Cefiderocol for treating severe aerobic Gram-negative bacterial infections: technology evaluation to inform a novel subscription-style payment model.

Background: To limit the use of antimicrobials without disincentivising the development of novel antimicrobials, there is interest in establishing innovative models that fund antimicrobials based on an evaluation of their value as opposed to the volumes used. The aim of this project was to evaluate the population-level health benefit of cefiderocol in the NHS in England, for the treatment of severe aerobic Gram-negative bacterial infections when used within its licensed indications. The results were used to inform the National Institute for Health and Care Excellence guidance in support of commercial discussions regarding contract value between the manufacturer and NHS England. Methods: The health benefit of cefiderocol was first derived for a series of high-value clinical scenarios. These represented uses that were expected to have a significant impact on patients' mortality risks and health-related quality of life. The clinical effectiveness of cefiderocol relative to its comparators was estimated by synthesising evidence on susceptibility of the pathogens of interest to the antimicrobials in a network meta-analysis. Patient-level costs and health outcomes of cefiderocol under various usage scenarios compared with alternative management strategies were quantified using decision modelling. Results were reported as incremental net health effects expressed in quality-adjusted life-years, which were scaled to 20-year population values using infection number forecasts based on data from Public Health England. The outcomes estimated for the high-value clinical scenarios were extrapolated to other expected uses for cefiderocol. Results: Among Enterobacterales isolates with the metallo-beta-lactamase resistance mechanism, the base-case network meta-analysis found that cefiderocol was associated with a lower susceptibility relative to colistin (odds ratio 0.32, 95% credible intervals 0.04 to 2.47), but the result was not statistically significant. The other treatments were also associated with lower susceptibility than colistin, but the results were not statistically significant. In the metallo-beta-lactamase Pseudomonas aeruginosa base-case network meta-analysis, cefiderocol was associated with a lower susceptibility relative to colistin (odds ratio 0.44, 95% credible intervals 0.03 to 3.94), but the result was not statistically significant. The other treatments were associated with no susceptibility. In the base case, patient-level benefit of cefiderocol was between 0.02 and 0.15 quality-adjusted life-years, depending on the site of infection, the pathogen and the usage scenario. There was a high degree of uncertainty surrounding the benefits of cefiderocol across all subgroups. There was substantial uncertainty in the number of infections that are suitable for treatment with cefiderocol, so population-level results are presented for a range of scenarios for the current infection numbers, the expected increases in infections over time and rates of emergence of resistance. The population-level benefits varied substantially across the base-case scenarios, from 896 to 3559 quality-adjusted life-years over 20 years. Conclusion: This work has provided quantitative estimates of the value of cefiderocol within its areas of expected usage within the NHS. Limitations: Given existing evidence, the estimates of the value of cefiderocol are highly uncertain. Future work: Future evaluations of antimicrobials would benefit from improvements to NHS data linkages; research to support appropriate synthesis of susceptibility studies; and application of routine data and decision modelling to assess enablement value. Study registration: No registration of this study was undertaken. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment Policy Research Programme (NIHR award ref: NIHR135591), conducted through the Policy Research Unit in Economic Methods of Evaluation in Health and Social Care Interventions, PR-PRU-1217-20401, and is published in full in Health Technology Assessment; Vol. 28, No. 28. See the NIHR Funding and Awards website for further award information.

This project tested new methods for estimating the value to the NHS of an antimicrobial, cefiderocol, so its manufacturer could be paid fairly even if very little drug is used in order to reduce the risk of bacteria becoming resistant to the product. Clinicians said that the greatest benefit of cefiderocol is when used for complicated urinary tract infections and pneumonia acquired within hospitals caused by two types of bacteria (called Enterobacterales and Pseudomonas aeruginosa), with a resistance mechanism called metallo-beta-lactamase. Because there were no relevant clinical trial data, we estimated how effective cefiderocol and alternative treatments were by doing a systematic literature review of studies that grew bacteria from infections in the laboratory and tested the drugs on them. We linked this to data estimating the long-term health and survival of patients. Some evidence was obtained by asking clinicians detailed questions about what they thought the effects would be based on their experience and the available evidence. We included the side effects of the alternative treatments, some of which can cause kidney damage. We estimated how many infections there would be in the UK, whether they would increase over time and how resistance to treatments may change over time. Clinicians told us that they would also use cefiderocol to treat intra-abdominal and bloodstream infections, and some infections caused by another bacteria called Stenotrophomonas. We estimated how many of these infections there would be, and assumed the same health benefits as for other types of infections. The total value to the NHS was calculated using these estimates. We also considered whether we had missed any additional elements of value. We estimated that the value to the NHS was £18­71 million over 20 years. This reflects the maximum the NHS could pay for use of cefiderocol if the health lost as a result of making these payments rather than funding other NHS services is not to exceed the health benefits of using this antimicrobial. However, these estimates are uncertain due to limitations with the evidence used to produce them and assumptions that had to be made.

