Definitive Radiation Therapy is a Viable Treatment for Locally Advanced Basal Cell Carcinoma Otherwise Requiring Radical or Disfiguring Resection.

PURPOSE: Standard treatment for basal cell carcinoma (BCC) is surgical resection. However, a subset of locally advanced BCCs may be unresectable, or surgery would result in unacceptable functional or cosmetic defects. Outcomes after definitive radiation therapy for locally advanced BCC in the contemporary era are not well established. We sought to determine locoregional control and disease-specific survival after definitive radiation therapy for locally advanced BCC. METHODS AND MATERIALS: Patients with locally advanced BCC treated with definitive radiation therapy between 2005 and 2020 from 4 academic tertiary care institutions were included. Locally advanced BCCs were defined as patients with unresectable disease, or locations where margin negative resection would lead to unacceptable cosmetic or functional deficit. Additionally, a set of 5 risk factors (size ≥4 cm, the presence of bone invasion, PNI, immunocompromised patient, and recurrent disease) was separately defined and outcomes were investigated. RESULTS: Six hundred eight locally advanced BCC cases were identified, of which 140 were treated with definitive radiation therapy. Median follow-up was 22.9 months (1.5-207.2 months). One hundred one (72.1%) tumors were treated with upfront definitive radiation therapy, whereas 39 (27.9%) were treated for a recurrence. Five-year Kaplan-Meier estimated locoregional control was 78%. The majority of locoregional failures were local recurrences (95.5%). Larger tumor diameter was a risk factor for locoregional failure (P = .045), whereas recurrent disease was not (P = .29). Cumulative incidence of BCC-related mortality at 5 years was 9.5%. Patients with 0 risk factors had a 5-year FF-LRF of 92.4%, whereas those with 1+ risk factors had a 5-year freedom from locoregional failure of 68.5% (P = .004). CONCLUSIONS: Definitive radiation therapy for locally advanced BCC has excellent locoregional control, with tumor size representing the only risk factor for recurrence in this study.

Lung Donation and Transplant Recipient Outcomes at Independent vs Hospital-Based Donor Care Units.

Importance: Centralizing deceased organ donor management and organ recovery into donor care units (DCUs) may mitigate the critical organ shortage by positively impacting donation and recipient outcomes. Objective: To compare donation and lung transplant outcomes between 2 common DCU models: independent (outside of acute-care hospitals) and hospital-based. Design, Setting, and Participants: This is a retrospective cohort study of Organ Procurement and Transplantation Network deceased donor registry and lung transplant recipient files from 21 US donor service areas with an operating DCU. Characteristics and lung donation rates among deceased donors cared for in independent vs hospital-based DCUs were compared. Eligible participants included deceased organ donors (aged 16 years and older) after brain death, who underwent organ recovery procedures between April 26, 2017, and June 30, 2022, and patients who received lung transplants from those donors. Data analysis was conducted from May 2023 to March 2024. Exposure: Organ recovery in an independent DCU (vs hospital-based DCU). Main Outcome and Measures: The primary outcome was duration of transplanted lung survival (through December 31, 2023) among recipients of lung(s) transplanted from cohort donors. A Cox proportional hazards model stratified by transplant year and program, adjusting for donor and recipient characteristics was used to compare graft survival. Results: Of 10 856 donors in the starting sample (mean [SD] age, 42.8 [15.2] years; 6625 male [61.0%] and 4231 female [39.0%]), 5149 (primary comparison group) underwent recovery procedures in DCUs including 1466 (28.4%) in 11 hospital-based DCUs and 3683 (71.5%) in 10 independent DCUs. Unadjusted lung donation rates were higher in DCUs than local hospitals, but lower in hospital-based vs independent DCUs (418 donors [28.5%] vs 1233 donors [33.5%]; P < .001). Among 1657 transplant recipients, 1250 (74.5%) received lung(s) from independent DCUs. Median (range) duration of follow-up after transplant was 734 (0-2292) days. Grafts recovered from independent DCUs had shorter restricted mean (SE) survival times than grafts from hospital-based DCUs (1548 [27] days vs 1665 [50] days; P = .04). After adjustment, graft failure remained higher among lungs recovered from independent DCUs than hospital-based DCUs (hazard ratio, 1.85; 95% CI, 1.28-2.65). Conclusions and Relevance: In this retrospective analysis of national donor and transplant recipient data, although lung donation rates were higher from deceased organ donors after brain death cared for in independent DCUs, lungs recovered from donors in hospital-based DCUs survived longer. These findings suggest that further work is necessary to understand which factors (eg, donor transfer, management, or lung evaluation and acceptance practices) differ between DCU models and may contribute to these differences.

The effects of delayed appropriate antimicrobial therapy on children with Staphylococcus aureus blood infection.

