5321 patients (3112 [58·5%] women and 2209 [41·5%] men): 781 (14·7%) who died due to pneumonia and 4540 (85·3%) who were alive on the index date. The third analysis included 54 530 patients (33 605 [61·6%] women and 20 925 [38·4%] men): 10 549 (19·3%) with lower respiratory tract infection treated with antibiotics and 43 981 (80·7%) without infection. In the multivariable analysis, pneumococcal vaccination was negatively associated with hospitalisation due to pneumonia (adjusted odds ratio 0·70 [95% CI 0·60-0·81]), death due to pneumonia (0·60 [0·48-0·76]), and lower respiratory tract infection treated with antibiotics (0·76 [0·72-0·80]). Pneumococcal vaccination is associated with protection against hospitalisation and death due to pneumonia in patients with immune-mediated inflammatory diseases, without apparent residual confounding. However, residual unmeasured confounding cannot be fully excluded in observational research, which includes nested case-control studies. These findings should also be corroborated with data from other countries, given that this study used UK-based data. National Institute for Health and Care Research. [Abstract copyright: Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.