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Measuring in situ soil fluxes of carbon dioxide (CO 2 ), methane (CH 4 ), and nitrous oxide (N 2 O) continuously at high frequency requires appropriate technology. We tested the combination of a commercial automated soil CO 2 flux chamber system (LI-8100A) with a CH 4 and N 2 O analyzer (Picarro G2308) in a tropical rainforest for 4 months. A chamber closure time of 2 min was sufficient for a reliable estimation of CO 2 and CH 4 fluxes (100% and 98.5% of fluxes were above minimum detectable flux - MDF, respectively). This closure time was generally not suitable for a reliable estimation of the low N 2 O fluxes in this ecosystem but was sufficient for detecting rare major peak events. A closure time of 25 min was more appropriate for reliable estimation of most N 2 O fluxes (85.6% of measured fluxes are above MDF±0.002 nmolm -2 s -1 ). Our study highlights the importance of adjusted closure time for each gas.

Fractionation of soil organic carbon (SOC) is crucial for mechanistic understanding and modeling of soil organic matter decomposition and stabilization processes. It is often aimed at separating the bulk SOC into fractions with varying turnover rates, but a comprehensive comparison of methods to achieve this is lacking. In this study, a total of 20 different SOC fractionation methods were tested by participating laboratories for their suitability to isolate fractions with varying turnover rates, using agricultural soils from three experimental sites with vegetation change from C3 to C4 22–36 years ago. Enrichment of C4-derived carbon was traced and used as a proxy for turnover rates in the fractions. Methods that apply a combination of physical (density, size) and chemical (oxidation, extraction) fractionation were identified as most effective in separating SOC into fractions with distinct turnover rates. Coarse light SOC separated by density fractionation was the most C4-carbon enriched fraction, while oxidation-resistant SOC left after extraction with NaOCl was the least C4-carbon enriched fraction. Surprisingly, even after 36 years of C4 crop cultivation in a temperate climate, no method was able to isolate a fraction with more than 76% turnover, which challenges the link to the most active plant-derived carbon pools in models. Particles with density >2.8 g cm−3 showed similar C4-carbon enrichment as oxidation-resistant SOC, highlighting the importance of sesquioxides for SOC stabilization. The importance of clay and silt-sized particles (

Introduction: This systematic review and meta-analysis aimed to evaluate the effectiveness and safety of adjunct systemic corticosteroid therapy in patients admitted to the intensive care unit (ICU) with bacterial community-acquired pneumonia (CAP)., Method: We searched MEDLINE, Embase and the Cochrane Library to identify randomised controlled trials (RCTs) published from the databases' inception to February 2024. All RCTs evaluating the effect of systemic corticosteroids on mortality, compared to standard of care among adult bacterial CAP patients admitted to ICU were included. Bayesian meta-analysis was conducted in line with the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. Independent authors reviewed each study for eligibility, extracted data and assessed risk of bias in duplicate, with discrepancies referred to senior reviewers., Results: A total of 6 RCTs comprising 1585 patients were included for analysis. In ICU patients with severe CAP who were treated with corticosteroids, there was no significant reduction in hospital mortality (risk ratio [RR] 0.70, 95% confidence interval [CI] 0.39-1.14, certainty of evidence: ⊕⊕⊝⊝ low) or all-cause mortality (RR 0.68, 95% CI 0.34-1.22, ⊕⊕⊝⊝ low) compared with placebo. The use of corticosteroids showed a significant reduction in mechanical ventilation post-intervention (RR 0.58, 95% CI 0.37-0.86, ⊕⊕⊕⊕ high) compared with placebo. In a subgroup analysis of patients treated with hydrocortisone, hospital mortality was significantly reduced (RR 0.45, 95% CI 0.20-0.88, ⊕⊕⊝⊝ low) compared with placebo. There was no significant increase in gastrointestinal bleeding, secondary infections or hyperglycaemia in patients treated with corticosteroids., Conclusion: Corticosteroids significantly reduced mechanical ventilation requirements, and hydrocor-tisone significantly reduced hospital mortality. Further work is required to determine whether other corticosteroids reduce mortality among ICU patients with CAP.