Early appropriate antimicrobial therapy plays a critical role for patients with Staphylococcus aureus bloodstream infection (SAB). We aim to determine the optimal time-window for appropriate antimicrobial therapy and evaluate the effects of delayed therapy on adverse clinical outcomes (in-hospital mortality, sepsis, and septic shock) in children with SAB by propensity score matching (PSM) analysis. Receiver-operating characteristic was used to determine the cut-off point of the time to appropriate therapy (TTAT), the patients were divided into timely and delayed appropriate antimicrobial therapy (delayed therapy) groups accordingly. The PSM was used to balance the characteristics between the two groups, controlling the effects of potential confounders. Kaplan-Meier methods and Cox proportional hazards regression were applied to the matched groups to analyze the association between delayed therapy and clinical outcomes. Inverse probability of treatment weighting and propensity score covariate adjustment were also performed to investigate the sensitivity of the results under different propensity score-based approaches. In total, 247 patients were included in this study. The optimal cut-off point of TTAT was identified as 6.4 h, with 85.0% sensitivity and 69.2% specificity (AUC 0.803, 95% confidence interval 0.702-0.904). Eighty-seven (35.22%) of the 247 patients who received delayed therapy (TTAT ≥ 6.4 h) had higher in-hospital mortality (19.54% vs 1.88%, p < 0.001), higher incidences of sepsis (44.83% vs 15.00%, p < 0.001) and septic shock (32.18% vs 6.25%, p < 0.001) when compared to timely therapy (TTAT < 6.4 h) patients. After PSM analysis, a total of 134 episodes (67 in each of the two matched groups) were further analyzed. No statistically significant difference was observed in in-hospital mortality between delayed and timely -therapy groups (log-rank test, P = 0.157). Patients with delayed therapy had a higher incidence of sepsis or septic shock than those with timely therapy (log-rank test, P = 0.009; P = 0.018, respectively). Compared to the timely-therapy group, the hazard ratio and 95% confidence interval in delayed-therapy group were 2.512 (1.227-5.144, P = 0.012) for sepsis, 3.109 (1.166-8.290, P = 0.023) for septic shock.    Conclusion: Appropriate therapy delayed 6.4 h may increase the incidence of sepsis and septic shock, with similar in-hospital mortality in patients with SAB. What is Known: • Staphylococcus aureus (S. aureus) is a major cause of bloodstream infections in children. Undoubtedly, early antimicrobial application plays a critical role in the treatment of children with Staphylococcus aureus bloodstream infections (SAB). • However, rapid, and aggressive administration of antimicrobials may lead to the overuse of these drugs and the emergence of multidrug-resistant microorganisms. Therefore, it is crucial to determine the optimal time-window for appropriate antimicrobial administration in children with SAB. Unfortunately, the optimal time-window for appropriate antimicrobial administration in children with SAB remains unclear. What is New: • Determining the optimal time-window for appropriate antimicrobial administration in patients with matched data variables is particularly important. The Propensity score matching (PSM) analysis effectively controls for confounding factors to a considerable extent when assessing the impact of treatment, thereby approximating the effects observed in randomized controlled trials. • To our knowledge, this is the first study using PSM method to assess the effects of delayed appropriate antimicrobial therapy on adverse outcomes in children with SAB. In low-risk populations with SAB, a delay of 6.4 h in appropriate therapy might increase the occurrence rate for sepsis and septic shock; however, no correlation has been found between this delay and an increased risk for hospital mortality.

The Role of Macrophages in Lung Fibrosis and the Signaling Pathway.

Lung fibrosis is a dysregulated repair process caused by excessive deposition of extracellular matrix that can severely affect respiratory function. Macrophages are a group of immune cells that have multiple functions and can perform a variety of roles. Lung fibrosis develops with the involvement of pro-inflammatory and pro-fibrotic factors secreted by macrophages. The balance between M1 and M2 macrophages has been proposed to play a role in determining the trend and severity of lung fibrosis. New avenues and concepts for preventing and treating lung fibrosis have emerged in recent years through research on mitochondria, Gab proteins, and exosomes. The main topic of this essay is the impact that mitochondria, Gab proteins, and exosomes have on macrophage polarization. In addition, the potential of these factors as targets to enhance lung fibrosis is also explored. We have also collated the functions and mechanisms of signaling pathways associated with the regulation of macrophage polarization such as Notch, TGF-ß/Smad, JAK-STAT and cGAS-STING. The goal of this article is to explain the potential benefits of focusing on macrophage polarization as a way to relieve lung fibrosis. We aspire to provide valuable insights that could lead to enhancements in the treatment of this condition.

