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The effect of membrane transporters on drug disposition, efficacy and safety is now well recognized. Since the initial publication from the International Transporter Consortium, significant progress has been made in understanding the roles and functions of transporters, as well as in the development of tools and models to assess and predict transporter-mediated activity, toxicity and drug-drug interactions (DDIs). Notable advances include an increased understanding of the effects of intrinsic and extrinsic factors on transporter activity, the application of physiologically based pharmacokinetic modelling in predicting transporter-mediated drug disposition, the identification of endogenous biomarkers to assess transporter-mediated DDIs and the determination of the cryogenic electron microscopy structures of SLC and ABC transporters. This article provides an overview of these key developments, highlighting unanswered questions, regulatory considerations and future directions.

Background and Aim: Identifying the factors contributing to the progression of metabolic dysfunction‐associated steatotic liver disease (MASLD), a lifestyle‐related disease, is crucial for preventing future liver‐related deaths. This study aimed to epidemiologically investigate factors, including single‐nucleotide polymorphisms (SNPs) associated with alanine aminotransferase (ALT) levels >30 U/L and potential risk factors for liver fibrosis, in a general population cohort of patients with MASLD. Methods: Among 1059 participants in the health checkup project, 228 who were diagnosed with MASLD were analyzed. Liver fat content and stiffness were measured using FibroScan, and 13 SNPs associated with non‐alcoholic fatty liver disease (NAFLD) were measured in addition to other clinical parameters. Results: In the multivariate analysis, male sex, younger age, and high triglyceride levels were significant risk factors for ALT levels >30 U/L (P‐value < 0.05). Furthermore, among the 13 SNPs measured, only the GG genotypes of patatin‐like phospholipase domain‐containing 3 gene (PNPLA3) rs738409 and rs2896019 were significant risk factors for ALT levels >30 U/L (P‐value 0.004 and 0.007). The GG genotypes of PNPLA3 rs738409 and rs2896019 had higher FibroScan‐aspartate aminotransferase (FAST) and APRI scores than the CC + CG and TT + TG genotypes (P‐value < 0.05). In addition, multivariate analysis revealed that the GG genotypes of rs738409 and rs2896019 were significant risk factors independent of cardiovascular metabolic risk for patients with MASLD (P‐value 0.038 and 0.021). Conclusion: An individualized treatment approach is warranted for patients with MASLD due to the influence of various factors on its progression, including genetic factors and lifestyle diseases. [ABSTRACT FROM AUTHOR]

Primary multiphase inclusions trapped in host minerals such as garnet may provide important information about the nature of fluids and melts and their crystallization products. The occurrence of melt and fluid inclusions in the same cluster suggests primary fluid-melt immiscibility during partial melting. Here we report the coexistence of diamond-bearing fluid inclusions with melt inclusions in metasedimentary UHP rocks of the Nordmannvik Nappe at Heia, in the Arctic Caledonides of Norway. Multiphase fluid inclusions (Type I) and primary melt inclusions (Type II) have been identified in garnet and studied in detail. Microscopic observations, Raman spectroscopy, FIB-SEM, and EDS analysis show that microdiamonds occur in situ, in multiphase fluid inclusions (Type I) distributed in clusters in the garnet mantle. The Raman spectra suggest partial transformation of diamond to disordered sp2-bonded carbon structure. Along with diamond, Type I inclusions contain (i) rutile and apatite as trapped solid phases, (ii) carbonates (magnesite-siderite) and Al-phyllosilicates (white mica, phlogopite, pyrophyllite) as daughter or step-daughter minerals, and (iii) CO2 as a residual fluid phase. Former melt inclusions (Type II) occur in the same microstructural position in the host garnet. They contain muscovite, paragonite, phlogopite, K-feldspar, plagioclase, albite and quartz as solid phases crystallized from a melt, and kyanite as accidentally trapped mineral. The occurrence of melt inclusions in the inner part of garnets thus suggests that garnet was growing in the presence of melt. Garnet is nearly homogeneous with respect to major elements Mg, Fe, Ca and Mn, expressed by pyrope (0.18–0.22 X Prp), grossular (0.09–0.12 X Grs), almandine (0.67–0.70 X Alm) and spessartine (0.01–0.03 X Sps) except local Ca enrichment in the rim. Trace elements show decreasing HREE and Y patterns from the core to the mantle suggesting garnet growth according to the Rayleigh fractionation model. Phosphorus shows an elevated content in the core and mantle. A positive correlation between P and Na indicates a coupled NaPM2+−1Si−1 substitution in garnet. Minimum P–T conditions of 3.7 to 3.8 GPa and 840°C to 870°C for the peak metamorphic stage were estimated from garnet composition (X Prp = 0.22), zirconium-in rutile thermometry of rutile inclusions in garnet (747–977 ppm of Zr) and diamond/graphite stability boundary. Partial melting on a prograde P–T path was controlled by the decomposition of phengite in the presence of C–O–H fluid, producing peritectic garnet ± kyanite along with melt, in the diamond stability field. The coexistence of diamond-bearing multiphase fluid inclusions with melt inclusions suggests primary fluid-melt immiscibility at UHP conditions. During exhumation, the rock underwent decompression and second partial melting, leading to enrichment in Ca, Y, Cr and Sc of garnet rims. Microdiamonds found in metasedimentary crustal rocks at Heia provide new evidence of UHP metamorphism in the Nordmannvik Nappe of the Arctic Caledonides. The results favour a correlation with the pre-Scandian subduction and arc–continent collision events of the Caledonian Orogeny. [ABSTRACT FROM AUTHOR]

