Experimental and Theoretical Evidence for Nitrogen-Fluorine Halogen Bonding in Silver-Initiated Radical Fluorinations

We report experimental and computational evidence for nitrogen–fluorine halogen bonding in Ag­(I)-initiated radical C–H fluorinations. Simple pyridines form [N–F–N]+ halogen bonds with Selectfluor to facilitate single-electron reduction by catalytic Ag­(I). Pyridine electronics affect the extent of halogen bonding, leading to significant differences in selectivity between mono- and difluorinated products. Electronic structure calculations show that halogen bonding to various pyridines alters the single-electron reduction potential of Selectfluor, which is consistent with experimental electrochemical analysis. Multinuclear correlation NMR also provides spectroscopic evidence for pyridine halogen bonding to Selectfluor under ambient conditions

Communicating new knowledge on previously reported genetic variants

Genetic tests often identify variants whose significance cannot be determined at the time they are reported. In many situations, it is critical that clinicians be informed when new information emerges on these variants. It is already extremely challenging for laboratories to provide these updates. These challenges will grow rapidly as an increasing number of clinical genetic tests are ordered and as the amount of patient DNA assayed per test expands; the challenges will need to be addressed before whole-genome sequencing is used on a widespread basis. Information technology infrastructure can be useful in this context. We have deployed an infrastructure enabling clinicians to receive knowledge updates when a laboratory changes the classification of a variant. We have gathered statistics from this deployment regarding the frequency of both variant classification changes and the effects of these classification changes on patients. We report on the system's functionality as well as the statistics derived from its use. Genet Med 2012:14(8):713–71

Identifying characteristics that enable resilient immunisation programmes: a scoping review

Objectives: The COVID-19 pandemic highlighted the fragility of immunisation programmes and resulted in a significant reduction in vaccination rates, with increasing vaccine-preventable disease outbreaks consequently reported. These vulnerabilities underscore the importance of resilient immunisation programmes to ensure optimal performance during crises. To date, a framework for assessing immunisation programme resilience does not exist. We conducted a scoping review of immunisation programmes during times of crisis to identify factors that characterise resilient immunisation programmes, which may inform an Immunisation Programme Resilience Tool. Design: Scoping review design followed the Arksey and O’Malley framework, and manuscript reporting followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses for Scoping Reviews guidelines. Data sources: CINAHL, CENTRAL, Embase, Google Scholar, MEDLINE, PsycINFO and Web of Science and databases were searched between 1 January 2011 and 2 September 2023. Citation searching of identified studies was also performed. Eligibility criteria: We included primary empirical peer-reviewed studies that discussed the resilience of immunisation programme to crises, shocks or disruptions. Data extraction and synthesis: Two independent reviewers screened records and performed data extraction. We extracted data on study location and design, crisis description, and resilience characteristics discussed, and identified evidence gaps in the literature. Findings were synthesised using tabulation and an evidence gap map. Results: Thirty-seven studies met the eligibility criteria. These studies captured research conducted across six continents, with most concentrated in Africa, Asia and Europe. One study had a randomised controlled trial design, while 36 studies had observational designs (15 analytical and 21 descriptive). We identified five characteristics of resilient immunisation programmes drawing on the Health System Resilience Index (Integration, Awareness, Resource Availability and Access, Adaptiveness and Self-regulation) and several evidence gaps in the literature. Conclusions: To our knowledge, no immunisation programme resilience tool exists. We identified factors from the Health System Resilience Index coupled with factors identified through primary empirical evidence, which may inform development of an immunisation programme resilience tool

Phenotype and genetic analysis of data collected within the first year of NeuroDev

Genetic association studies have made significant contributions to our understanding of the etiology of neurodevelopmental disorders (NDDs). However, these studies rarely focused on the African continent. The NeuroDev Project aims to address this diversity gap through detailed phenotypic and genetic characterization of children with NDDs from Kenya and South Africa. We present results from NeuroDev’s first year of data collection, including phenotype data from 206 cases and clinical genetic analyses of 99 parent-child trios. Most cases met criteria for global developmental delay/intellectual disability (GDD/ID, 80.3%). Approximately half of the children with GDD/ID also met criteria for autism. Analysis of exome-sequencing data identified a pathogenic or likely pathogenic variant in 13 (17%) of the 75 cases from South Africa and 9 (38%) of the 24 cases from Kenya. Data from the trio pilot are publicly available, and the NeuroDev Project will continue to develop resources for the global genetics community