Acute hospitalizations after proton therapy versus intensity-modulated radiotherapy for locally advanced non-small cell lung cancer in the durvalumab era.

INTRODUCTION: It was hypothesized that use of proton beam therapy (PBT) in patients with locally advanced non-small cell lung cancer treated with concurrent chemoradiation and consolidative immune checkpoint inhibition is associated with fewer unplanned hospitalizations compared with intensity-modulated radiotherapy (IMRT). METHODS: Patients with locally advanced non-small cell lung cancer treated between October 2017 and December 2021 with concurrent chemoradiation with either IMRT or PBT ± consolidative immune checkpoint inhibition were retrospectively identified. Logistic regression was used to assess the association of radiation therapy technique with 90-day hospitalization and grade 3 (G3+) lymphopenia. Competing risk regression was used to compare G3+ pneumonitis, G3+ esophagitis, and G3+ cardiac events. Kaplan-Meier method was used for progression-free survival and overall survival. Inverse probability treatment weighting was applied to adjust for differences in PBT and IMRT groups. RESULTS: Of 316 patients, 117 (37%) received PBT and 199 (63%) received IMRT. The PBT group was older (p < .001) and had higher Charlson Comorbidity Index scores (p = .02). The PBT group received a lower mean heart dose (p < .0001), left anterior descending artery V15 Gy (p = .001), mean lung dose (p = .008), and effective dose to immune circulating cells (p < .001). On inverse probability treatment weighting analysis, PBT was associated with fewer unplanned hospitalizations (adjusted odds ratio, 0.55; 95% CI, 0.38-0.81; p = .002) and less G3+ lymphopenia (adjusted odds ratio, 0.55; 95% CI, 0.37-0.81; p = .003). There was no difference in other G3+ toxicities, progression-free survival, or overall survival. CONCLUSIONS: PBT is associated with fewer unplanned hospitalizations, lower effective dose to immune circulating cells and less G3+ lymphopenia compared with IMRT. Minimizing dose to lymphocytes may be warranted, but prospective data are needed.

Pneumonitis Rates Before and After Adoption of Immunotherapy Consolidation in Patients With Locally Advanced Non-Small Cell Lung Cancer Treated With Concurrent Chemoradiation.

PURPOSE: We hypothesized that after adoption of immune checkpoint inhibitor (ICI) consolidation for patients with locally advanced non-small cell lung cancer (LA-NSCLC) receiving concurrent chemoradiation therapy (cCRT), rates of symptomatic pneumonitis would increase, thereby supporting efforts to reduce lung radiation dose. METHODS AND MATERIALS: This single institution, multisite retrospective study included 783 patients with LA-NSCLC treated with definitive cCRT either before introduction of ICI consolidation (pre-ICI era cohort [January 2011-September 2017]; N = 448) or afterward (ICI era cohort [October 2017-December 2021]; N = 335). Primary endpoint was grade ≥2 pneumonitis (G2P) and secondary endpoint was grade ≥3 pneumonitis (G3P), per Common Terminology Criteria for Adverse Events v5.0. Pneumonitis was compared between pre-ICI era and ICI era cohorts using the cumulative incidence function and Gray's test. Inverse probability of treatment weighting (IPTW)-adjusted Fine-Gray models were generated. Logistic models were developed to predict the 1-year probability of G2P as a function of lung dosimetry. RESULTS: G2P was higher in the ICI era than in the pre-ICI era (1-year cumulative incidence 31.4% vs 20.1%; P < .001; IPTW-adjusted multivariable subdistribution hazard ratio, 2.03; 95% confidence interval, 1.53-2.70; P < .001). There was no significant interaction between ICI era treatment and either lung volume receiving ≥20 Gy (V20) or mean lung dose in Fine-Gray regression for G2P; however, the predicted probability of G2P was higher in the ICI era at clinically relevant values of lung V20 (≥24%) and mean lung dose (≥14 Gy). Cut-point analysis revealed a lung V20 threshold of 28% in the ICI era (1-year G2P rate 46.0% above vs 19.8% below; P < .001). Among patients receiving ICI consolidation, lung V5 was not associated with G2P. G3P was not higher in the ICI era (1-year cumulative incidence 7.5% vs 6.0%; P = .39; IPTW-adjusted multivariable subdistribution hazard ratio, 1.12; 95% confidence interval, 0.63-2.01; P = .70). CONCLUSIONS: In patients with LA-NSCLC treated with cCRT, the adoption of ICI consolidation was associated with an increase in G2P but not G3P. With ICI consolidation, stricter lung dose constraints may be warranted.

Phase 2 Trial of Consolidation Pembrolizumab After Proton Reirradiation for Thoracic Recurrences of Non-Small Cell Lung Cancer.