Background: Tryptase, a mast cell protease, has been identified as a potential therapeutic target in managing patients with refractory asthma. We assessed the efficacy, safety, pharmacokinetics, and pharmacodynamics of MTPS9579A, an anti‐tryptase antibody, in a phase 2a randomized trial for patients with uncontrolled asthma and a phase 1c trial to understand activity within the lower respiratory tract. Methods: Phase 2a patients (n = 134) received 1800 mg MTPS9579A or placebo intravenously every 4 weeks for 48 weeks. The primary endpoint was time to the first composite exacerbation event. Phase 1c patients (n = 27) received one intravenous dose of 300 or 1800 mg MTPS9579A or placebo. Both trials measured MTPS9579A concentrations and effects on tryptase in serum and nasal lining fluid; phase 1c also analyzed bronchial lining fluid. Results: MTPS9579A did not meet the primary endpoint (hazard ratio = 0.90; 95% CI: 0.55–1.47; p = 0.6835); exacerbation rates in the placebo group were low. Serum and nasal MTPS9579A pharmacokinetics and tryptase levels were consistent with data from healthy volunteers. However, in phase 1c patients, compared to nasal levels, MTPS9579A bronchial concentrations were 6.8‐fold lower, and bronchial active and total tryptase levels were higher (119‐fold and 30‐fold, respectively). Pharmacokinetic/pharmacodynamic modeling predicted intravenous doses of 3800 mg every 4 weeks would be necessary to achieve 95% active tryptase inhibition from baseline. Conclusions: The MTPS9579A dose tested in the phase 2a study was insufficient to inhibit tryptase in bronchial lining fluid, likely contributing to the observed lack of efficacy. [ABSTRACT FROM AUTHOR]

On 8 October 2023 (UTC), unique earthquakes occurred in the Izu‐Ogasawara Arc, Japan, in which the P‐ and S‐phases were barely visible and only the T‐phases were evident, followed by tsunamis that reached islands in the Izu‐Ogasawara Arc and a wide area of the Pacific coast of southwest Japan. Our estimated T‐phase source area coincides with the Sofu Seamount, which was previously unrecognized as an active submarine volcano. A bathymetric survey of the seamount conducted 1 month after the event revealed characteristics of the seamount with a caldera and a central cone. Compared to the bathymetry in 1987, the topography in the caldera had changed significantly such as a crater forming in the central cone. This seamount is likely to be an active volcano. The topographic changes on the caldera‐sized scale that occurred at the caldera can be explained as a source of the October tsunami. Plain Language Summary: On 8 October 2023 (UTC), earthquakes were followed by tsunamis in the Izu‐Ogasawara Arc of Japan that were higher than that estimated from the magnitude of the earthquake. The tsunamis were observed on islands in the Izu‐Ogasawara Arc and a wide area of the Pacific coast of southwest Japanese islands. Strong T‐phases that are underwater acoustic waves were observed accompanying that event. We estimated that the T‐phases originated from the area around the Sofu Seamount, which has not been recognized as an active submarine volcano until now. One month after the event, we conducted a bathymetric survey of the seamount and revealed the characteristics of a caldera and a central cone within the caldera. Compared to the bathymetric data obtained in 1987, the caldera and central cone topography have changed significantly, such as a crater forming in the central cone, indicating that this seamount is likely to have been an active submarine volcano. The topographic changes that occurred at the depth of the caldera (∼1,000 m) and its scale (diameter ∼5 km) can be associated with the source of the tsunami on 8 October 2023. Key Points: A bathymetric survey of the Sofu Seamount was conducted after the unique T‐phase dominant earthquakes and tsunamis on 8 October 2023Compared to data in 1987, the caldera and central cone topography have changed, indicating that this seamount is an active submarine volcanoThe observed seafloor displacement at the caldera scale may have contributed to the source of the tsunami on 8 October 2023 [ABSTRACT FROM AUTHOR]