Single-Cell RNA Sequencing Reveals HIF1A as a Severity-Sensitive Immunological Scar in Circulating Monocytes of Convalescent Comorbidity-Free COVID-19 Patients.

COVID-19, caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), is characterized by a wide range of clinical symptoms and a poorly predictable disease course. Although in-depth transcriptomic investigations of peripheral blood samples from COVID-19 patients have been performed, the detailed molecular mechanisms underlying an asymptomatic, mild or severe disease course, particularly in patients without relevant comorbidities, remain poorly understood. While previous studies have mainly focused on the cellular and molecular dissection of ongoing COVID-19, we set out to characterize transcriptomic immune cell dysregulation at the single-cell level at different time points in patients without comorbidities after disease resolution to identify signatures of different disease severities in convalescence. With single-cell RNA sequencing, we reveal a role for hypoxia-inducible factor 1-alpha (HIF1A) as a severity-sensitive long-term immunological scar in circulating monocytes of convalescent COVID-19 patients. Additionally, we show that circulating complexes formed by monocytes with either T cells or NK cells represent a characteristic cellular marker in convalescent COVID-19 patients irrespective of their preceding symptom severity. Together, these results provide cellular and molecular correlates of recovery from COVID-19 and could help in immune monitoring and in the design of new treatment strategies.

Only bioactive forms of PTH (n-oxPTH and Met18(ox)-PTH) inhibit synthesis of sclerostin - evidence from in vitro and human studies.

Sclerostin (SOST) is produced by osteocytes and is known as a negative regulator of bone homeostasis. Parathyroid hormone (PTH) regulates calcium, phosphate as well as vitamin D metabolism, and is a strong inhibitor of SOST synthesis in vitro and in vivo. PTH has two methionine amino acids (positions 8 and 18) which can be oxidized. PTH oxidized at Met18 (Met18(ox)-PTH) continues to be bioactive, whereas PTH oxidized at Met8 (Met8(ox)-PTH) or PTH oxidized at Met8 and Met18 (Met8, Met18(di-ox)-PTH) has minor bioactivity. How non-oxidized PTH (n-oxPTH) and oxidized forms of PTH act on sclerostin synthesis is unknown. The effects of n-oxPTH and oxidized forms of PTH on SOST gene expression were evaluated in UMR106 osteoblast-like cells. Moreover, we analyzed the relationship of SOST with n-oxPTH and all forms of oxPTH in 516 stable kidney transplant recipients using an assay system that can distinguish in clinical samples between n-oxPTH and the sum of all oxidized PTH forms (Met8(ox)-PTH, Met18(ox)-PTH, and Met8, Met18(di-ox)-PTH). We found that both n-oxPTH and Met18(ox)-PTH at doses of 1, 3, 20, and 30 nmol/L significantly inhibit SOST gene expression in vitro, whereas Met8(ox)-PTH and Met8, Met18(di-ox)-PTH only have a weak inhibitory effect on SOST gene expression. In the clinical cohort, multivariate linear regression showed that only n-oxPTH, but not intact PTH (iPTH) nor oxPTH, is independently associated with circulating SOST after adjusting for known confounding factors. In conclusion, only bioactive PTH forms such as n-oxPTH and Met18(ox)-PTH, inhibit SOST synthesis.

GSK343 modulates macrophage M2 polarization through the EZH2/MST1/YAP1 signaling axis to mitigate neurological damage induced by hypercalcemia in CKD mice.

