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Thyroid hormones (thyroxine, T4, and triiodothyronine, T3) are indispensable for sustaining vertebrate life, and their deficiency gives rise to a wide range of symptoms characteristic of hypothyroidism, affecting 5–10% of the world’s population. The precursor for thyroid hormone synthesis is thyroglobulin (Tg), a large iodoglycoprotein consisting of upstream regions I-II-III (responsible for synthesis of most T4) and the C-terminal CholinEsterase-Like (ChEL) domain (responsible for synthesis of most T3, which can also be generated extrathyroidally by T4 deiodination). Using CRISPR/Cas9-mediated mutagenesis, we engineered a knock-in of secretory ChEL into the endogenous TG locus. Secretory ChEL acquires Golgi-type glycans and is properly delivered to the thyroid follicle lumen, where T3 is first formed. Homozygous knock-in mice are capable of thyroidal T3 synthesis but largely incompetent for T4 synthesis such that T4-to-T3 conversion contributes little. Instead, T3 production is regulated thyroidally by thyrotropin (TSH). Compared to cog/cog mice with conventional hypothyroidism (low serum T4 and T3), the body size of ChEL-knock-in mice is larger; although, these animals with profound T4 deficiency did exhibit a marked elevation of serum TSH and a large goiter, despite normal circulating T3 levels. ChEL knock-in mice exhibited a normal expression of hepatic markers of thyroid hormone action but impaired locomotor activities and increased anxiety-like behavior, highlighting tissue-specific differences in T3 versus T4 action, reflecting key considerations in patients receiving thyroid hormone replacement therapy.

Abstract Disclosure: C.E. Citterio: None. B. Morales-Rodriguez: None. X. Liao: None. C. Vu: None. R. Nguyen: None. J. Tsai: None. J. Le: None. I. Metawea: None. M. Liu: None. D.P. Olson: None. S. Refetoff: None. P. Arvan: None. Thyroid hormones (T4 and T3) are indispensable for sustaining vertebrate life, and their deficiency gives rise to a wide range of symptoms characteristic of hypothyroidism, affecting 5-10% of the world’s population. T3 and T4 may make distinct contributions to the physiology of different organ systems, and a subset of hypothyroid patients treated with T4 do not fully normalize their symptoms despite achieving normal TSH levels. The precursor for thyroid hormone synthesis is thyroglobulin (Tg), consisting of upstream regions I-II-III (responsible for synthesis of most T4) and the C-terminal CholinEsterase-Like (ChEL) domain (responsible for synthesis of most T3, which can also be generated extrathyroidally by T4 deiodination). Genetically-engineered mice with a thyroid gland designed for disproportionate T3 generation from the T3-forming ChEL domain of Tg, named ChEL-KI, are capable of thyroidal T3 synthesis but largely incompetent for T4 synthesis such that T4-to-T3 conversion contributes little. We have examined the physiology of a thyroidally-derived T3-centric hormonal environment. Compared to cog/cog mice with conventional hypothyroidism (low serum T4and T3), body size was greater in ChEL-KI mice; although these animals with profound T4 deficiency, despite normal circulating T3 levels, did exhibit a marked elevation of serum TSH and developed a large goiter. ChEL-KI mice exhibited normal expression of the hepatic markers of thyroid hormone action ME1 and D1, indicating that these markers do not require normal circulating levels of T4 but are supported by circulating levels of T3. In contrast with the liver, the CNS is thought to rely substantially on local T3 production from T4 via D2-mediated 5’-deiodination. We examined additional CNS functions that have been reported to be linked to phenotypes in hypothyroid rodents and humans. Both ChEL-KI and cog/cog mice exhibited similar behavioral abnormalities such as impaired motor activity and locomotion, as well as increased anxiety-like behavior compared to euthyroid controls. Thus, we conclude that normal circulating T3 cannot efficiently replace the role of T4 in supporting these behaviors that require local generation of T3 in the CNS. This work highlights tissue-specific differences in T3 versus T4 action, reflecting key considerations in hypothyroid patients receiving thyroid hormone replacement therapy. Presentation: Saturday, July 12, 2025