PURPOSE: Reirradiation (reRT) with proton beam therapy (PBT) may offer a chance of cure while minimizing toxicity for patients with isolated intrathoracic recurrences of non-small cell lung cancer (NSCLC). However, distant failure remains common, necessitating strategies to integrate more effective systemic therapy. METHODS AND MATERIALS: This was a phase 2, single-arm trial (NCT03087760) of consolidation pembrolizumab after PBT reRT for locoregional recurrences of NSCLC. Four to 12 weeks after completion of 60 to 70 Gy PBT reRT, patients without progressive disease received pembrolizumab for up to 12 months. Primary endpoint was progression-free survival (PFS), measured from the start of reRT. Secondary endpoints were overall survival (OS) and National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0 toxicity. RESULTS: Between 2017 and 2021, 22 patients received PBT reRT. Median interval from prior radiation end to reRT start was 20 months. Most recurrences (91%) were centrally located. Most patients received concurrent chemotherapy (95%) and pencil beam scanning PBT (77%), and 36% had received prior durvalumab. Fifteen patients (68%) initiated consolidation pembrolizumab on trial and received a median of 3 cycles (range, 2-17). Pembrolizumab was discontinued most commonly due to toxicity (n = 5; 2 were pembrolizumab-related), disease progression (n = 4), and completion of 1 year (n = 3). Median follow-up was 38.7 months. Median PFS and OS were 8.8 months (95% CI, 4.2-23.7) and 22.8 months (95% CI, 6.9-not reached), respectively. There was only one isolated in-field failure after reRT. Grade ≥3 toxicities occurred in 10 patients (45%); 2 were pembrolizumab-related. There were 2 grade 5 toxicities, an aorto-esophageal fistula at 6.9 months and hemoptysis at 46.8 months, both probably from reRT. The trial closed early due to widespread adoption of immunotherapy off-protocol. CONCLUSIONS: In the first-ever prospective trial combining PBT reRT with consolidation immunotherapy, PFS was acceptable and OS favorable. Late grade 5 toxicity occurred in 2 of 22 patients. This approach may be considered in selected patients with isolated thoracic recurrences of NSCLC.

Cardiac radiation dose is associated with inferior survival but not cardiac events in patients with locally advanced non-small cell lung cancer in the era of immune checkpoint inhibitor consolidation.

PURPOSE: We assessed the association of cardiac radiation dose with cardiac events and survival post-chemoradiation therapy (CRT) in patients with locally advanced non-small cell lung cancer (LA-NSCLC) after adoption of modern radiation therapy (RT) techniques, stricter cardiac dose constraints, and immune checkpoint inhibitor (ICI) consolidation. METHODS AND MATERIALS: This single-institution, multi-site retrospective study included 335 patients with LA-NSCLC treated with definitive, concurrent CRT between October 2017 and December 2021. All patients were evaluated for ICI consolidation. Planning dose constraints included heart mean dose < 20 Gy (<10 Gy if feasible) and heart volume receiving ≥ 50 Gy (V50Gy) < 25 %. Twenty-one dosimetric parameters for three different cardiac structures (heart, left anterior descending coronary artery [LAD], and left ventricle) were extracted. Primary endpoint was any major adverse cardiac event (MACE) post-CRT, defined as acute coronary syndrome, heart failure, coronary revascularization, or cardiac-related death. Secondary endpoints were: grade ≥ 3 cardiac events (per CTCAE v5.0), overall survival (OS), lung cancer-specific mortality (LCSM), and other-cause mortality (OCM). RESULTS: Median age was 68 years, 139 (41 %) had baseline coronary heart disease, and 225 (67 %) received ICI consolidation. Proton therapy was used in 117 (35 %) and intensity-modulated RT in 199 (59 %). Median LAD V15Gy was 1.4 % (IQR 0-22) and median heart mean dose was 8.7 Gy (IQR 4.6-14.4). Median follow-up was 3.3 years. Two-year cumulative incidence of MACE was 9.5 % for all patients and 14.3 % for those with baseline coronary heart disease. Two-year cumulative incidence of grade ≥ 3 cardiac events was 20.4 %. No cardiac dosimetric parameter was associated with an increased risk of MACE or grade ≥ 3 cardiac events. On multivariable analysis, cardiac dose (LAD V15Gy and heart mean dose) was associated with worse OS, driven by an association with LCSM but not OCM. CONCLUSIONS: With modern RT techniques, stricter cardiac dose constraints, and ICI consolidation, cardiac dose was associated with LCSM but not OCM or cardiac events in patients with LA-NSCLC.

JTE-013 Alleviates Pulmonary Fibrosis by Affecting the RhoA/YAP Pathway and Mitochondrial Fusion/Fission.