Chronic kidney disease (CKD) often culminates in hypercalcemia, instigating severe neurological injuries that are not yet fully understood. This study unveils a mechanism, where GSK343 ameliorates CKD-induced neural damage in mice by modulating macrophage polarization through the EZH2/MST1/YAP1 signaling axis. Specifically, GSK343 downregulated the expression of histone methyltransferase EZH2 and upregulated MST1, which suppressed YAP1, promoting M2 macrophage polarization and thereby, alleviating neural injury in hypercalcemia arising from renal failure. This molecular pathway introduced herein not only sheds light on the cellular machinations behind CKD-induced neurological harm but also paves the way for potential therapeutic interventions targeting the identified axis, especially considering the M2 macrophage polarization as a potential strategy to mitigate hypercalcemia-induced neural injuries.

Three new species of the spider genus Utivarachna Kishida, 1940 (Araneae, Trachelidae) from China and Vietnam.

Three new species belonging to the kinabaluensis group of the trachelid genus Utivarachna Kishida, 1940 are reported from China and Vietnam: U.linyejieisp. nov. (♂♀), U.tamdaosp. nov. (♂♀), and U.zhengguoisp. nov. (♂♀). Type specimens are deposited in the Institute of Zoology, Chinese Academy of Sciences (IZCAS) in Beijing, China and the Vietnam National Museum of Nature (VNMN) in Hanoi, Vietnam.

One new genus and four new species of Liocranidae Simon, 1897 (Arachnida, Araneae) from China and Vietnam.

Four new species of the family Liocranidae are described from China and Vietnam. The new genus Sinocranumgen. nov., is erected to accommodate S.menghaisp. nov. (♂♀) from China. Further new species described include Koppeningersp. nov. (♀) from China, Xanthariabaizilongisp. nov. (♂♀) from China and X.cucphuongsp. nov. (♂) from Vietnam. In addition, Xantharia is transferred from Miturgidae to Liocranidae. Koppe and Xantharia are reported from China and Vietnam, respectively, for the first time.

Fibroblast growth factor 23 is associated with the development of gestational diabetes mellitus.

BACKGROUND: Besides its established impact on bone and mineral metabolism, it was suggested that fibroblast growth factor 23 (FGF23) might play an important role in the pathogenesis of type 2 diabetes. The impact of FGF23 on gestational diabetes mellitus (GDM), however, is not well understood. iFGF23 ELISAs measure the intact FGF23 molecule, whereas cFGF23 assays measure intact FGF23 as well as degradation products of FGF23. OBJECTIVES: The aim of this study is to compare the association of maternal and foetal cFGF23 and iFGF23 with GDM in a German birth cohort. METHODS: cFGF23 and iFGF23 were analysed in 826 random mother/child pairs from the Berlin Birth Cohort. RESULTS: Mothers who developed GDM had higher concentrations of iFGF-23 compared to mothers who did not suffer from GDM (19.73 vs. 13.23 pg/mL, p < 0.0001), but not higher concentrations of cFGF-23. Multivariant regression analyses showed that gestational diabetes is associated with iFGF23 independently of confounding factors such as age, BMI, ethnic background, family history of diabetes, smoking during pregnancy, and recurrent pregnancy loss. This, however, was only seen when using an iFGF23 ELISA measuring just the full length FGF23 and not in addition FGF23 fragments. No differences in both iFGF23 and cFGF23 concentrations between the GDM and non-GDM groups were detected in cord blood samples of the offspring. CONCLUSIONS: This study of a representative German birth cohort showed that maternal but not foetal iFGF23 is independently associated with GDM.

Three new species of liocranid spiders (Arachnida: Araneae) from China and Nepal.

Three new species of spiders belonging to the genera Oedignatha Thorell, 1881 and Paratus Simon, 1898 of the family Liocranidae Simon, 1897 are described from China and Nepal: Oedignatha shaanxi sp. nov. (female only; Shaanxi, China), Paratus bagmati sp. nov. (male only; Bagmati, Nepal), and P. ledong sp. nov. (both sexes; Hainan, China). In addition, Liocranidae is reported from Nepal for the first time.

