Combinatorial metabolic engineering of Bacillus subtilis for de novo production of polymyxin B.

Polymyxin is a lipopeptide antibiotic that is effective against multidrug-resistant Gram-negative bacteria. However, its clinical development is limited due to low titer and the presence of homologs. To address this, the polymyxin gene cluster was integrated into Bacillus subtilis, and sfp from Paenibacillus polymyxa was expressed heterologously, enabling recombinant B. subtilis to synthesize polymyxin B. Regulating NRPS domain inhibited formation of polymyxin B2 and B3. The production of polymyxin B increased to 329.7 mg/L by replacing the native promoters of pmxA, pmxB, and pmxE with PfusA, C2up, and PfusA, respectively. Further enhancement in this production, up to 616.1 mg/L, was achieved by improving the synthesis ability of 6-methyloctanoic acid compared to the original strain expressing polymyxin heterologously. Additionally, incorporating an anikasin-derived domain into the hybrid nonribosomal peptide synthase of polymyxin increased the B1 ratio in polymyxin B from 57.5% to 62.2%. Through optimization of peptone supply in the fermentation medium and fermentation in a 5.0-L bioreactor, the final polymyxin B titer reached 962.1 mg/L, with a yield of 19.24 mg/g maltodextrin and a productivity of 10.02 mg/(L·h). This study demonstrates a successful approach for enhancing polymyxin B production and increasing the B1 ratio through combinatorial metabolic engineering.

Obscured Contribution of Oxygenated Intermediate-Volatility Organic Compounds to Secondary Organic Aerosol Formation from Gasoline Vehicle Emissions.

Secondary organic aerosol (SOA) formation from gasoline vehicles spanning a wide range of emission types was investigated using an oxidation flow reactor (OFR) by conducting chassis dynamometer tests. Aided by advanced mass spectrometric techniques, SOA precursors, including volatile organic compounds (VOCs) and intermediate/semivolatile organic compounds (I/SVOCs), were comprehensively characterized. The reconstructed SOA produced from the speciated VOCs and I/SVOCs can explain 69% of the SOA measured downstream of an OFR upon 0.5-3 days' OH exposure. While VOCs can only explain 10% of total SOA production, the contribution from I/SVOCs is 59%, with oxygenated I/SVOCs (O-I/SVOCs) taking up 20% of that contribution. O-I/SVOCs (e.g., benzylic or aliphatic aldehydes and ketones), as an obscured source, account for 16% of total nonmethane organic gas (NMOG) emission. More importantly, with the improvement in emission standards, the NMOG is effectively mitigated by 35% from China 4 to China 6, which is predominantly attributed to the decrease of VOCs. Real-time measurements of different NMOG components as well as SOA production further reveal that the current emission control measures, such as advances in engine and three-way catalytic converter (TWC) techniques, are effective in reducing the "light" SOA precursors (i.e., single-ring aromatics) but not for the I/SVOC emissions. Our results also highlight greater effects of O-I/SVOCs to SOA formation than previously observed and the urgent need for further investigation into their origins, i.e., incomplete combustion, lubricating oil, etc., which requires improvements in real-time molecular-level characterization of I/SVOC molecules and in turn will benefit the future design of control measures.

An Engineered Microbial Consortium Provides Precursors for Fengycin Production by Bacillus subtilis.

Fengycin has great potential for applications in biological control because of its biosafety and degradability. In this study, the addition of exogenous precursors increased fengycin production by Bacillus subtilis. Corynebacterium glutamicum was engineered to produce high levels of precursors (Thr, Pro, Val, and Ile) to promote the biosynthesis of fengycin. Furthermore, recombinant C. glutamicum and Yarrowia lipolytica providing amino acid and fatty acid precursors were co-cultured to improve fengycin production by B. subtilis in a three-strain artificial consortium, in which fengycin production was 2100 mg·L-1. In addition, fengycin production by the consortium in a 5 L bioreactor reached 3290 mg·L-1. Fengycin had a significant antifungal effect on Rhizoctonia solani, which illustrates its potential as a food preservative. Taken together, this work provides a new strategy for improving fengycin production by a microbial consortium and metabolic engineering.

