Reply to: Association Between Alendronate and All-Cause Mortality and Cardiovascular Mortality Among Hip Fracture: An Alternative Explanation.

To the Editor: We are thankful to Prof. Nguyen and Dr. Tran for their interest in our study and we appreciate the opportunity to respond to their comments. As Prof. Nguyen and Dr. Tran suggested that censoring patients at the time of switching medications might have inflated the effect size, we investigated this potential bias by excluding patients with switching of medications. Of the 3,081 alendronate-treated patients, 281 patients (9.1%) switched the therapy during the study period. After excluding these patients, we observed similar findings (Table), suggesting that bias due to treatment of censoring data should be minimal in our study

Non-standard interactions versus non-unitary lepton flavor mixing at a neutrino factory

The impact of heavy mediators on neutrino oscillations is typically described by non-standard four-fermion interactions (NSIs) or non-unitarity (NU). We focus on leptonic dimension-six effective operators which do not produce charged lepton flavor violation. These operators lead to particular correlations among neutrino production, propagation, and detection non-standard effects. We point out that these NSIs and NU phenomenologically lead, in fact, to very similar effects for a neutrino factory, for completely different fundamental reasons. We discuss how the parameters and probabilities are related in this case, and compare the sensitivities. We demonstrate that the NSIs and NU can, in principle, be distinguished for large enough effects at the example of non-standard effects in the $\mu$-$\tau$-sector, which basically corresponds to differentiating between scalars and fermions as heavy mediators as leading order effect. However, we find that a near detector at superbeams could provide very synergistic information, since the correlation between source and matter NSIs is broken for hadronic neutrino production, while NU is a fundamental effect present at any experiment.Comment: 32 pages, 5 figures. Final version published in JHEP. v3: Typo in Eq. (27) correcte

Future therapeutic targets in rheumatoid arthritis?

Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by persistent joint inflammation. Without adequate treatment, patients with RA will develop joint deformity and progressive functional impairment. With the implementation of treat-to-target strategies and availability of biologic therapies, the outcomes for patients with RA have significantly improved. However, the unmet need in the treatment of RA remains high as some patients do not respond sufficiently to the currently available agents, remission is not always achieved and refractory disease is not uncommon. With better understanding of the pathophysiology of RA, new therapeutic approaches are emerging. Apart from more selective Janus kinase inhibition, there is a great interest in the granulocyte macrophage-colony stimulating factor pathway, Bruton's tyrosine kinase pathway, phosphoinositide-3-kinase pathway, neural stimulation and dendritic cell-based therapeutics. In this review, we will discuss the therapeutic potential of these novel approaches

Multivariate analysis of rs182052 with plasma ADM level (ln-transformed).

*<p>Standardized regression coefficient is shown.</p>**<p>Unstandardized regression coefficient is shown.</p>∧<p>P values remain significant after permutation test for 1000 times (P<0.05).</p><p>Model 1: Unadjusted model.</p><p>Model 2: Adjusted for age and sex only.</p><p>Model 3: Further adjusted for biochemical parameters including waist circumference, LDL cholesterol, SBP, fibrinogen and natural log of triglycerides, HOMA-IR, fasting glucose level, hsCRP, adiponectin, interleukin-6, TNF-α R2, ALP and GGT.</p><p>Model 4: Further adjusted for lifestyle factors such as regular drinking, smoking and exercise.</p

A diagram showing plasma ADM levels with different genotypes in rs182052.

<p>The error bars represent mean ±95% CI. P values were calculated using natural log-transformed levels after adjusting for age and sex.</p

A Putative Bacterial ABC Transporter Circumvents the Essentiality of Signal Peptidase

The type I signal peptidase of Staphylococcus aureus, SpsB, is an attractive antibacterial target because it is essential for viability and extracellularly accessible. We synthesized compound 103, a novel arylomycin-derived inhibitor of SpsB with significant potency against various clinical S. aureus strains (MIC of ~1 µg/ml). The predominant clinical strain USA300 developed spontaneous resistance to compound 103 with high frequency, resulting from single point mutations inside or immediately upstream of cro/cI, a homolog of the lambda phage transcriptional repressor cro. These cro/cI mutations led to marked (>50-fold) overexpression of three genes encoding a putative ABC transporter. Overexpression of this ABC transporter was both necessary and sufficient for resistance and, notably, circumvented the essentiality of SpsB during in vitro culture. Mutation of its predicted ATPase gene abolished resistance, suggesting a possible role for active transport; in these bacteria, resistance to compound 103 occurred with low frequency and through mutations in spsB. Bacteria overexpressing the ABC transporter and lacking SpsB were capable of secreting a subset of proteins that are normally cleaved by SpsB and instead were cleaved at a site distinct from the canonical signal peptide. These bacteria secreted reduced levels of virulence-associated proteins and were unable to establish infection in mice. This study reveals the mechanism of resistance to a novel arylomycin derivative and demonstrates that the nominal essentiality of the S. aureus signal peptidase can be circumvented by the upregulation of a putative ABC transporter in vitro but not in vivo

Proceedings of The HKIE Geotechnical Division 43rd Annual Seminar: Towards a Smart-Green-Resilient Geo-Future for World-class City

This seminar proceedings contain articles on the various research ideas of the academic community and practitioners presented at The HKIE Geotechnical Division 43rd Annual Seminar (GDAS2023). This seminarprovides a platform for policymakers, practitioners, and academia to share their insights and brainstorm ideas with a view to seizing future opportunities and shaping the new future of Hong Kong. GDAS2023 was organized by the Geotechnical Division, The Hong Kong Institution of Engineers on 19th May 2023. Seminar Title: The HKIE Geotechnical Division 43rd Annual SeminarSeminar Acronym: GDAS2023Seminar Date: 19 May 2023Seminar Location:  Hong KongSeminar Organizers: Geotechnical Division, The Hong Kong Institution of Engineers Link to the GDAS2021 Proceedings: Proceedings of The HKIE Geotechnical Division 41st Annual Seminar Link to the GDAS2022 Proceedings: Proceedings of The HKIE Geotechnical Division 42nd Annual Semina