Immune response of heterologous versus homologous prime-boost regimens with adenoviral vectored and mRNA COVID-19 vaccines in immunocompromised patients.

Due to rare but major adverse reactions to the AstraZeneca adenoviral ChAdOx1-S-nCoV-19 vaccine (ChAd), German health authorities recommended adults under 60 who received one dose of ChAd, to receive a second dose of the BioNTech mRNA BNT162b2 vaccine (BNT) as a booster. Studies in the general population suggest an enhanced efficacy of the heterologous (ChAd-BNT) compared to the homologous (BNT-BNT) vaccination regimen. However, an analysis of the efficacy in patient populations with a high risk of severe COVID-19 due to acquired immunodeficiency is still missing. We therefore compared both vaccination regimens in healthy controls, patients with gynecological tumors after chemotherapy, patients on dialysis and patients with rheumatic diseases concerning the humoral and cellular immune response. The humoral and cellular immune response differed substantially in healthy controls compared to patients with acquired immunodeficiency. Overall, the most significant differences between the two immunization regimens were found in neutralizing antibodies. These were always higher after a heterologous immunization. Healthy controls responded well to both vaccination regimens. However, the formation of neutralizing antibodies was more pronounced after a heterologous immunization. Dialysis patients, on the other hand, only developed an adequate humoral and particularly cellular immune response after a heterologous immunization. Tumor and rheumatic patients also - to a weaker extent compared to dialysis patients - benefited from a heterologous immunization. In conclusion, the heterologous COVID-19 vaccination regimens (ChAd-BNT) seem to have an advantage over the homologous vaccination regimens, especially in immunocompromised patients such as patients with end-stage kidney disease treated with hemodialysis.

Two new genera and five new species of Corinnidae Karsch, 1880 (Arachnida, Araneae) from China and Vietnam.

Six species of the family Corinnidae Karsch, 1880 are described from China and Vietnam. Fengzhengen. nov. is erected to accommodate F.menglasp. nov. (♂♀) from China; Penggen. nov. is erected to accommodate P.birmanicus (Thorell, 1897), comb. nov., P.borneensis (Yamasaki, 2017), comb. nov. and P.taprobanicus (Simon, 1897), comb. nov., transferred from Sphecotypus O. Pickard-Cambridge, 1895. Further new species described include Allomedmassatamdaosp. nov. (♂), Echinaxbaishasp. nov. (♂), Medmassalingshuisp. nov. (♂), and Spinirtashaoguansp. nov. (♂). The male of P.birmanicus is described for the first time.

On two new Oedignatha species from Xishuangbanna, China, and the first description of the female of Jacaenamenglaensis Mu & Zhang, 2020 (Araneae, Liocranidae).

Liocranid spiders from the Xishuangbanna Tropical Botanical Garden in Yunnan, China are studied. Two new species of Oedignatha Thorell, 1881, O.dian Lu & Li, sp. nov. (♂♀) and O.menglun Lu & Li, sp. nov. (♂♀), are described, and the female of Jacaenamenglaensis Mu & Zhang, 2020 is described for the first time. The specimens studied are deposited in the Institute of Zoology, Chinese Academy of Sciences (IZCAS) in Beijing, China.

25(OH)D-but not 1,25(OH)2D-Is an independent risk factor predicting graft loss in stable kidney transplant recipients.

Background: Vitamin D deficiency (VDD) or vitamin D insufficiency is common in kidney transplant recipients (KTRs). The impact of VDD on clinical outcomes in KTRs remain poorly defined and the most suitable marker for assessing vitamin D nutritional status in KTRs is unknown so far. Methods: We conducted a prospective study including 600 stable KTRs (367 men, 233 women) and a meta-analysis to pool existing evidence to determine whether 25(OH)D or 1,25(OH)2D predicted graft failure and all-cause mortality in stable KTRs. Results: Compared with a higher 25(OH)D concentration, a low concentration of 25(OH)D was a risk factor for graft failure (HR 0.946, 95% CI 0.912-0.981, p = 0.003), whereas 1,25 (OH)2D was not associated with the study end-point graft loss (HR 0.993, 95% CI 0.977-1.009, p = 0.402). No association was found between either 25(OH)D or 1,25 (OH)2D and all-cause mortality. We furthermore conducted a meta-analysis including 8 studies regarding the association between 25(OH)D or 1,25(OH)2D and graft failure or mortality, including our study. The meta-analysis results were consistent with our study in finding that lower 25(OH)D levels were significantly associated with the risk of graft failure (OR = 1.04, 95% CI: 1.01-1.07), but not associated with mortality (OR = 1.00, 95% CI: 0.98-1.03). Lower 1,25(OH)2D levels were not associated with the risk of graft failure (OR = 1.01, 95% CI: 0.99-1.02) and mortality (OR = 1.01, 95% CI: 0.99-1.02). Conclusion: Baseline 25(OH)D concentrations but not 1,25(OH)2D concentrations were independently and inversely associated with graft loss in adult KTRs.