The impact of intraoperative hypotension on postoperative acute kidney injury, mortality and length of stay following off-pump coronary artery bypass grafting surgery: a single-center retrospective cohort study.

BACKGROUND: Off-pump coronary artery bypass grafting (OPCABG) presents distinct hemodynamic characteristics, yet the relationship between intraoperative hypotension and short-term adverse outcomes remains clear. Our study aims to investigate association between intraoperative hypotension and postoperative acute kidney injury (AKI), mortality and length of stay in OPCABG patients. METHODS: Retrospective data of 494 patients underwent OPCABG from January 2016 to July 2023 were collected. We analyzed the relationship between intraoperative various hypotension absolute values (MAP > 75, 65 < MAP ≤ 75, 55 < MAP ≤ 65, MAP ≤ 55 mmHg) and postoperative AKI, mortality and length of stay. Logistic regression assessed the impacts of exposure variable on AKI and postoperative mortality. Linear regression was used to analyze risk factors on the length of intensive care unit stay (ICU) and hospital stay. RESULTS: The incidence of AKI was 31.8%, with in-hospital and 30-day mortality at 2.8% and 3.5%, respectively. Maintaining a MAP greater than or equal 65 mmHg [odds ratio (OR) 0.408; p = 0.008] and 75 mmHg (OR 0.479; p = 0.024) was significantly associated with a decrease risk of AKI compared to MAP less than 55 mmHg for at least 10 min. Prolonged hospital stays were linked to low MAP, while in-hospital mortality and 30-day mortality were not linked to IOH but exhibited correlation with a history of myocardial infarction. AKI showed correlation with length of ICU stay. CONCLUSIONS: MAP > 65 mmHg emerges as a significant independent protective factor for AKI in OPCABG and IOH is related to length of hospital stay. Proactive intervention targeting intraoperative hypotension may provide a potential opportunity to reduce postoperative renal injury and hospital stay. TRIAL REGISTRATION: ChiCTR2400082518. Registered 31 March 2024. https://www.chictr.org.cn/bin/project/edit?pid=225349 .

Predictive Role of Preoperative Nutritional Status on Early Postoperative Outcomes in Different-Aged Patients Undergoing Heart Valve Surgery.

OBJECTIVES: The authors sought to elucidate the role and predictive effects of preoperative nutritional status on postoperative outcomes across different age groups undergoing heart valve surgery. DESIGN: A retrospective study with intergroup comparison, receiver operating characteristic curve analysis, and logistic regression analysis. SETTING: A hospital affiliated with a medical university. PARTICIPANTS: Three thousand nine hundred five patients undergoing heart valve surgery between October 2016 and December 2020. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Patients were categorized into 3 age subgroups: young (aged 18-44 years), middle-aged (aged 45-59 years), and older (aged ≥60 years) adults. The Nutritional Risk Index (NRI), Prognostic Nutritional Index, and Controlling Nutritional Status scores were evaluated. Young adults with an NRI <99 experienced a significantly higher rate of prolonged intensive care unit stay (28.3% v 4.1%, p < 0.001), with a relative risk of 4.58 (95% CI: 2.04-10.27). Similarly, young adults with an NRI <97 had a significantly increased occurrence of mortality within 30 days after surgery (6.3% v 0.2%, p < 0.001), with a relative risk of 41.11 (95% CI: 3.19-529.48). CONCLUSIONS: In patients who undergo heart valve surgery, early postoperative outcomes can be influenced by nutritional status before the surgery. In the young-adult group, NRI <99 and NRI <97 effectively could predict prolonged intensive care unit stay and 30-day mortality, respectively.

Association of sleep quality on the night of operative day with postoperative delirium in elderly patients: A prospective cohort study.

