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IntroductionPirtobrutinib, a highly selective, noncovalent (reversible) Bruton tyrosine kinase inhibitor, has demonstrated promising efficacy in B-cell malignancies and is associated with low rates of discontinuation and dose reduction. Pirtobrutinib is administered until disease progression or toxicity, necessitating an understanding of the safety profile in patients with extended treatment.MethodsHere we report the safety of pirtobrutinib in patients with relapsed/refractory B-cell malignancies with extended (≥12 months) drug exposure from the BRUIN trial. Assessments included median time-to-first-occurrence of adverse events (AEs), dose reductions, and discontinuations due to treatment-emergent AEs (TEAEs) and select AEs of interest (AESIs).ResultsOf 773 patients enrolled, 326 (42%) received treatment for ≥12 months. In the extended exposure cohort, the median time-on-treatment was 19 months. The most common all-cause TEAEs were fatigue (32%) and diarrhea (31%). TEAEs leading to dose reduction occurred in 23 (7%) and discontinuations in 11 (3%) extended exposure patients. One patient had a fatal treatment-related AE (COVID-19 pneumonia). Infections (73.0%) were the most common AESI with a median time-to-first-occurrence of 7.4 months. Majority of TEAEs and AESIs occurred during the first year of therapy.ConclusionsPirtobrutinib therapy continues to demonstrate an excellent safety profile amenable to long-term administration without evidence of new or worsening toxicity signals.

UNLABELLED: Wastewater treatment plants (WWTPs) are indispensable biotechnology facilities for modern cities and play an essential role in modern urban infrastructure by employing microorganisms to remove pollutants in wastewater, thus protecting public health and the environment. This study conducted a 13-month bacterial community survey of six full-scale WWTPs in Hong Kong with samples of influent, activated sludge (AS), and effluent to explore their synchronism and asynchronism of bacterial community. Besides, we compared AS results of six Hong Kong WWTPs with data from 1,186 AS amplicon data in 269 global WWTPs and a 9-year metagenomic sequencing survey of a Hong Kong WWTP. Our results showed the compositions of bacterial communities varied and the bacterial community structure of AS had obvious differences across Hong Kong WWTPs. The co-occurrence analysis identified 40 pairs of relationships that existed among Hong Kong WWTPs to show solid associations between two species and stochastic processes took large proportions for the bacterial community assembly of six WWTPs. The abundance and distribution of the functional bacteria in worldwide and Hong Kong WWTPs were examined and compared, and we found that ammonia-oxidizing bacteria had more diversity than nitrite-oxidizing bacteria. Besides, Hong Kong WWTPs could make great contributions to the genome mining of microbial dark matter in the global wanted list. Operational parameters had important effects on OTUs abundance, such as the temperature to the genera of Tetrasphaera, Gordonia and Nitrospira. All these results obtained from this study can deepen our understanding of the microbial ecology in WWTPs and provide foundations for further studies. IMPORTANCE: Wastewater treatment plants (WWTPs) are an indispensable component of modern cities, as they can remove pollutants in wastewater to prevent anthropogenic activities. Activated sludge (AS) is a fundamental wastewater treatment process and it harbors a highly complex microbial community that forms the main components and contains functional groups. Unveiling who is there is a long-term goal of the research on AS microbiology. High-throughput sequencing provides insights into the inventory diversity of microbial communities to an unprecedented level of detail. At present, the analysis of communities in WWTPs usually comes from a specific WWTP and lacks comparisons and verification among different WWTPs. The wide-scale and long-term sampling project and research in this study could help us evaluate the AS community more accurately to find the similarities and different results for different WWTPs in Hong Kong and other regions of the world.

To evaluate the fermentation potential of Guizhou’s specialty fruits, the contents of organic acids and polyphenols juices in juices and laboratory prepared wines from crystal grapes, brier grapes, kiwifruits, golden prickly pears and blueberries grown in Guizhou were analyzed and compared with those of commercial wines. The results showed that the contents of organic acids and polyphenols varied significantly among the five fruit juices, with the highest contents of organic acids (72.30 g/L), total phenols (2 457.16 mg/L), and tannins (1 112.84 mg/L) being found in golden prickly pear juice and the lowest values (organic acids 7.63 g/L, total phenols 8.52 mg/L, and tannins 7.45 mg/L) in crystal grape juice. During the fermentation process, the contents of organic acids and polyphenols changed. The content of total organic acids significantly decreased in all wine samples, the contents of total phenols and anthocyanins increased in blueberry and brier grape wine, and the contents of total phenols and tannins decreased in kiwifruit and golden prickly pear wine but did not change significantly in crystal grape wine. Resveratrol was only detected in commercial red wine and blueberry wine at low levels ranging from 0.29 to 5.98 mg/L. Compared with commercial wines, laboratory prepared golden prickly pear wine had higher contents of organic acids, total phenols and tannins, and laboratory prepared kiwifruit wine had higher contents of organic acids. The anthocyanin content in laboratory prepared brier grape wine was the highest, which was two to three times higher than that of all commercial wines. To sum up, each of the specialty fruits from Guizhou has their own unique characteristics in the composition of organic acids and polyphenols, and their organic acid and polyphenol composition change differently after fermentation into wine. This study provides a theoretical basis for the selection of different technological methods such as maceration in wine processing from Guizhou’s specialty fruits and for the design of wine body from mixed fruit juices.