The Journal of Physical Chemistry 最新文献

Metagenomic next-generation sequencing (mNGS) of cerebrospinal fluid (CSF) is an agnostic method for broad-based diagnosis of central nervous system (CNS) infections. Here we analyzed the 7-year performance of clinical CSF mNGS testing of 4,828 samples from June 2016 to April 2023 performed by the University of California, San Francisco (UCSF) clinical microbiology laboratory. Overall, mNGS testing detected 797 organisms from 697 (14.4%) of 4,828 samples, consisting of 363 (45.5%) DNA viruses, 211 (26.4%) RNA viruses, 132 (16.6%) bacteria, 68 (8.5%) fungi and 23 (2.9%) parasites. We also extracted clinical and laboratory metadata from a subset of the samples (n = 1,164) from 1,053 UCSF patients. Among the 220 infectious diagnoses in this subset, 48 (21.8%) were identified by mNGS alone. The sensitivity, specificity and accuracy of mNGS testing for CNS infections were 63.1%, 99.6% and 92.9%, respectively. mNGS testing exhibited higher sensitivity (63.1%) than indirect serologic testing (28.8%) and direct detection testing from both CSF (45.9%) and non-CSF (15.0%) samples (P < 0.001 for all three comparisons). When only considering diagnoses made by CSF direct detection testing, the sensitivity of mNGS testing increased to 86%. These results justify the routine use of diagnostic mNGS testing for hospitalized patients with suspected CNS infection.

Relapsed/refractory peripheral T cell lymphomas (PTCLs) are aggressive tumors with a poor prognosis. Unlike B cell lymphomas, treatment of PTCL has not benefited from advances in immunotherapy. This is largely due to a lack of suitable target antigens that discriminate malignant from normal T cells, thus avoiding severe immunosuppression consequent to depletion of the entire T cell compartment. We recently described a targeting strategy based on the mutually exclusive expression of T cell antigen receptor beta-chain constant domain (TRBC) 1 and 2. Selective targeting of the T cell antigen receptor beta-chain expressed by the (clonal) malignancy spares normal T cells expressing the other chain. The LibraT1 study is an ongoing, multicenter, international, single-arm phase 1/2 study of TRBC1-directed autologous chimeric antigen receptor (CAR) T cells (AUTO4) in relapsed/refractory TRBC1-positive PTCL. Primary objectives were assessment of safety and tolerability of AUTO4 infusion. Key secondary endpoints included efficacy, CAR T cell expansion and persistence. Here we describe the findings from dose escalation in LibraT1 in the first ten patients, in a non-prespecified interim analysis. AUTO4 resulted in low frequency of severe immunotoxicity, with one of ten patients developing grade 3 cytokine release syndrome. Complete metabolic response was observed in four of ten evaluable patients, with remissions being durable beyond 1 year in two patients. While an absence of circulating CAR T cells was observed, CAR T cells were readily detected in lymph node biopsy samples from sites of original disease suggesting homing to tumor sites. These results support the continuing exploration of TRBC1 targeting in PTCL. ClinicalTrials.gov registration: NCT03590574.

There is a critical unmet need for safe and efficacious neoadjuvant treatment for cisplatin-ineligible patients with muscle-invasive bladder cancer. Here we launched a phase 1b study using the combination of intravesical cretostimogene grenadenorepvec (oncolytic serotype 5 adenovirus encoding granulocyte–macrophage colony-stimulating factor) with systemic nivolumab in cisplatin-ineligible patients with cT2-4aN0-1M0 muscle-invasive bladder cancer. The primary objective was to measure safety, and the secondary objective was to assess the anti-tumor efficacy as measured by pathologic complete response along with 1-year recurrence-free survival. No dose-limiting toxicity was encountered in 21 patients enrolled and treated. Combination treatment achieved a pathologic complete response rate of 42.1% and a 1-year recurrence-free survival rate of 70.4%. Pathologic response was associated with baseline free E2F activity and tumor mutational burden but not PD-L1 status. Although T cell infiltration was broadly induced after intravesical oncolytic immunotherapy, the formation, enlargement and maturation of tertiary lymphoid structures was specifically associated with complete response, supporting the importance of coordinated humoral and cellular immune responses. Together, these results highlight the potential of this combination regimen to enhance therapeutic efficacy in cisplatin-ineligible patients with muscle-invasive bladder cancer, warranting additional study as a neoadjuvant therapeutic option. ClinicalTrials.gov identifier: NCT04610671.