BACKGROUND: Sleep disturbances in the peri-operative period have been associated with adverse outcomes, including postoperative delirium (POD). However, research on sleep quality during the immediate postoperative period is limited. OBJECTIVES: This study aimed to investigate the association between sleep quality on the night of the operative day assessed using the Sleep Quality Numeric Rating Scale (SQ-NRS), and the incidence of POD in a large cohort of surgical patients. DESIGN: A prospective cohort study. SETTING: A tertiary hospital in China. PATIENTS: This study enrolled patients aged 65 years or older undergoing elective surgery under general anaesthesia. The participants were categorised into the sleep disturbance and no sleep disturbance groups according to their operative night SQ-NRS. MAIN OUTCOME MEASURES: The primary outcome was delirium incidence, whereas the secondary outcomes included acute kidney injury, stroke, pulmonary infection, cardiovascular complications and all-cause mortality within 1 year postoperatively. RESULTS: In total, 3072 patients were included in the analysis of this study. Among them, 791 (25.72%) experienced sleep disturbances on the night of operative day. Patients in the sleep disturbance group had a significantly higher risk of developing POD (adjusted OR 1.43, 95% CI 1.11 to 1.82, P  = 0.005). Subgroup analysis revealed that age 65-75 years; male sex; ASA III and IV; haemoglobin more than 12 g l -1 ; intra-operative hypotension; surgical duration more than 120 min; and education 9 years or less were significantly associated with POD. No interaction was observed between the subgroups. No significant differences were observed in the secondary outcomes, such as acute kidney injury, stroke, pulmonary infection, cardiovascular complications and all-cause mortality within 1 year postoperatively. CONCLUSIONS: The poor subjective sleep quality on the night of operative day was independently associated with increased POD risk, especially in certain subpopulations. Optimising peri-operative sleep may reduce POD. Further research should investigate potential mechanisms and causal relationships. TRIAL REGISTRY: chictr.org.cn: ChiCTR1900028545.

Occult lymph node metastasis is not a favorable factor for resected NSCLC patients.

BACKGROUND: This study was to compare the clinical presentations and survivals between the non-small cell lung cancer (NSCLC) patients with occult lymph node metastasis (OLNM) and those with evident lymph node metastasis (ELNM). We also intended to analyze the predictive factors for OLNM. METHODS: Kaplan-Meier method with log-rank test was used to compare survivals between groups. Propensity score matching (PSM) was used to reduce bias. The least absolute shrinkage and selection operator (LASSO)-penalized Cox multivariable analysis was used to identify the prognostic factors. Random forest was used to determine the predictive factors for OLNM. RESULTS: A total of 2,067 eligible cases (N0: 1,497 cases; occult N1: 165 cases; evident N1: 54 cases; occult N2: 243 cases; evident N2: 108 cases) were included. The rate of OLNM was 21.4%. Patients with OLNM were tend to be female, non-smoker, adenocarcinoma and had smaller-sized tumors when compared with the patients with ELNM. Survival curves showed that the survivals of the patients with OLNM were similar to those of the patients with ELNM both before and after PSM. Multivariable Cox analysis suggested that positive lymph nodes (PLN) was the only prognostic factor for the patients with OLNM. Random forest showed that clinical tumor size was an important predictive factor for OLNM. CONCLUSIONS: OLNM was not rare. OLNM was not a favorable sign for resected NSCLC patients with lymph node metastasis. PLN determined the survivals of the patients with OLNM. Clinical tumor size was a strong predictive factor for OLNM.

Is prior cancer history a hindrance for non-small cell lung cancer patients to participate in clinical trials?

BACKGROUND: This study aimed to explore the effect of a prior cancer history on the survivals of resected non-small cell lung cancer (NSCLC) patients. METHODS: Kaplan-Meier method with a log-rank test was used to compare overall survival (OS) and disease-free survival (DFS) between groups. Propensity score matching (PSM) method was used to reduce bias. The least absolute shrinkage and selection operator (LASSO)-penalized Cox multivariable analysis was used to identify the prognostic factors. RESULTS: A total of 4,102 eligible cases were included in this study. The rate of patients with a prior cancer was 8.2% (338/4,102). Patients with a prior cancer tended to be younger and have early-stage tumors when compared with those without prior cancer. Before PSM, the survivals of the patients with a prior cancer were similar to those of the patients without prior cancer (OS: P = 0.591; DFS: P = 0.847). After PSM, patients with a prior cancer and those without prior cancer still had comparable survival rates (OS: P = 0.126; DFS: P = 0.054). The LASSO-penalized multivariable Cox analysis further confirmed that a prior cancer history was not a prognostic factor for both OS and DFS. CONCLUSIONS: A prior cancer history was not associated with resected NSCLC patients' survivals, and we proposed that it might be reasonable for clinical trials to enroll the NSCLC patients with a prior cancer.