On Nov 20, 2013, then-Chairman Max Baucus of the US Senate Committee on Finance released a staff discussion draft of proposed reforms to the administration of the tax laws. The Discussion Draft includes provisions intended to simplify the tax filing process and expand electronic filing, address tax-related identify theft, and reduce the tax gap through enhancements to information reporting. The Section of Taxation of the American Bar Association supports the goals underlying these proposals. The Discussion Draft proposes to amend 31 USC § 330 to clarify that the Treasury Department and the Service have the authority to regulate all paid tax return preparers. The Discussion Draft also requested comment on reforming the current tax penalty structure to ensure that penalties are used appropriately to effectively promote taxpayer compliance. The Discussion Draft also requested comment on whether to update the \"Taxpayer Bill of Rights,\" which was last addressed by Congress as part of the Internal Revenue Service Restructuring and Reform Act of 1998.

Clinical decision support systems leveraging artificial intelligence (AI) are increasingly integrated into health care practices, including pharmacy medication verification. Communicating uncertainty in an AI prediction is viewed as an important mechanism for boosting human collaboration and trust. Yet, little is known about the effects on human cognition as a result of interacting with such types of AI advice. This study aimed to evaluate the cognitive interaction patterns of pharmacists during medication product verification when using an AI prototype. Moreover, we examine the impact of AI's assistance, both helpful and unhelpful, and the communication of uncertainty of AI-generated results on pharmacists' cognitive interaction with the prototype. In a randomized controlled trial, 30 pharmacists from professional networks each performed 200 medication verification tasks while their eye movements were recorded using an online eye tracker. Participants completed 100 verifications without AI assistance and 100 with AI assistance (either with black box help without uncertainty information or uncertainty-aware help, which displays AI uncertainty). Fixation patterns (first and last areas fixated, number of fixations, fixation duration, and dwell times) were analyzed in relation to AI help type and helpfulness. Pharmacists shifted 19%-26% of their total fixations to AI-generated regions when these were available, suggesting the integration of AI advice in decision-making. AI assistance did not reduce the number of fixations on fill images, which remained the primary focus area. Unhelpful AI advice led to longer dwell times on reference and fill images, indicating increased cognitive processing. Displaying AI uncertainty led to longer cognitive processing times as measured by dwell times in original images. Unhelpful AI increases cognitive processing time in the original images. Transparency in AI is needed in \"black box\" systems, but showing more information can add a cognitive burden. Therefore, the communication of uncertainty should be optimized and integrated into clinical workflows using user-centered design to avoid increasing cognitive load or impeding clinicians' original workflow. ClinicalTrials.gov NCT06795477; https://clinicaltrials.gov/study/NCT06795477.

In nine patients with chronic lymphocytic leukemia that responded to the noncovalent BTK inhibitor pirtobrutinib and then developed resistance, analysis revealed a number of new mutations in the BTK kinase domain and occasional mutations in downstream PLCγ2. Despite the inactivity of BTK, alternative pathways of B-cell–receptor signaling were evident.