Automated radiology report generation has the potential to improve patient care and reduce the workload of radiologists. However, the path toward real-world adoption has been stymied by the challenge of evaluating the clinical quality of artificial intelligence (AI)-generated reports. We build a state-of-the-art report generation system for chest radiographs, called Flamingo-CXR, and perform an expert evaluation of AI-generated reports by engaging a panel of board-certified radiologists. We observe a wide distribution of preferences across the panel and across clinical settings, with 56.1% of Flamingo-CXR intensive care reports evaluated to be preferable or equivalent to clinician reports, by half or more of the panel, rising to 77.7% for in/outpatient X-rays overall and to 94% for the subset of cases with no pertinent abnormal findings. Errors were observed in human-written reports and Flamingo-CXR reports, with 24.8% of in/outpatient cases containing clinically significant errors in both report types, 22.8% in Flamingo-CXR reports only and 14.0% in human reports only. For reports that contain errors we develop an assistive setting, a demonstration of clinician–AI collaboration for radiology report composition, indicating new possibilities for potential clinical utility.

Climate Change has severe and wide-ranging health impacts, especially for vulnerable groups. Despite growing evidence of heat-associated adverse maternal and neonatal health outcomes, there remains a lack of synthesis quantifying associations and identifying specific risk periods. We systematically reviewed the literature on heat impacts on maternal, fetal, and neonatal health, and quantified impacts through meta-analyses. We found 198 studies across66 countries, predominantly high income (63.3%) and temperature climate zones (40.1%), and 23 outcomes. Results showed increased odds of preterm birth of 1.04 (95%CI = 1.03, 1.06; n = 12) per 1°C increase in heat exposure and 1.26 (95%CI = 1.08, 1.47; n = 10) during heatwaves. Similarly high heat exposure increased the risk for stillbirths (OR = 1.13 (95%CI=0.95, 1.34; n = 9)), congenital anomalies (OR=1.48 (95%CI = 1.16, 1.88; n = 6)), and gestational diabetes mellitus (OR = 1.28 (95%CI = 1.05, 1.74; n = 4)). The odds of any obstetric complication increased by 1.25 (95%CI = 1.09, 1.42; n = 11) during heatwaves. Patterns in susceptibility windows varied by condition. The findings were limited by heterogeneity in exposure metrics and study designs. The systematic review demonstrated that escalating heat exposure poses a major threat to maternal and neonatal health, highlighting research priorities, guiding the selection and monitoring of heat-health indicators, and emphasising the need to prioritise maternal and neonatal health in national climate-health programmes.

Metabolic dysfunction-associated steatohepatitis (MASH) is a major cause of liver-related morbidity and mortality, yet treatment options are limited. Manual scoring of liver biopsies, currently the gold standard for clinical trial enrollment and endpoint assessment, suffers from high reader variability. This study represents the most comprehensive multisite analytical and clinical validation of an artificial intelligence (AI)-based pathology system, AI-based measurement of metabolic dysfunction-associated steatohepatitis (AIM-MASH), to assist pathologists in MASH trial histology scoring. AIM-MASH demonstrated high repeatability and reproducibility compared to manual scoring. AIM-MASH-assisted reads by expert MASH pathologists were superior to unassisted reads in accurately assessing inflammation, ballooning, MAS ≥ 4 with ≥1 in each score category and MASH resolution, while maintaining non-inferiority in steatosis and fibrosis assessment. These findings suggest that AIM-MASH could mitigate reader variability, providing a more reliable assessment of therapeutics in MASH clinical trials.