Pulmonary fibrosis may be due to the proliferation of fibroblasts and the aggregation of extracellular matrix, resulting in the stimulation of inflammation damage, destroying lung tissue structure, seriously affecting the patient's respiratory function, and even leading to death. We investigated the role and mechanism of JTE-013 in attenuating bleomycin (BLM)-induced pulmonary fibrosis. BLM-induced pulmonary fibrosis was established in mice. Type 2 alveolar epithelial cells (MLE-12) were stimulated with sphingosine monophosphate (S1P) in vitro. JTE-013, an S1PR2 (sphingosine 1-phosphate receptor 2) antagonist, and Verteporfin were administered in vivo and in vitro. IL-4, IL-5, TNF-α, and IFN-γ were measured by ELISA. IL-4 and IFN-γ positive cells were detected by flow cytometry. Inhibition of S1PR2 with JTE-013 significantly ameliorated BLM-induced pathological changes and inflammatory cytokine levels. JTE-013 also significantly reduced the expression of RHOA/YAP pathway proteins and mitochondrial fission protein Drp1, apoptosis, and the colocalization of α-SMA with YAP, Drp1, and Tom20, as detected by immunohistochemistry, immunofluorescence staining, TUNEL, and Western blot. In vitro, S1PR2 and YAP knockdown downregulated RHOA/YAP pathway protein expression, Drp1 phosphorylation, and Drp1 translocation, promoted YAP phosphorylation and phenotypic transformation of MFN2, and inhibited the up-regulation of mitochondrial membrane potential, reactive oxygen species production, and cell apoptosis (7.13% vs. 18.14%), protecting the integrity of the mitochondrial dynamics. JTE-013 also inhibited the expression of fibrosis markers α-SMA, MMP-9, and COL1A1, and alleviated the symptoms of pulmonary fibrosis. Conclusively, JTE-013 has great anti-pulmonary fibrosis potential by regulating RHOA/YAP and mitochondrial fusion/fission.

Inappropriate empirical antibiotic therapy was an independent risk factor of pediatric persistent S. aureus bloodstream infection.

Persistent S. aureus bloodstream infection (PSBSI) increased the incidence of metastatic infection and mortality. We aimed to clarify its risk factors and correlation with metastatic infection and septic shock in children. This retrospective and observational study enrolled children with S. aureus bloodstream infection who admitted to Children's Hospital of Chongqing Medical University between January 2016 and December 2021. The logistic regression model was used for multivariable analyses to determine independent factors associated with PSBSI and clarify the effect of persistent S. aureus bloodstream infection and other factors on metastatic infection and septic shock. One hundred and twenty-seven children were included in this study retrospectively. There were thirty-two cases in the persistent S. aureus bloodstream infection group and ninety-five children in the non-persistent infection group. Multivariate logistic regression analysis indicated that inappropriate empirical antibiotic therapy (OR, 7.26; 95%CI, 2.48-21.30; P<0.01) was an independent risk factor of persistent S. aureus bloodstream infection. Persistent S. aureus bloodstream infection (OR, 6.40; 95%CI, 2.08-19.70; P<0.01) and community-acquired S. aureus bloodstream infection (OR, 4.75; 95%CI, 1.34-16.89; P=0.02) were independent predictors of metastatic infection. Pittsburgh bacteremia scores ≥ 2 (OR, 28.81; 95%CI, 5.26-157.99; P<0.01), hypoalbuminemia (OR, 13.34; 95%CI, 2.43-73.28; P<0.01) and persistent S. aureus bloodstream infection (OR, 5.48; 95%CI, 1.13-26.54; P=0.04) were independent risk factors of septic shock. CONCLUSION: Inappropriate empirical antibiotic therapy was an independent risk factor of pediatric persistent S. aureus bloodstream infection. Pediatric persistent S. aureus bloodstream infection was associated with metastatic infection and septic shock. WHAT IS KNOWN: • Pathogenic features such as Methicillin-resistant S. aureus and sources of infection such as central venous catheter related infection were risk factors of PSBSI in adults. • PSBSI increased the incidence of metastatic infection and mortality in adults. WHAT IS NEW: • Inappropriate empirical antibiotic therapy was an independent risk factor of pediatric persistent S. aureus bloodstream infection. • Pediatric persistent S. aureus bloodstream infection was associated with metastatic infection and septic shock.

Higher Rates of Dialysis and Subsequent Mortality in the New Allocation Era for Heart Transplants.