Most cases of hepatocellular carcinoma occur in the Asia-Pacific region, where chronic hepatitis B infection is an important aetiological factor. Assessing the efficacy and safety of new therapeutic options in an Asia-Pacific population is thus important. We did a multinational phase III, randomised, double-blind, placebo-controlled trial to assess the efficacy and safety of sorafenib in patients from the Asia-Pacific region with advanced (unresectable or metastatic) hepatocellular carcinoma. Between Sept 20, 2005, and Jan 31, 2007, patients with hepatocellular carcinoma who had not received previous systemic therapy and had Child-Pugh liver function class A, were randomly assigned to receive either oral sorafenib (400 mg) or placebo twice daily in 6-week cycles, with efficacy measured at the end of each 6-week period. Eligible patients were stratified by the presence or absence of macroscopic vascular invasion or extrahepatic spread (or both), Eastern Cooperative Oncology Group performance status, and geographical region. Randomisation was done centrally and in a 2:1 ratio by means of an interactive voice-response system. There was no predefined primary endpoint; overall survival, time to progression (TTP), time to symptomatic progression (TTSP), disease control rate (DCR), and safety were assessed. Efficacy analyses were done by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00492752. 271 patients from 23 centres in China, South Korea, and Taiwan were enrolled in the study. Of these, 226 patients were randomly assigned to the experimental group (n=150) or to the placebo group (n=76). Median overall survival was 6·5 months (95% CI 5·56–7·56) in patients treated with sorafenib, compared with 4·2 months (3·75–5·46) in those who received placebo (hazard ratio [HR] 0·68 [95% CI 0·50–0·93]; p=0·014). Median TTP was 2·8 months (2·63–3·58) in the sorafenib group compared with 1·4 months (1·35–1·55) in the placebo group (HR 0·57 [0·42–0·79]; p=0·0005). The most frequently reported grade 3/4 drug-related adverse events in the 149 assessable patients treated with sorafenib were hand-foot skin reaction (HFSR; 16 patients [10·7%]), diarrhoea (nine patients [6·0%]), and fatigue (five patients [3·4%]). The most common adverse events resulting in dose reductions were HFSR (17 patients [11·4%]) and diarrhoea (11 patients [7·4%]); these adverse events rarely led to discontinuation. Sorafenib is effective for the treatment of advanced hepatocellular carcinoma in patients from the Asia-Pacific region, and is well tolerated. Taken together with data from the Sorafenib Hepatocellular Carcinoma Assessment Randomised Protocol (SHARP) trial, sorafenib seems to be an appropriate option for the treatment of advanced hepatocellular carcinoma. Bayer HealthCare Pharmaceuticals and Onyx Pharmaceuticals, Inc.

The rationale for intraperitoneal (IP) chemotherapy is to expose peritoneal tumors to high drug concentrations. While multiple phase III trials have established the significant survival advantage by adding IP therapy to intravenous therapy in optimally debulked ovarian cancer patients, the use of IP chemotherapy is limited by the complications associated with indwelling catheters and by the local chemotherapy-related toxicity. The present study evaluated the effects of drug carrier on the disposition and efficacy of IP paclitaxel, for identifying strategies for further development of IP treatment. Three paclitaxel formulations, i.e., Cremophor micelles, Cremophor-free paclitaxel-loaded gelatin nanoparticles and polymeric microparticles, were evaluated for peritoneal targeting advantage and antitumor activity in mice after IP injection. Whole body autoradiography and scanning electron microscopy were used to visualize the spatial drug distribution in tissues. A kinetic model, depicting the multiple processes involved in the peritoneal-to-plasma transfer of paclitaxel and its carriers, was established to determine the mechanisms by which a drug carrier alters the peritoneal targeting advantage. Autoradiographic results indicated that IP injection yielded much higher paclitaxel concentrations in intestinal tissues relative to intravenous injection. Compared to the Cremophor and nanoparticle formulations, the microparticles showed slower drug clearance from the peritoneal cavity, slower absorption into the systemic circulation, longer residence time, 10- to 45-times greater peritoneal targeting advantage and approximately 2-times longer increase in survival time (p < 0.01 for all parameters). Our results indicate the important roles of drug carrier in determining the peritoneal targeting advantage and antitumor activity of IP treatment.