Introduction: Knowledge of femoral and tibial morphology is important for patient-specific surgery in both joint reconstruction and preservation procedures. Studies evaluating morphological variance in femoral and tibial alignments in Asian populations are scarce. This is the first descriptive study evaluating the femoral and tibial phenotypes of varus alignment in a Southeast Asian population., Methods: Long-leg coronal standing radiographs of 2021 limbs were obtained, and the hip-knee-ankle angle, mechanical lateral distal femoral angle, medial proximal tibial angle and joint line convergence angle were measured. Joint line obliquity was calculated, and the knees were classified according to the Coronal Plane Alignment of Knee (CPAK) classification. Descriptive analyses on alignment parameters and demographic data (age, gender, ethnicity and body mass index [BMI]) were performed and entered into a linear regression model., Results: The highest frequency of limb alignment in the population was found to be CPAK type I (52.71%, n = 1003). Tibial varus was the largest contributor of varus malignment. Of the varus knees (n = 1247), varus deformity was found solely in the tibia (68.60%), solely in the femur (2.07%) and was contributed by both the femur and the tibia (4.97%). In the linear regression model, BMI was found to be a strong determinant for femoral varus (P = 0.004) and joint line incongruence (P < 0.001)., Conclusion: The findings of this study will be important to surgeons during planning for joint preservation procedures (such as corrective osteotomies) and joint arthroplasties to restore alignment., (Copyright © 2024 Copyright: © 2024 Singapore Medical Journal.)

Background: Isolated knee medial compartmental osteoarthritis(MOA) can be treated with High Tibial Osteotomy (HTO) or Unicompartmental Knee Arthroplasty (UKA). This study aims to describe and compare outcomes of HTO and UKA in patients with isolated severe MOA. The authors hypothesized that similar outcomes can be achieved., Methods: Data was collected prospectively of HTOs and UKAs performed between January-2016 and April-2021 by a knee surgeon. Oxford Knee Score (OKS), Knee Society Knee Score (KSKS) and Function Score (KSFS) were collected pre-operatively, six-months and two-years post-surgery. OA severity was graded on pre-operative radiograph. Medial Proximal Tibia Angle (MPTA), Lateral Distal Femoral Angle (LDFA), Joint Line Convergence Angle (JLCA) and Hip-Knee-Ankle Angle (HKAA), were measured on full-length radiograph. 47 HTO and 74 UKA were included. Propensity score matching was performed, accounting for preoperative scores, age, gender and body mass index (BMI), before statistical analysis. Level of significance was set at 0.05., Results: Both groups were similar in age(56.42 vs 58.57, p = 0.067), BMI(29.82 vs 29.09, p = 0.484), gender distribution (p = 0.663) and laterality (p = 0.836). Pre-operatively, both groups were similar in clinical scores and lower limb alignment. On follow-up, both groups achieved similar improvements in clinical scores. However, the HTO group reported poorer extension at 6-months (7.91° vs 4.80°, p = 0.013) and 2-years (5.57° vs 3.24°, p = 0.018). Three cases of hinge fracture and six cases of implant removal occurred in the HTO group. One case of tibial fracture occurred in the UKA group., Conclusions: In severe MOA, similar outcomes were achieved with HTO and UKA at two years., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Background & Aims: Knee osteoarthritis (KOA) is a progressive degenerative disease of chronic nature. The mainstay of surgical management for KOA would be total knee arthroplasty. Joint preserving options like High Tibial Osteotomy (HTO) and Proximal Fibular Osteotomy (PFO) have been offered as an inexpensive option by knee preservation surgeons. Current literature on PFO outcomes lack of clarity for specific indications for offering PFO based on degree of severity of KOA. Therefore, this systematic review aims to critically evaluate clinical and radiological outcomes of PFO stratified by severity of KOA., Methods: PubMed, Scopus, CINAHL and Google Scholar databases were searched. Eligible studies included those published up till August 2023, with 271 studies obtained. After duplicate removal, title-abstract screening, and a full text screen based on inclusion and exclusion criteria, 11 papers were included. 46 papers were further identified from snowballing of 7 existing systematic reviews, with 2 additional papers subsequently included., Results: 13 included articles analysed 788 knees. Our study found that indications based on KL grading of KOA do not seem to differ in terms of post-operative clinical outcomes (VAS score) and radiological measures also found that hip knee alignment was improved regardless of KL grading of KOA. Additionally, the most common post-operative complication reported was deep peroneal nerve palsy., Conclusion: PFO is a viable knee joint preserving surgery for medial compartment KOA, however given the high risk for complications reported in the literature, surgeons should pay close attention to the neuroanatomical landmarks and techniques to avoid neurovascular injury., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 Delhi Orthopedic Association. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Objective: The use of synthetic bone substitute material (BSM) as osteotomy gap fillers have been reported to improve outcomes in medial opening wedge high tibial osteotomy (MOWHTO). This study aims to evaluate the early radiological outcomes (bone union) and complication rates of the novel patient-specific 3D-printed honeycomb-structured polycaprolactone and tricalcium phosphate (PCL-TCP) synthetic graft compared to allogeneic bone grafts as an osteotomy gap filler in MOWHTO., Methods: A retrospective matched-pair analysis of patients who underwent MOWHTO with either PCL-TCP synthetic graft or allogenic femoral head allograft as osteotomy gap filler was performed. The osteotomy gap was split into equal zones (Zone 1-5), and bone union was evaluated on anteroposterior radiographs based on the van Hemert classification at 1, 3, 6, and 12 months postoperatively. Postoperative complications including infection, lateral hinge fractures, and persistent pain was measured. The study and control group were matched for age, smoking status, diabetes mellitus, and osteotomy gap size., Results: Significantly greater bone union progression was observed in the PCL-TCP group than in the allograft group at 1 month (Zones 1-3), 3 months (Zones 1-4), 6 months (Zones 1-2, 4), and 12 months (Zones 2-3, 5) postoperatively ( P < 0.05). No significant difference in complications rates was noted between the two groups at 1 year., Conclusions: Bone union rates observed in patients who underwent MOWHTO with the PCL-TCP synthetic graft osteotomy gap filler were superior to those in the allograft group at 1 year postoperatively, with no significant difference in complication rates (postoperative infection, lateral hinge fractures, and persistent pain)., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Ca2+-activated BK channels in renal intercalated cells (ICs) mediate luminal flow-induced K+ secretion (FIKS), but how ICs sense increased flow remains uncertain. We examined whether PIEZO1, a mechanosensitive Ca2+-permeable channel expressed in the basolateral membranes of ICs, is required for FIKS. In isolated cortical collecting ducts (CCDs), the mechanosensitive cation-selective channel inhibitor GsMTx4 dampened flow-induced increases in intracellular Ca2+ concentration ([Ca2+]i), whereas the PIEZO1 activator Yoda1 increased [Ca2+]i and BK channel activity. CCDs from mice fed a high-K+ (HK) diet exhibited a greater Yoda1-dependent increase in [Ca2+]i than CCDs from mice fed a control K+ diet. ICs in CCDs isolated from mice with a targeted gene deletion of Piezo1 in ICs (IC-Piezo1-KO) exhibited a blunted [Ca2+]i response to Yoda1 or increased flow, with an associated loss of FIKS in CCDs. Male IC-Piezo1-KO mice selectively exhibited an increased blood [K+] in response to an oral K+ bolus and blunted urinary K+ excretion following a volume challenge. Whole-cell expression of BKα subunit was reduced in ICs of IC-Piezo1-KO mice fed an HK diet. We conclude that PIEZO1 mediates flow-induced basolateral Ca2+ entry into ICs, is upregulated in the CCD in response to an HK diet, and is necessary for FIKS.