Enigma of Urban Gaseous Oxygenated Organic Molecules: Precursor Type, Role of NOx, and Degree of Oxygenation.

Oxidation of volatile organic compounds (VOCs) forms oxygenated organic molecules (OOMs), which contribute to secondary pollution. Herein, we present measurement results of OOMs using chemical ionization mass spectrometry with nitrate as the reagent ion in Shanghai. Compared to those in forests and laboratory studies, OOMs detected at this urban site were of relatively lower degree of oxygenation. This was attributed to the high NOx concentrations (∼44 ppb), which overall showed a suppression on the propagation reactions. As another result, a large fraction of nitrogenous OOMs (75%) was observed, and this fraction further increased to 84% under a high NO/VOC ratio. By applying a novel framework on OOM categorization and supported by VOC measurements, 50 and 32% OOMs were attributed to aromatic and aliphatic precursors, respectively. Furthermore, aromatic OOMs are more oxygenated (effective oxygen number, nOeff = 4-6) than aliphatic ones (nOeff = 3-4), which can be partly explained by the difference in initiation mechanisms and points to possible discrimination in termination reactions. This study highlights the roles of NOx in OOM formation in urban areas, as well as the formation of nitrogenous products that might show discrimination between aromatic and aliphatic VOCs.

Fermentation optimization of surfactin production of Bacillus amyloliquefaciens HM618.

This work isolated a strain named Bacillus amyloliquefaciens HM618 from the soil, which can inhibit the growths of Botrytis cinerea, Rhizoctonia solani, and Escherichia coli DH5α. Based on the results of response surface methodology, the surfactin levels of strain HM618 were elevated from 0.724 to 1.876 g/L and 0.995 to 1.888 g/L under the pure culture with the optimized medium (containing 62.39 g/L sucrose, 15.06 g/L yeast extracts, and 3.27 g/L aspartate) and under the coculture of strains HM618 and Bacillus subtilis 168 with the optimized medium (containing 50.52 g/L sucrose, 19.76 g/L yeast extracts, and 1.02 g/L glutamate), respectively. Additionally, influences of nonconstitutive amino acids involved in the biosynthesis of surfactin were also explored. The highest surfactin level reached 2.04 g/L after adding 3.0 g/L exogenous ornithine. However, the surfactin production of strain HM618 was significantly inhibited after adding the mixtures of nonconstitutive amino acids.

Investigation of Early-Stage Non-Small Cell Lung Cancer Patients with Different T2 Descriptors: Real Word Data From a Large Database.

INTRODUCTION: The current study evaluated a large cohort of T2N0M0 NSCLC patients with different T2 descriptors to investigate the prognostic disparities and further externally validate the T category of these patients. METHODS: The Kaplan-Meier Method with the log-rank test was used to plot survival curves. The propensity score matching (PSM) method was used to reduce bias. Univariable and multivariable Cox analyses were used to determine prognostic factors. RESULTS: A total of 13,015 eligible T2N0M0 NSCLC patients were included. There were 5,287, 2,577 and 5,151 patients in the T2a, T2b and non-sized determined T2N0M0 (T2non-sized) groups, respectively. Before PSM, the survival of T2non-sized patients was comparable to that of T2a patients (P = 0.080) but was superior to that of T2b patients (P < 0.001). After PSM, the survival of T2non-sized patients was inferior to that of T2a patients (P = 0.028) but was similar to that of T2b patients (P = 0.325). The T category was further subdivided based on the specific non-sized T2 descriptors and tumor size. The results of the multivariate Cox analysis found that the prognosis of T2 tumors with visceral pleural invasion (size: 0-30 mm) was better than that of T2a tumors, and the prognosis of T2 tumors with visceral pleural invasion (size: 30-40 mm) was inferior to that of T2a tumors but comparable to that of T2b tumors. CONCLUSION: T2 tumors with visceral pleural invasion (size: 30-40 mm) should be assigned to the T2b category, and those with a size interval of 0-30 mm should be assigned to a better prognostic T2a category.