The Great American Biotic Interchange (GABI) was a key biogeographic event in the history of the Americas. The rising of the Panamanian land bridge ended the isolation of South America and ushered in a period of dispersal, mass extinction, and new community assemblages, which sparked competition, adaptation, and speciation. Diversification across many bird groups, and the elevational zonation of others, ties back to events triggered by the GABI. But the exact timing of these events is still being revealed, with recent studies suggesting a much earlier time window for faunal exchange, perhaps as early as 20 million years ago (Mya). Using a time‐calibrated phylogenetic tree, we show that the jay genus Cyanolyca is emblematic of bird dispersal trends, with an early, pre‐land bridge dispersal from Mesoamerica to South America 6.3–7.3 Mya, followed by a back‐colonization of C. cucullata to Mesoamerica 2.3–4.8 Mya, likely after the land bridge was complete. As Cyanolyca species came into contact in Mesoamerica, they avoided competition due to a prior shift to lower elevation in the ancestor of C. cucullata. This shift allowed C. cucullata to integrate itself into the Mesoamerican highland avifauna, which our time‐calibrated phylogeny suggests was already populated by higher‐elevation, congeneric dwarf‐jays (C. argentigula, C. pumilo, C. mirabilis, and C. nanus). The outcome of these events and fortuitous elevational zonation was that C. cucullata could continue colonizing new highland areas farther north during the Pleistocene. Resultingly, four C. cucullata lineages became isolated in allopatric, highland regions from Panama to Mexico, diverging in genetics, morphology, plumage, and vocalizations. At least two of these lineages are best described as species (C. mitrata and C. cucullata). Continued study will further document the influence of the GABI and help clarify how dispersal and vicariance shaped modern‐day species assemblages in the Americas. Cyanolyca jays are representative of general trends in avian movements during the Great American Biotic Interchange: dispersal from Mesoamerica to South America during a pre‐land bridge pulse before 5 million years ago, followed by dispersal from South America to Mesoamerica after the land linkage. Upon back‐colonizing Mesoamerica, the Azure‐hooded Jay (C. cucullata) diversified on a Pleistocene landscape already sculpted by geologic processes and populated by higher‐elevation congeners.

This paper provides a content analysis of studies in technology-based learning (TBL) that were published in five Social Sciences Citation Index (SSCI) journals (i.e. the British Journal of Educational Technology, Computers ＆ Education, Educational Technology Research ＆ Development, Educational Technology ＆ Society, the Journal of Computer Assisted Learning) from 2000 to 2009. A total of 2,976 articles were cross-analyzed by three categories including research topic, research sample group, and learning domain. It was found that ＂Pedagogical design and theories＂ was the most popular research topic, ＂Higher Education＂ was the most utilized sample group, and ＂Non-specified＂ and ＂Engineering/Computer sciences＂ were the most selected learning domains in the last decade. However, topics in ＂Motivation, Perceptions and Attitudes＂ drew more attention in the latest five years, while the number of articles in ＂Digital game and intelligent toy enhanced learning＂ and ＂Mobile and Ubiquitous Learning＂ grew significantly between 2005 and 2009. Furthermore, the Chi-square analysis results showed that there were significant associations among these three categories. The results of the analysis provide insights for educators and researchers into research trends and patterns of technology-based learning.

This article investigates the effects of continuous positive airway pressure (CPAP) on hearing impairment in sensorineural hearing loss (SNHL) patients with sleep-disordered breathing (SDB). This retrospective and observational study took place from September 2016 to February 2021, accumulating 77 subjects with SNHL and SDB (60.7 ± 11.1 years). Of which, 28 received CPAP treatment (63.0 ± 8.5 years). In our methodology, hearing thresholds at low, medium, high, and average frequencies are assessed by pure-tone audiometry at baseline (BL), three (3 m), six (6 m), and 12 (12 m) months. Our results show that the BL of at least three frequencies in all subjects is positively associated with old age, males, smoking, alcohol, coronary artery disease, hypertension, and apnea-hypopnea index [AHI] (all p < 0.05). Moreover, low, medium, and average frequencies are negatively correlated at CPAP-6 m (−5.60 ± 2.33, −5.82 ± 2.56, and −5.10 ± 2.26 dB; all p < 0.05) and CPAP-12 m (−7.97 ± 2.74, −8.15 ± 2.35, and −6.67 ± 2.37 dB; all p < 0.01) against corresponding measures of CPAP-BL. High, medium, and average frequencies positively correlated with age (p < 0.001 for high and average frequencies and <0.01 for medium frequencies). We conclude that in SNHL patients with SDB, hearing thresholds at low and medium frequencies improves under CPAP use after six months, which persists at least to the end of one year.