Effect of BIM expression on the prognostic value of PD-L1 in advanced non-small cell lung cancer patients treated with EGFR-TKIs.

The role of Programmed Cell Death Ligand 1 (PD-L1) expression in predicting epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKIs) efficacy remains controversial. Recent studies have highlighted that tumor-intrinsic PD-L1 signaling can be modulated by STAT3, AKT, MET oncogenic pathway, epithelial-mesenchymal transition, or BIM expression. This study aimed to investigate whether these underlying mechanisms affect the prognostic role of PD-L1. We retrospectively enrolled patients with EGFR mutant advanced stage NSCLC who received first-line EGFR-TKI between January 2017 and June 2019, the treatment efficacy of EGFR-TKI was assessed. Kaplan-Meier analysis of progression-free survival (PFS) revealed that patients with high BIM expression had shorter PFS, regardless of PD-L1 expression. This result was also supported by the COX proportional hazard regression analysis. In vitro, we further proved that the knockdown of BIM, instead of PDL1, induced more cell apoptosis following gefitinib treatment. Our data suggest that among the pathways affecting tumor-intrinsic PD-L1 signaling, BIM is potentially the underlying mechanism that affects the role of PD-L1 expression in predicting response to EGFR TKI and mediates cell apoptosis under treatment with gefitinib in EGFR-mutant NSCLC. Further prospective studies are required to validate these results.

Transmission modeling to infer tuberculosis incidence prevalence and mortality in settings with generalized HIV epidemics.

Tuberculosis (TB) killed more people globally than any other single pathogen over the past decade. Where surveillance is weak, estimating TB burden estimates uses modeling. In many African countries, increases in HIV prevalence and antiretroviral therapy have driven dynamic TB epidemics, complicating estimation of burden, trends, and potential intervention impact. We therefore develop a novel age-structured TB transmission model incorporating evolving demographic, HIV and antiretroviral therapy effects, and calibrate to TB prevalence and notification data from 12 African countries. We use Bayesian methods to include uncertainty for all TB model parameters, and estimate age-specific annual risks of TB infection, finding up to 16.0%/year in adults, and the proportion of TB incidence from recent (re)infection, finding a mean across countries of 34%. Rapid reduction of the unacceptably high burden of TB in high HIV prevalence settings will require interventions addressing progression as well as transmission.

New genera and new species of Hahniidae (Araneae) from China, Laos, Myanmar, and Vietnam.

Four new genera and 11 new species of Hahniidae Bertkau, 1878 are described. The new genera are Goblinia Lin & Li, gen. nov., with the type species G.tiane Lin & Li, sp. nov. (♂♀) from Guangxi, China; Myahnia Lin & Li, gen. nov., with the type species M.kanpetlet Lin & Li, sp. nov. (♂♀) from Chin, Myanmar; Troglohnia Lin & Li, gen. nov., with the type species Tr.qiubei Lin & Li, sp. nov. (♂♀) from Yunnan, China and Typhlohnia Lin & Li, gen. nov., with the type species Ty.rongshui Lin & Li, sp. nov. (♂♀) from Guangxi, China. Seven additional new species are described: Tr.dafang Lin & Li, sp. nov. (♂♀) from Guizhou, China; Tr.shidian Lin & Li, sp. nov. (♀) from Yunnan, China; Tr.wuding Lin & Li, sp. nov. (♂♀) from Yunnan, China; Ty.banlaksao Lin & Li, sp. nov. (♀) from Bolikhamxay, Laos; Ty.kaiyang Lin & Li, sp. nov. (♀) from Guizhou, China; Ty.sondoong Lin & Li, sp. nov. (♂♀) from Quang Binh, Vietnam and Ty.suiyang Lin & Li, sp. nov. (♀) from Guizhou, China.