Risk-adapted stereotactic body radiotherapy for patients with cervical spinal metastases.

Owing to the complex anatomical structure and biomechanics, the current standard palliative treatments for cervical spinal metastases are associated with a high risk of recurrence and complications. Stereotactic body radiotherapy (SBRT) can provide radical dose to tumors while protecting normal organs to the maximum extent. However, the efficacy and safety of SBRT for cervical spinal metastases is not well characterized. Data from 71 patients with cervical spine metastases who were treated with SBRT using CyberKnife between 2006 and 2021 were obtained from our prospectively maintained database. Primary endpoint was pain response at 12 weeks following SBRT completion; secondary endpoints included local control (LC), overall survival (OS), and adverse events. Standard-risk patients were planned to receive 30 Gy (range 21-36) with median fractions of 3 (range 1-3) and high-risk patients 35 Gy (range 24-50) with median fractions of 5 (range 4-5) according to the spinal cord and esophagus dose constraints. The median follow-up time was 17.07 months (range 3.1-118.9). After 12 weeks of SBRT completion, 54 (98.2%) of 55 patients with baseline pain achieved pain response and 46 (83.6%) achieved complete pain response. LC rates were 93.1% and 90% at 1 year and 2 year, respectively. The 1-year and 2-year OS rates were 66.2% and 37.4%, respectively. Eight patients experienced grades 1-4 adverse events (six vertebral compression fracture [VCF], five of them had VCF before SBRT; and two hemiparesis). No grade 5 adverse events were observed. Therefore, risk-adapted SBRT for cervical spine metastases achieved high pain control and LC rates with acceptable adverse events.

General Method for the Amination of Aryl Halides with Primary and Secondary Alkyl Amines via Nickel Photocatalysis.

The Buchwald-Hartwig C-N coupling reaction has been ranked as one of the 20 most frequently used reactions in medicinal chemistry. Owing to its much lower cost and higher reactivity toward less reactive aryl chlorides than palladium, the C-N coupling reaction catalyzed by Ni-based catalysts has received a great deal of attention. However, there appear to be no universal, practical Ni catalytic systems so far that could enable the coupling of electron-rich and electron-poor aryl halides with both primary and secondary alkyl amines. In this study, it is reported that a Ni(II)-bipyridine complex catalyzes efficient C-N coupling of aryl chlorides and bromides with various primary and secondary alkyl amines under direct excitation with light. Intramolecular C-N coupling is also demonstrated. The feasibility and applicability of the protocol in organic synthesis is attested by more than 200 examples.

Fate of Oxygenated Volatile Organic Compounds in the Yangtze River Delta Region: Source Contributions and Impacts on the Atmospheric Oxidation Capacity.

The Community Multiscale Air Quality model (CMAQv5.2) was implemented to investigate the sources and sinks of oxygenated volatile organic compounds (OVOCs) during a high O3 and high PM2.5 season in the Yangtze River Delta (YRD) region, based on constraints from observations. The model tends to overpredict non-oxygenated VOCs and underpredict OVOCs, which has been improved with adjusted emissions of all VOCs. The OVOCs in the YRD are dominated by ketones, aldehydes, and alcohols. Ketones and aldehydes mainly originate from direct emissions and secondary formation in the northern YRD, and primarily originate from secondary formation in the southern part influenced by biogenic emissions. The concentration of secondary organic aerosols (SOA) produced by OVOCs is 0.5-1.5 µg/m3, with 40-80% originated from organic nitrates, 20-70% originated from dicarbonyls, and 0-20% originated from isoprene epoxydiols. The influences of OVOCs on the atmospheric oxidation capacity are dominated by the OH• pathway during the day (∼350%) and by the NO3• pathway at night (∼150%). Consequently, O3 is enhanced by 30-70% in the YRD. Aerosols are also enhanced by 50-140%, 20-80%, and ∼20% for SOA, nitrate, and sulfate, respectively.