Identifying factors that can be used to assess a country’s readiness to deploy a new vaccine or improve uptake of an underutilised vaccine: a scoping review

Objectives: Identifying whether a country is ready to deploy a new vaccine or improve uptake of an existing vaccine requires knowledge of a diverse range of interdependent, context-specific factors. This scoping review aims to identify common themes that emerge across articles, which include tools or guidance that can be used to establish whether a country is ready to deploy a new vaccine or increase uptake of an underutilised vaccine. Design: Scoping review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses for Scoping Reviews guidelines. Data sources: Embase, CINAHL, Cochrane Library, Google Scholar, MEDLINE, PsycINFO and Web of Science were searched for articles published until 9 September 2023. Relevant articles were also identified through expert opinion. Eligibility criteria: Articles published in any year or language that included tools or guidance to identify factors that influence a country’s readiness to deploy a new or underutilised vaccine. Data extraction and synthesis: Two independent reviewers screened records and performed data extraction. Findings were synthesised by conducting a thematic analysis. Results: 38 articles met our inclusion criteria; these documents were created using methodologies including expert review panels and Delphi surveys and varied in terms of content and context-of-use. 12 common themes were identified relevant to a country’s readiness to deploy a new or underutilised vaccine. These themes were as follows: (1) legal, political and professional consensus; (2) sociocultural factors and communication; (3) policy, guidelines and regulations; (4) financing; (5) vaccine characteristics and supply logistics; (6) programme planning; (7) programme monitoring and evaluation; (8) sustainable and integrated healthcare provision; (9) safety surveillance and reporting; (10) disease burden and characteristics; (11) vaccination equity and (12) human resources and training of professionals. Conclusions: This information has the potential to form the basis of a globally applicable evidence-based vaccine readiness assessment tool that can inform policy and immunisation programme decision-makers

‘Great inhumanity’: scandal, child punishment and policymaking in the early years of the New Poor Law workhouse system

New Poor Law scandals have usually been examined either to demonstrate the cruelty of the workhouse regime or to illustrate the failings or brutality of union staff. Recent research has used these and similar moments of crisis to explore the relationship between local and central levels of welfare administration (the Boards of Guardians in unions across England and Wales and the Poor Law Commission in Somerset House in London) and how scandals in particular were pivotal in the development of further policies. This article examines both the inter-local and local-centre tensions and policy consequences of the Droxford Union and Fareham Union scandal (1836–1837), which exposed the severity of workhouse punishments towards three young children. The article illustrates the complexities of union cooperation and, as a result of the escalation of public knowledge into the cruelties and investigations thereafter, how the vested interests of individuals within a system manifested themselves in particular (in)actions and viewpoints. While the Commission was a reactive and flexible welfare authority, producing new policies and procedures in the aftermath of crises, the policies developed after this particular scandal made union staff, rather than the welfare system as a whole, individually responsible for the maltreatment and neglect of the poor

Performance of a Kinetic Inductance Phonon-Mediated Detector at the NEXUS Cryogenic Facility

Microcalorimeters that leverage microwave kinetic inductance detectors to read out phonon signals in the particle-absorbing target, referred to as kinetic inductance phonon-mediated (KIPM) detectors, offer an attractive detector architecture to probe dark matter (DM) down to the fermionic thermal relic mass limit. A prototype KIPM detector featuring a single aluminum resonator patterned onto a 1-gram silicon substrate was operated in the NEXUS low-background facility at Fermilab for characterization and evaluation of this detector architecture's efficacy for a dark matter search. An energy calibration was performed by exposing the bare substrate to a pulsed source of 470 nm photons, resulting in a baseline resolution on the energy absorbed by the phonon sensor of $2.1\pm0.2$ eV, a factor of two better than the current state-of-the-art, enabled by millisecond-scale quasiparticle lifetimes. However, due to the sub-percent phonon collection efficiency, the resolution on energy deposited in the substrate is limited to $\sigma_E=318 \pm 28$ eV. We further model the signal pulse shape as a function of device temperature to extract quasiparticle lifetimes, as well as the observed noise spectra, both of which impact the baseline resolution of the sensor

Homologous and heterologous desensitization of guanylyl cyclase-B signaling in GH3 somatolactotropes