BACKGROUND: In 2018, a United Network for Organ Sharing (UNOS) policy change increased prioritization of patients bridged with temporary mechanical circulatory support devices, such as venoarterial ECMO, for cardiac transplantation. Considering increased waitlist acuity, we sought to characterize whether this was associated with an increased risk for development of postoperative acute renal failure requiring dialysis (AKI-D) and risk of death after transplantation. METHODS: Dialysis-naive adults receiving single-organ heart transplant between November 2009 and February 2020 were stratified by receipt of AKI-D. Era 1 and era 2 were defined by the periods of UNOS allocation before and after policy change, respectively. Multivariable logistic regression was performed to determine risk factors for AKI-D. Rates of AKI-D were compared by propensity score-matched cohorts. Survival was compared by Kaplan-Meier analysis. RESULTS: A total of 20 698 patients were included. Venoarterial ECMO use significantly increased in era 2 (5.6% vs 0.58%; P < .01). Overall prevalence of AKI-D was greater in era 2 (13.5% vs 10.2%; P < .01). Use of preoperative ECMO, intra-aortic balloon pump, and ventilators and longer ischemia times were identified as independent risk factors for development of AKI-D. Five- and 10-year survival rates were significantly decreased for patients with AKI-D. There was no short-term survival difference of patients with AKI-D between era 2 and the more contemporary era 1. CONCLUSIONS: Patients in whom AKI-D develops after transplantation have significantly worse short- and long-term outcomes. Preoperative use of ECMO, preoperative ventilator support, and longer ischemia times are risk factors for development of AKI-D, and their prevalence has increased since the allocation policy change.

The Impact of Baseline Anxiety on Drug Placebo Separation and Drug/Placebo Response in an Acute Schizophrenia Clinical Trial-A Post-hoc Analysis.

Objectives: We sought to evaluate the impact of baseline anxiety levels on drug placebo separation and drug and placebo response in acutely psychotic schizophrenic subjects. Methods: In this post-hoc analysis, modified intent-to-treat Positive and Negative Syndrome Scale data were obtained from a phase 2, multi-center, 5 week, randomized, double-blind, placebo-controlled trial of KarXT in hospitalized adults with DSM-5 schizophrenia experiencing an acute exacerbation or relapse of symptoms. We investigated the impact of anxiety on drug placebo separation and drug and placebo response in 2 ways. In the first set of analyses, we dichotomized the data based on the absence or presence of anxiety symptoms. In the second set of analyses, we categorized subjects by levels of anxiety. All analyses were conducted using generalized linear models with normal distribution and identity link function. Results: On average, subjects entering the trial were suffering from a moderate level of anxiety. Subjects with no baseline anxiety had a significant increase in placebo response, a decrease in drug response and did not separate drugs from placebo. With increasing levels of baseline anxiety, a larger drug placebo difference was observed. Discussion: Our analyses identified that absence of anxiety at baseline was associated with a loss of signal at end of treatment between drug and placebo driven by a differential effect on placebo and treatment response. The effect observed was not related to the overall baseline symptom severity and was not mediated by improvement in anxiety itself. Interpretation of the results is caveated by the retrospective nature of the analyses.

Self-supervised acoustic representation learning via acoustic-embedding memory unit modified space autoencoder for underwater target recognition.

Since the expensive annotation of high-quality signals obtained from passive sonars and the weak generalization ability of the single feature in the ocean, this paper proposes the self-supervised acoustic representation learning under acoustic-embedding memory unit modified space autoencoder (ASAE) and performs the underwater target recognition task. In the manner of the animal-like acoustic auditory system, the first step is to design a self-supervised representation learning method called space autoencoder (SAE) to merge Mel filter-bank (FBank) with the acoustic discrimination and gammatone filter-bank (GBank) with the anti-noise robustness into SAE spectrogram (SAE Spec). Meanwhile, due to poor high-level semantic information in SAE Spec, an acoustic-embedding memory unit (AEMU) is introduced as the strategy of adversarial enhancement. During the auxiliary task, more negative samples are joined in the improved contrastive loss function to obtain adversarial enhanced features called ASAE spectrogram (ASAE Spec). Ultimately, the comprehensive contrast experiments and ablation experiments on two underwater datasets show that ASAE Spec increases by more than 0.96% in accuracy, convergence rate, and anti-noise robustness of other mainstream acoustic features. The results prove the potential value of ASAE in practical applications.

Lack of volume-outcome association in ECMO bridge to heart transplantation.