Impact of Angiopoietin-2 on Kidney Diseases.

Background: Angiopoietins (Ang) are essential angiogenic factors involved in angiogenesis, vascular maturation, and inflammation. The most studied angiopoietins, angiopoietin-1 (Ang-1) and angiopoietin-2 (Ang-2), behave antagonistically to each other in vivo to sustain vascular endothelium homeostasis. While Ang-1 typically acts as the endothelium-protective mediator, its context-dependent antagonist Ang-2 can promote endothelium permeability and vascular destabilization, hence contributing to a poor outcome in vascular diseases via endothelial injury, vascular dysfunction, and microinflammation. The pathogenesis of kidney diseases is associated with endothelial dysfunction and chronic inflammation in renal diseases. Summary: Several preclinical studies report overexpression of Ang-2 in renal tissues of certain kidney disease models; additionally, clinical studies show increased levels of circulating Ang-2 in the course of chronic kidney disease, implying that Ang-2 may serve as a useful biomarker in these patients. However, the exact mechanisms of Ang-2 action in renal diseases remain unclear. Key Messages: We summarized the recent findings on Ang-2 in kidney diseases, including preclinical studies and clinical studies, aiming to provide a systematic understanding of the role of Ang-2 in these diseases.

Two new species of the genus Asceua Thorell, 1887 (Araneae, Zodariidae) from China.

Background: The spider genus Asceua Thorell, 1887 contains 34 species, almost entirely limited to Indochina, India, Sri Lanka and China, with a regional distribution. Eleven species of Asceua are currently only known from China, five of them are described only from one sex. New information: Two new spider species of the genus Asceua are reported from China, A.haocongi sp. n. (♂♀, Hainan) and A.zijin sp. n. (♂♀, Jiangsu). Photos and a morphological description of the new species are provided.

Risk factors for sudden cardiac arrest in patients with ST-segment elevation myocardial infarction: a retrospective cohort study.

BACKGROUND: Sudden cardiac arrest (SCA) is a critical complication of acute myocardial infarction, especially ST-segment elevation myocardial infarction (STEMI). This study identified the risk factors for SCA in patients with STEMI before receiving catheterization. METHODS: We retrospectively analyzed the data of patients with STEMI and cardiac arrest who presented to a tertiary care center in Taiwan between January 1, 2016, and December 31, 2019. Only patients with coronary artery disease (CAD) confirmed by coronary angiography were included in this study. We collected the patients' demographic and clinical data, such as age, sex, medical history, estimated glomerular filtration rate (eGFR), and coronary angiographic findings. The primary outcome of this study was SCA in patients with STEMI. Continuous and nominal variables were compared using the two-sample Student's t-test and chi-squared test, respectively. The results of logistic regression were subjected to multivariate analysis with adjustment for possible confounders. RESULTS: A total of 920 patients with STEMI and coronary angiography-documented CAD and 108 patients with SCA who presented between January 1, 2016, and December 31, 2019, were included. The bivariate logistic regression analysis of patients' demographic data revealed that patients with STEMI and SCA were slightly younger, were more likely to have diabetes mellitus, and had a lower eGFR than did the patients without SCA. The coronary angiographic findings indicated a higher prevalence of left main CAD and three-vessel disease in patients with SCA than in patients without SCA. Multivariate logistic regression revealed that left main CAD (odds ratio [OR]: 3.77; 95% confidence interval [CI], 1.84 to 7.72), a lower eGFR (OR: 0.97; 95% CI, 0.96 to 0.98), and younger age (OR: 0.98; 95% CI, 0.96 to 0.99) were the risk factors for SCA in patients with STEMI. CONCLUSIONS: Left main CAD, lower eGFR, and younger age are the risk factors for cardiac arrest in patients with acute myocardial infarction.