Field Detection of Highly Oxygenated Organic Molecules in Shanghai by Chemical Ionization-Orbitrap.

Secondary organic aerosol, formed through atmospheric oxidation processes, plays an important role in affecting climate and human health. In this study, we conducted a comprehensive campaign in the megacity of Shanghai during the 2019 International Import Expo (EXPO), with the first deployment of a chemical ionization─Orbitrap mass spectrometer for ambient measurements. With the ultrahigh mass resolving power of the Orbitrap mass analyzer (up to 140,000 Th/Th) and capability in dealing with massive spectral data sets by positive matrix factorization, we were able to identify the major gas-phase oxidation processes leading to the formation of oxygenated organic molecules (OOM) in Shanghai. Nine main factors from three independent sub-range analysis were identified. More than 90% of OOM are of anthropogenic origin and >60% are nitrogen-containing molecules, mainly dominated by the RO2 + NO and/or NO3 chemistry. The emission control during the EXPO showed that even though the restriction was effectual in significantly lowering the primary pollutants (20-70% decrease), the secondary oxidation products responded less effectively (14% decrease), or even increased (50 to >200%) due to the enhancement of ozone and the lowered condensation sink, indicating the importance of a stricter multi-pollutant coordinated strategy in primary and secondary pollution mitigation.

Understanding the journeys of patients with an asthma exacerbation requiring urgent therapy at a primary care clinic.

BACKGROUND: Asthma is a significant health issue in primary care. We examined the journeys of patients with asthma exacerbations requiring urgent therapy at a primary care clinic in Singapore. METHODS: Face-to-face semi-structured interviews were conducted with patients who received urgent therapy for asthma exacerbation at a primary care clinic. Data collected was used to construct themes. RESULTS: Fifteen multi-ethnic adult patients were recruited. Participants cited treatment cost, underuse of preventer medication, difficulties attending routine asthma care due to work, and stigma as barriers to asthma control. Reasons for delay in seeking urgent care for asthma were: inability to access medical care out of hours, competing priorities, perception that an exacerbation was 'not serious enough', difficulty recognizing symptoms of asthma exacerbation, and being tired or despondent. Participants were triggered to seek care due to failure of reliever inhalers, duration of symptoms, sleep disturbance, inability to work, or advice from others. During an exacerbation, participants often initiated other self-management measures besides using reliever medication. This included over-the-counter medications and non-pharmacological interventions (e.g. drinking water). Of the 15 patients interviewed, only one stepped up preventer inhaler adequately, according to their Asthma Action Plan (AAP). CONCLUSIONS: In caring for patients with asthma, primary care providers should address patients' asthma self-management skills, such as recognizing symptoms of asthma exacerbations and regular preventer use, and provide clear instructions on how to respond to asthma symptoms (AAP). Minimizing direct (medication and consultation fees) and indirect costs (loss of earnings and adverse impact on employment prospects) are also important considerations.

Stereotactic body radiotherapy for recurrent and oligometastatic soft tissue sarcoma.

BACKGROUND: Soft tissue sarcoma (STS) is a malignant tumor of highly heterogeneous mesenchymal origin. STS has a biological pattern and clinical transformation with localized invasive growth and is susceptible to hematogenous metastasis. Local therapeutic strategies may treat recurrent and oligometastatic STS, including surgery and radiation therapy. This study aimed to evaluate the safety and efficacy of stereotactic body radiotherapy (SBRT) for recurrent and oligometastatic STS. METHODS: We retrospectively analyzed 37 recurrent and oligometastatic STS patients with 58 lesions treated with SBRT from 2009 to 2019 at our institution. Oligometastatic is defined as metastatic lesions less than or equal to 3. The primary endpoint was local control (LC); secondary endpoints were survival and toxicity. RESULTS: The median follow-up was 21.0 months (3.0 to 125.0 months). Among 37 patients, 18 were recurrent patients, and 19 were oligometastatic patients. Median LC was 25.0 months (95% CI 20.0-45.0). The 1-, 2-, and 3-year LC rates were 80.2%, 58.3%, and 46.6%, respectively. Median overall survival (OS) was 24.0 months (95% CI 13.0-28.0), and the survival rates after SBRT were 71.5%, 40.0%, and 29.1% at 1, 2, and 3-year, respectively. Median progression-free survival (PFS) was 10.0 months (95% CI 8.0-15.0 months), PFS rate after SBRT was 43.6%, 26.8%, and 18.4% at 1, 2, and 3 years, respectively. Late grade 3 radiation dermatitis was observed in one patient (2.7%). Using univariate and multivariate COX analysis, better OS, PFS, and LC were obtained in the histologic grade 1(G1) group, and tumor size and a number of lesions influenced LC. CONCLUSIONS: SBRT is a safe and effective treatment for patients with recurrent and oligometastatic STS. Histological grade influences local control and survival. SBRT may be a promising treatment option for recurrent and oligometastatic STS.