The guanylyl cyclases, GC-A and GC-B, are selective receptors for atrial and C-type natriuretic peptides (ANP and CNP, respectively). In the anterior pituitary, CNP and GC-B are major regulators of cGMP production in gonadotropes and yet mouse models of disrupted CNP and GC-B indicate a potential role in growth hormone secretion. In the current study, we investigate the molecular and pharmacological properties of the CNP/GC-B system in somatotrope lineage cells. Primary rat pituitary and GH3 somatolactotropes expressed functional GC-A and GC-B receptors that had similar EC50 properties in terms of cGMP production. Interestingly, GC-B signaling underwent rapid homologous desensitization in a protein phosphatase 2A (PP2A)-dependent manner. Chronic exposure to either CNP or ANP caused a significant down-regulation of both GC-A- and GC-B-dependent cGMP accumulation in a ligand-specific manner. However, this down-regulation was not accompanied by alterations in the sub-cellular localization of these receptors. Heterologous desensitization of GC-B signaling occurred in GH3 cells following exposure to either sphingosine-1-phosphate or thyrotrophin-releasing hormone (TRH). This heterologous desensitization was protein kinase C (PKC)-dependent, as pre-treatment with GF109203X prevented the effect of TRH on CNP/GC-B signaling. Collectively, these data indicate common and distinct properties of particulate guanylyl cyclase receptors in somatotropes and reveal that independent mechanisms of homologous and heterologous desensitization occur involving either PP2A or PKC. Guanylyl cyclase receptors thus represent potential novel therapeutic targets for treating growth-hormone-associated disorders

Centers For Mendelian Genomics: a Decade of Facilitating Gene Discovery

PURPOSE: Mendelian disease genomic research has undergone a massive transformation over the past decade. With increasing availability of exome and genome sequencing, the role of Mendelian research has expanded beyond data collection, sequencing, and analysis to worldwide data sharing and collaboration. METHODS: Over the past 10 years, the National Institutes of Health-supported Centers for Mendelian Genomics (CMGs) have played a major role in this research and clinical evolution. RESULTS: We highlight the cumulative gene discoveries facilitated by the program, biomedical research leveraged by the approach, and the larger impact on the research community. Beyond generating a list of gene-phenotype relationships and participating in widespread data sharing, the CMGs have created resources, tools, and training for the larger community to foster understanding of genes and genome variation. The CMGs have participated in a wide range of data sharing activities, including deposition of all eligible CMG data into the Analysis, Visualization, and Informatics Lab-space (AnVIL), sharing candidate genes through the Matchmaker Exchange and the CMG website, and sharing variants in Genotypes to Mendelian Phenotypes (Geno2MP) and VariantMatcher. CONCLUSION: The work is far from complete; strengthening communication between research and clinical realms, continued development and sharing of knowledge and tools, and improving access to richly characterized data sets are all required to diagnose the remaining molecularly undiagnosed patients

The Simons Observatory: Galactic Science Goals and Forecasts

Observing in six frequency bands from 27 to 280 GHz over a large sky area, the Simons Observatory (SO) is poised to address many questions in Galactic astrophysics in addition to its principal cosmological goals. In this work, we provide quantitative forecasts on astrophysical parameters of interest for a range of Galactic science cases. We find that SO can: constrain the frequency spectrum of polarized dust emission at a level of $\Delta\beta_d \lesssim 0.01$ and thus test models of dust composition that predict that $\beta_d$ in polarization differs from that measured in total intensity; measure the correlation coefficient between polarized dust and synchrotron emission with a factor of two greater precision than current constraints; exclude the non-existence of exo-Oort clouds at roughly 2.9$\sigma$ if the true fraction is similar to the detection rate of giant planets; map more than 850 molecular clouds with at least 50 independent polarization measurements at 1 pc resolution; detect or place upper limits on the polarization fractions of CO(2-1) emission and anomalous microwave emission at the 0.1% level in select regions; and measure the correlation coefficient between optical starlight polarization and microwave polarized dust emission in $1^\circ$ patches for all lines of sight with $N_{\rm H} \gtrsim 2\times10^{20}$ cm$^{-2}$. The goals and forecasts outlined here provide a roadmap for other microwave polarization experiments to expand their scientific scope via Milky Way astrophysics.Comment: Submitted to AAS journals. 33 pages, 10 figure