BACKGROUND: Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) is increasingly used as a bridge to cardiac transplantation. As the 2018 United Network for Organ Sharing (UNOS) heart allocation policy change elevated waitlist status for patients receiving mechanical circulatory support (MCS), we aimed to determine if a center's annual heart transplant volume was associated with ECMO-support duration and posttransplant outcomes. METHODS: Adults heart transplant candidates between January 1, 2011, and December 31, 2021, were isolated in the UNOS database. VA-ECMO use was identified at the time of listing for transplant. Average annual transplant volume was calculated by the center, with stratification as high (≥20 cardiac transplants, high volume center [HVC]) or low (<20 cardiac transplants, low volume center [LVC]) volume centers. Results are reported as mean (interquartile range) or n (%). RESULTS: In total, 543 patients at HVCs and 275 at LVCs were listed for transplant supported with VA-ECMO. Those listed at HVCs were more likely to be supported by intra-aortic balloon pump (103 [19%] vs. 32 [11.6%], p = .008) and inotropes (267 [49.2%] vs. 106 [38.5%], p = .004) at time of listing. Patients at HVCs received ECMO support for 6 [4-9] days, compared to 8 [4-15] days at low-volume centers (p = .030), and but were cannulated a similar time before listing (2 [1-5] vs. 3 [1-7] days, p = .517). There were no differences in rates of transplant (p = .2126), waitlist mortality (p = .8645), delisting due to clinical deterioration (p = .8419), or recovery (p = .1773) between groups. Among transplanted patients, there were no differences in support duration (6 [4-8] vs. 6 [4-10], p = .187), or time from registration to transplant (5 [2-20] vs. 7 [3-22] days, p = .560). Posttransplant survival did not vary (p = .293). CONCLUSIONS: LVCs can successfully bridge patients to transplant with VA-ECMO and achieve comparable outcomes to HVCs.

Cassava (Manihot esculenta) Slow Anion Channel (MeSLAH4) Gene Overexpression Enhances Nitrogen Assimilation, Growth, and Yield in Rice.

Nitrogen is one of the most important nutrient elements required for plant growth and development, which is also immensely related to the efficient use of nitrogen by crop plants. Therefore, plants evolved sophisticated mechanisms and anion channels to extract inorganic nitrogen (nitrate) from the soil or nutrient solutions, assimilate, and recycle the organic nitrogen. Hence, developing crop plants with a greater capability of using nitrogen efficiently is the fundamental research objective for attaining better agricultural productivity and environmental sustainability. In this context, an in-depth investigation has been conducted into the cassava slow type anion channels (SLAHs) gene family, including genome-wide expression analysis, phylogenetic relationships with other related organisms, chromosome localization, and functional analysis. A potential and nitrogen-responsive gene of cassava (MeSLAH4) was identified and selected for overexpression (OE) analysis in rice, which increased the grain yield and root growth related performance. The morpho-physiological response of OE lines was better under low nitrogen (0.01 mm NH4NO3) conditions compared to the wild type (WT) and OE lines under normal nitrogen (0.5 mm NH4NO3) conditions. The relative expression of the MeSLAH4 gene was higher (about 80-fold) in the OE line than in the wild type. The accumulation and flux assay showed higher accumulation of NO 3 - and more expansion of root cells and grain dimension of OE lines compared to the wild type plants. The results of this experiment demonstrated that the MeSLAH4 gene may play a vital role in enhancing the efficient use of nitrogen in rice, which could be utilized for high-yielding crop production.

Activity Monitoring for Toxicity Detection and Management in Patients Undergoing Chemoradiation for Gastrointestinal Malignancies.

PURPOSE: Physical activity is associated with decreased hospitalization during cancer treatment. We hypothesize that activity data can help identify and triage high-risk patients with GI cancer undergoing concurrent chemoradiation. MATERIALS AND METHODS: This prospective study randomly assigned patients to activity monitoring versus observation. In the intervention arm, a 20% decrease in daily steps or 20% increase in heart rate triggered triage visits to provide supportive care, medication changes, and escalation of care. In the observation group, activity data were recorded but not monitored. The primary objective was to show a 20% increase in triage visits in the intervention group. Secondary objectives were estimating the rates of emergency department (ED) visits and hospitalizations. Crude and adjusted odds ratios were computed using logistic regression modeling. RESULTS: There were 22 patients in the intervention and 18 in the observation group. Baseline patient and treatment characteristics were similar. The primary objective was met, with 3.4 more triage visits in the intervention group than in the observation group (95% CI, 2.10 to 5.50; P < .0001). Twenty-six (65.0%) patients required at least one triage visit, with a higher rate in the intervention arm compared with that in the observation arm (86.4% v 38.9%; odds ratio, 9.95; 95% CI, 2.13 to 46.56; P = .004). There was no statistically significant difference in ED visit (9.1% v 22.2%; P = .38) or hospitalization (4.5% v 16.7%; P = .31). CONCLUSION: It is feasible to use activity data to trigger triage visits for symptom management. Further studies are investigating whether automated activity monitoring can assist with early outpatient management to decrease ED visits and hospitalizations.

Risk Factors for Diagnosis of Psoriatic Arthritis, Psoriasis, Rheumatoid Arthritis, and Ankylosing Spondylitis: A Set of Parallel Case-control Studies.