Aims: Atrial fibrillation (AF) is frequently associated with heart failure with preserved ejection fraction (HFpEF), but the diagnosis and prediction of the outcomes of HFpEF are difficult. Notably, the Heart Failure Association of the European Society of Cardiology proposed the use of the HFA–PEFF score in the diagnosis of HFpEF. This study aimed to assess the prognostic value of the pre‐ and post‐procedural HFA–PEFF scores in patients with preserved ejection fraction (EF) after catheter ablation (CA) for AF. The primary endpoint was a composite of cardiac hospitalization for cardiovascular events and all‐cause mortality. The secondary endpoint was AF recurrence. Methods and results: Overall, 354 patients with AF and preserved EF who underwent CA as well as blood tests and transthoracic echocardiography 2 weeks before and 6 months after CA from January 2018 to December 2019 were retrospectively enrolled in the study. In the 354 participants, univariate analysis showed that the post‐procedural HFA–PEFF score was associated with a 3‐year risk of the primary endpoint (hazard ratio [HR] = 3.73; 95% confidence interval [CI] = 2.07–6.73; P < 0.001), whereas the pre‐procedural HFA–PEFF score was not (HR = 1.24, 95% CI = 0.82–1.86, P = 0.307). Further, the association between the post‐procedural HFA–PEFF score and primary endpoint was not modified even after including other relevant variables into the score. Similar to the primary endpoint, the post‐procedural HFA–PEFF score was associated with the 3‐year risk of AF recurrence (P < 0.001). Conclusions: In patients with preserved EF undergoing AF ablation, the HFA–PEFF score at 6 months after CA was associated with the primary endpoint and AF recurrence at the 3‐year follow‐up. [ABSTRACT FROM AUTHOR]

Recently, conduction system pacing has been performed in patients with impaired cardiac function. We report a case in which a DF4 implantable cardioverter defibrillator lead was screwed directly into the left bundle branch area with the support of a steerable delivery sheath. [ABSTRACT FROM AUTHOR]

Many factors are associated with the development and progression of metabolic dysfunction-associated steatotic liver disease (MASLD); however, genetics and gut microbiota are representative factors. Recent studies have highlighted the link between host genes and the gut microbiota. Although there have been many studies on the separate effects of single nucleotide polymorphisms (SNPs) and gut bacteria on MASLD, few epidemiological studies have examined how SNPs and gut bacteria interact in the development and progression of MASLD. This study aimed to investigate the association between PNPLA3 rs738409, a representative MASLD-related SNP, and gut bacteria in MASLD using a cross-sectional study of the general population. The 526 participants (318 normal and 208 MASLD groups) were grouped into the PNPLA3 rs738409 SNP, CC, CG, and GG genotypes, and the differences in the gut microbiota were investigated in each group. The PNPLA3 rs738409 CC and CG genotypes were associated with decreased Blautia and Ruminococcaceae in the MASLD group. They were negatively correlated with controlled attenuation parameter levels, body mass index, serum blood glucose, and triglycerides. In contrast, there was no association between the normal and MASLD groups and the gut bacteria in the PNPLA3 rs738409, the GG genotype group. This finding implies that dietary interventions and probiotics may be more effective in preventing and treating MASLD in individuals with the PNPLA3 rs738409 CC and CG genotypes. In contrast, their efficacy may be limited in those with the GG genotype. [ABSTRACT FROM AUTHOR]

This study aimed to investigate the effect of Japanese dietary patterns on metabolic dysfunction-associated steatotic liver disease (MASLD) and liver fibrosis. After excluding factors affecting the diagnosis of hepatic steatosis, 727 adults were analyzed as part of the Health Promotion Project. The dietary patterns of the participants were classified into rice, vegetable, seafood, and sweet based on their daily food intake. Liver stiffness measurements and controlled attenuation parameters were performed using FibroScan. Energy and nutrient intake were calculated using the Brief-type Self-administered Diet History Questionnaire. Univariate and multivariate analyses were used to identify the risk factors for liver fibrosis within the MASLD population. The vegetable group had significantly lower liver fibrosis indicators in the MASLD population than the rice group. The multivariate analysis identified a body mass index ≥ 25 kg/m2 (odds ratio [OR], 1.83; 95% confidence interval [CI], 1.01–1.83; p = 0.047) and HOMA-IR ≥ 1.6 (OR, 3.18; 95% CI, 1.74–5.78; p < 0.001) as risk factors for liver fibrosis, and vegetable group membership was a significant low-risk factor (OR, 0.38; 95% CI, 0.16–0.88; p = 0.023). The multivariate analysis of nutrients in low-risk foods revealed high intake of α-tocopherol (OR, 0.74; 95% CI, 0.56–0.99; p = 0.039) as a significant low-risk factor for liver fibrosis. This study suggests that a vegetable-based Japanese dietary pattern, through the antioxidant effects of α-tocopherol, may help prevent liver fibrosis in MASLD and the development of MASLD. [ABSTRACT FROM AUTHOR]

One of the characteristics of chronic kidney disease (CKD) is the accumulation of uremic solutes in the plasma. Less is known about the effects of uremic solutes on transporters that may play critical roles in pharmacokinetics. We evaluated the effect of 72 uremic solutes on organic anion transporter 1 and 3 (OAT1 and OAT3) using a fluorescent probe substrate, 6-carboxyfluorescein. A total of 12 and 13 solutes were identified as inhibitors of OAT1 and OAT3, respectively. Several of them inhibited OAT1 or OAT3 at clinically relevant concentrations and reduced the transport of other OAT1/3 substrates in vitro. Review of clinical studies showed that the active secretion of most drugs that are known substrates of OAT1/3 deteriorated faster than the renal filtration in CKD. Collectively, these data suggest that through inhibition of OAT1 and OAT3, uremic solutes contribute to the decline in renal drug clearance in patients with CKD.