Efficacy and safety of sirolimus early conversion protocol in liver transplant patients with hepatocellular carcinoma: A single-arm, multicenter, prospective study.

Mammalian target of rapamycin (mTOR) inhibitor as an attractive drug target with promising antitumor effects has been widely investigated. High quality clinical trial has been conducted in liver transplant (LT) recipients in Western countries. However, the pertinent studies in Eastern world are paucity. Therefore, we designed a clinical trial to test whether sirolimus can improve recurrence-free survival (RFS) in hepatocellular carcinoma (HCC) patients beyond the Milan criteria after LT. This is an open-labeled, single-arm, prospective, multicenter, and real-world study aiming to evaluate the clinical outcomes of early switch to sirolimus-based regimens in HCC patients after LT. Patients with a histologically proven HCC and beyond the Milan criteria will be enrolled. The initial immunosuppressant regimens are center-specific for the first 4-6 weeks. The following regimens integrated sirolimus into the regimens as a combination therapy with reduced calcineurin inhibitors based on the condition of patients and centers. The study is planned for 4 years in total with a 2-year enrollment period and a 2-year follow-up. We predict that sirolimus conversion regimen will provide survival benefits for patients particular in the key indicator RFS as well as better quality of life. If the trial is conducted successfully, we will have a continued monitoring over a longer follow-up time to estimate indicator of overall survival. We hope that the outcome will provide better evidence for clinical decision-making and revising treatment guidelines based on Chinese population data. Trial register: Trial registered at http://www.chictr.org.cn: ChiCTR2100042869.

Establishing Quality and Safety in Hospital-based 3D Printing Programs: Patient-first Approach.

The adoption of three-dimensional (3D) printing is rapidly spreading across hospitals, and the complexity of 3D-printed models and devices is growing. While exciting, the rapid growth and increasing complexity also put patients at increased risk for potential errors and decreased quality of the final product. More than ever, a strong quality management system (QMS) must be in place to identify potential errors, mitigate those errors, and continually enhance the quality of the product that is delivered to patients. The continuous repetition of the traditional processes of care, without insight into the positive or negative impact, is ultimately detrimental to the delivery of patient care. Repetitive tasks within a process can be measured, refined, and improved and translate into high levels of quality, and the same is true within the 3D printing process. The authors share their own experiences and growing pains in building a QMS into their 3D printing processes. They highlight errors encountered along the way, how they were addressed, and how they have strived to improve consistency, facilitate communication, and replicate successes. They also describe the vital intersection of health care providers, regulatory groups, and traditional manufacturers, who contribute essential elements to a common goal of providing quality and safety to patients. ©RSNA, 2021.

Transforming COVID-19 vaccines into vaccination : Challenges and opportunities for management scientists.

Amid the prolonged COVID-19 pandemic, the miraculous breakthroughs of multiple effective and safe COVID-19 vaccines offer hopeful prospects. Yet, the endgame of the pandemic is not vaccines; it is vaccination. The daunting challenge of vaccinating the world offers ample investigative opportunities for management scientists who are interested in improving the efficiency and equity of vaccine supply chains. In this article, we provide a brief overview of these opportunities through three constituent parts: (1) supply, (2) demand, and (3) matching supply with demand.