OBJECTIVE: To compare potential risk factors for the diagnosis of psoriatic arthritis (PsA), psoriasis (PsO), rheumatoid arthritis (RA), and ankylosing spondylitis (AS). METHODS: Four parallel case-control studies were conducted within The Health Improvement Network using data between 1994 and 2015. Patients with PsA, PsO, RA, or AS were identified using validated code lists and matched to controls on age, sex, practice, and year. Risk factors were selected in the time prior to diagnosis. Multivariable logistic regression models were constructed for each disease using automated stepwise regression to test potential risk factors. RESULTS: Patients with incident PsA (n = 7594), PsO (n = 111,375), RA (n = 28,341), and AS (n = 3253) were identified and matched to 75,930, 1,113,345, 283,226, and 32,530 controls, respectively. Median diagnosis age was 48 (IQR 38-59), 43 (IQR 28-60), 60 (IQR 48-71), and 41 (IQR 32-54) years, respectively. In multivariable models, there were some shared and some differing risk factors across all 4 diseases: PsA was associated with obesity, pharyngitis, and skin infections; PsA and PsO were associated with obesity and moderate alcohol intake; PsA and AS were associated with uveitis; and PsA and RA were associated with preceding gout. Both RA and AS were associated with current smoking, former moderate drinking, anemia, osteoporosis, and inflammatory bowel disease. All shared former or current smoking as a risk factor; statin use was inversely associated with all 4 diseases. CONCLUSION: Shared and different risk factors for PsA, PsO, RA, and AS were identified. Statin use was inversely associated with all 4 conditions.

The Impact of Aberrant Data Variability on Drug-Placebo Separation and Drug/Placebo Response in an Acute Schizophrenia Clinical Trial.

OBJECTIVE: In the current posthoc analyses, we evaluated the impact of markers of aberrant data variability on drug placebo separation and placebo and drug response in an acute schizophrenia clinical trial. METHODS: Positive and negative syndrome scale data were obtained from a phase 2, randomized, double-blind, placebo controlled trial in hospitalized adults with schizophrenia experiencing an acute exacerbation. We assessed the impact of a total of six markers of aberrant data variability: erratic ratings, unusually large postbaseline improvement, high and low mean square successive difference (MSSD), identical and nearly identical ratings and compared the drug placebo difference, drug and treatment response at last visit in affected subjects vs those not affected. All analyses were conducted using generalized linear models. RESULTS: In this posthoc analysis, drug placebo separation decreased with the presence of most markers of aberrant data variability. The only exception was high MSSD was associated with significant increase in the signal. In the affected subjects, the presence of indicators of increased data variability augmented the response to placebo, in the case of large postbaseline change and high MSSD, significantly. The presence of indicators of decreased variability numerically but not statistically decreased the response to placebo. Similar findings were observed in the drug treatment group with the exception of erratic ratings that numerically but not statistically decreased the response to the drug. DISCUSSION: The presence of most indicators of aberrant data variability had a detrimental effect on drug-placebo separation and showed different effects on placebo and treatment response.

Risk factors for poor prognosis in children and adolescents with COVID-19: A systematic review and meta-analysis.

BACKGROUND: This study provides the first systematic review and meta-analysis to identify the predictors of unfavorable prognosis of COVID-19 in children and adolescents. METHODS: We searched literature databases until July 2021 for studies that investigated risk factors for unfavorable prognosis of children and adolescents with COVID-19. We used random-effects models to estimate the effect size with 95% confidence interval (CI). FINDINGS: We identified 56 studies comprising 79,104 individuals. Mortality was higher in patients with multisystem inflammatory syndrome (MIS-C) (odds ratio [OR]=58.00, 95% CI 6.39-526.79) and who were admitted to intensive care (OR=12.64, 95% CI 3.42-46.68). Acute respiratry distress syndrme (ARDS) (OR=29.54, 95% CI 12.69-68.78) and acute kidney injury (AKI) (OR=55.02, 95% CI 6.26-483.35) increased the odds to be admitted to intensive care; shortness of breath (OR=16.96, 95% CI 7.66-37.51) increased the need of respiratory support; and neurological diseases (OR=5.16, 95% CI 2.30-11.60), C-reactive protein (CRP) level ≥80 mg/L (OR=11.70, 95% CI 4.37-31.37) and D-dimer level ≥0.5ug/mL (OR=20.40, 95% CI 1.76-236.44) increased the odds of progression to severe or critical disease. INTERPRETATION: Congenital heart disease, chronic pulmonary disease, neurological diseases, obesity, MIS-C, shortness of breath, ARDS, AKI, gastrointestinal symptoms, elevated CRP and D-dimer are associated with unfavourable prognosis in children and adolescents with COVID-19.