Background: The incidence of lateral hinge fractures (LHFs) during medial opening wedge high tibial osteotomy (MOW-HTO) is unacceptably high, especially with distractions >10 mm. LHFs result in malunion, loss of correction, and recurrence of symptoms adversely affecting clinical outcomes., Purpose: (1) To investigate the incidence of LHF when a protective guide wire is utilized during MOW-HTO in small and large corrections and (2) to study the effect of correction size on early clinical outcomes., Study Design: Cohort study; Level of evidence, 3., Methods: A retrospective analysis was performed of 96 knees that underwent MOW-HTO between 2019 and 2020. A protective wire applied intraoperatively across the lateral hinge point before opening wedge distraction was performed for all patients. Patients were divided into 2 groups based on opening wedge sizes: group A (opening distraction <10 mm) and group B (opening distraction ≥10 mm). LHF and wound complications were recorded. Prospective Knee Score and Function Score (Knee Society), Oxford Knee Score, and Physical and Mental Component Summaries of the 36-Item Short Form Health Survey questionnaire were recorded preoperatively and at 6 months and 2 years after surgery., Results: Incidence of LHF was low in group A (n = 2; 6.1%) and group B (n = 3; 9.1%). A single case of intraoperative LHF was noted in each group, with each case resulting in a type 1 fracture. The incidence of postoperative fractures was comparable between groups (groups A vs B, n = 1 vs 2). At 6 months, clinical outcomes in group A were superior to those of group B (Knee Score, 85.7 ± 14.7 vs 73.1 ± 20.3, P = 0.028; Function Score, 73.5 ± 16.5 vs 63.1 ± 19.5, P = 0.047; Oxford Knee Score, 20.2 ± 4.7 vs 25.6 ± 8.5, P = 0.008; Physical Component Summary, 46.8 ± 8.1 vs 40.2 ± 10.9, P = 0.018). However, clinical outcomes were comparable at 2 years ( P > .05)., Conclusion: A protective wire was associated with a low incidence of LHF, even in larger MOW-HTO corrections. Large corrections had poorer clinical outcomes as compared with small corrections at 6 months. However, clinical outcomes between groups were comparable at 2 years.

Background and Aims: This study aimed to investigate safety and efficacy of silmitasertib, an oral small molecule casein kinase 2 inhibitor, plus gemcitabine and cisplatin (G+C) versus G+C in locally advanced/metastatic cholangiocarcinoma., Approach and Results: This work is a Phase 1b/2 study (S4-13-001). In Phase 2, patients received silmitasertib 1000 mg twice daily for 10 days with G+C on Days 1 and 8 of a 21-day cycle. Primary efficacy endpoint was progression-free survival (PFS) in the modified intent-to-treat population (defined as patients who completed at least one cycle of silmitasertib without dose interruption/reduction) from both phases (silmitasertib/G+C n = 55, G+C n = 29). The response was assessed by Response Evaluation Criteria in Solid Tumors v1.1. The median PFS was 11.2 months (95% confidence interval [CI], 7.6, 14.7) versus 5.8 months (95% CI, 3.1, not evaluable [NE]) ( p  = 0.0496); 10-month PFS was 56.1% (95% CI, 38.8%, 70.2%) versus 22.2% (95% CI, 1.8%, 56.7%); and median overall survival was 17.4 months (95% CI, 13.4, 25.7) versus 14.9 months (95% CI, 9.9, NE) with silmitasertib/G+C versus G+C. Overall response rate was 34.0% versus 30.8%; the disease control rate was 86.0% versus 88.5% with silmitasertib/G+C versus G+C. Almost all silmitasertib/G+C (99%) and G+C (93%) patients reported at least one treatment emergent adverse event (TEAE). The most common TEAEs (all grades) with silmitasertib/G+C versus G+C were diarrhea (70% versus 13%), nausea (59% vs. 30%), fatigue (47% vs. 47%), vomiting (39% vs. 7%), and anemia (39% vs. 30%). Twelve patients (10%) discontinued treatment because of TEAEs during the study., Conclusions: Silmitasertib/G+C demonstrated promising preliminary evidence of efficacy for the first-line treatment of patients with locally advanced/metastatic cholangiocarcinoma., (Copyright © 2023 American Association for the Study of Liver Diseases.)

Purpose: Immune checkpoint inhibitors (ICIs) alone or in combination with chemotherapy can improve the limited efficacy of colorectal cancer (CRC) immunotherapy. CX-5461 causes substantial DNA damage and genomic instability and can increase ICIs' therapeutic efficacies through tumor microenvironment alteration., Results: We analyzed whether CX-5461 enhances ICIs' effects in CRC and discovered that CX-5461 causes severe DNA damage, including cytosolic dsDNA appearance, in various human and mouse CRC cells. Our bioinformatics analysis predicted CX-5461-based interferon (IFN) signaling pathway activation in these cells, which was verified by the finding that CX-5461 induces IFN-α and IFN-β secretion in these cells. Next, cGAMP, phospho-IRF3, CCL5, and CXCL10 levels exhibited significant posttreatment increases in CRC cells, indicating that CX-5461 activates the cGAS-STING-IFN pathway. CX-5461 also enhanced PD-L1 expression through STAT1 activation. CX-5461 alone inhibited tumor growth and prolonged survival in mice. CX-5461+anti-PD-1 or anti-PD-L1 alone exhibited synergistic growth-suppressive effects against CRC and breast cancer. CX-5461 alone or CX-5461+anti-PD-1 increased cytotoxic T-cell numbers and reduced myeloid-derived suppressor cell numbers in mouse spleens., Conclusions: Therefore, clinically, CX-5461 combined with ICIs for CRC therapy warrants consideration because CX-5461 can turn cold tumors into hot ones., Competing Interests: Declaration of Competing Interest The authors have no competing interests to declare that are relevant to the content of this article., (Copyright © 2022. Published by Elsevier Inc.)

CX-5461 is a G-quadruplex stabilizer that exhibits synthetic lethality in homologous recombination-deficient models. In this multicentre phase I trial in patients with solid tumors, 40 patients are treated across 10 dose levels (50-650 mg/m 2 ) to determine the recommended phase II dose (primary outcome), and evaluate safety, tolerability, pharmacokinetics (secondary outcomes). Defective homologous recombination is explored as a predictive biomarker of response. CX-5461 is generally well tolerated, with a recommended phase II dose of 475 mg/m 2 days 1, 8 and 15 every 4 weeks, and dose limiting phototoxicity. Responses are observed in 14% of patients, primarily in patients with defective homologous recombination. Reversion mutations in PALB2 and BRCA2 are detected on progression following initial response in germline carriers, confirming the underlying synthetic lethal mechanism. In vitro characterization of UV sensitization shows this toxicity is related to the CX-5461 chemotype, independent of G-quadruplex synthetic lethality. These results establish clinical proof-of-concept for this G-quadruplex stabilizer. Clinicaltrials.gov NCT02719977., (© 2022. The Author(s).)