bluuebunny/crossref_metadata_2025 huggingface dataset:
Ophthalmic services in Shanghai 2017: a cataract-centric city-wide government survey
Authors: Zhu Xiangjia , Du Yu , He Wenwen , Dai Jinhui , Chen Minjie , Yao Peijun , Chen Han , Ren Hui , Fang Yuan , Tan Shensheng , Lu Yi
Published: October 2021

Background

Demand for eye care has increased in recent decades in China due to rapid socioeconomic development and demographic shift. Knowledge of output and productivity of ophthalmic services would allow policymakers to optimize resource allocation, and is therefore essential. This study sought to map the landscape of ophthalmic services available in Shanghai, China.

Methods

In 2018, a government-led survey was conducted of all 86 tertiary/secondary hospitals and five major private hospitals providing eye care in Shanghai in the form of electronic questionnaire, which encompassed ophthalmic services (outpatient and emergency room [ER] visit, inpatient admissions, and surgical volume) and service productivity in terms of annual outpatient and ER visits per doctor, inpatient admissions per bed, and surgical volume per doctor. Comparisons were made among different levels of hospitals with categorical variables tested by Chi-square analysis.

Results

The response rate was 85.7%. The Eye and Ear, Nose, and Throat (EENT) Hospital was the largest tertiary specialty hospital, and alone contributed to the highest 21.0% of annual ophthalmic outpatient and ER visits (visits per doctor: 5460), compared with other 26 tertiary hospitals, 46 secondary hospitals and five private hospitals (visits per doctor: 3683, 4651 and 1876). The annual inpatient admission was 20,103, 56,992, 14,090, and 52,047 for the EENT Hospital, all the other tertiary hospitals, secondary hospitals and five private hospitals, respectively. Turnover rates were highest for the EENT Hospital and private hospitals. The average surgical volume at the EENT Hospital was 72,666, exceeding that of private (15,874.8) and other tertiary hospitals (3366.7). The EENT Hospital and private hospitals performed 16,982 (14.2%) and 55,538 (46.6%) of all cataract surgeries. Proportions of both complicated cataractous cases and complicated cataract surgeries at the EENT Hospital was the highest, followed by other tertiary and secondary/private hospitals (P < 0.0001).

Conclusions

In Shanghai, public providers dominate ophthalmic services especially for complicated cases, with almost one fifth of services provided by the EENT Hospital alone, while private sectors, though not large in number, still effectively help meet large proportions of eye care demand. Optimization of hierarchical medical system is warranted to improve the efficiency and standardization of ophthalmic services.
Impact of Beijing healthcare reform on the curative care expenditure of outpatients with noncommunicable diseases based on SHA2011 and interrupted time series analysis
Authors: Liu Liming , Xu Yue , Jiang Yan , Zhao Liying , Yin Xuejun , Shen Chen , Yang Yong , Bai Qian , Man Xiaowei , Cheng Wei
Published: October 2021

Background

To analyse the changes in curative care expenditure (CCE) associated with noncommunicable diseases (NCDs) before and after the Beijing healthcare reform, thus providing a reference for the healthcare system.

Methods

A total of 60 medical institutions were selected using multistage stratified cluster random sampling in Beijing, China. The records of approximately 100 million outpatients with NCDs in 2016–2018 were extracted. System of Health Accounts 2011 (SHA2011) was used to estimate the CCE. The segmented regression model was established to observe both the instant change and the slope change of intervention in interrupted time series analysis (ITSA). The study was conducted from December 2019 to May 2020 in Beijing, China.

Results

From SHA2011, we found that the CCE for outpatients with NCDs in Beijing were 58.59, 61.46 and 71.96 billion RMB in 2016, 2017 and 2018, respectively. The CCE continued to rise at all hospital levels, namely, tertiary, secondary, and community-level hospitals. However, the proportion of CCE in tertiary hospitals decreased. From ITSA, we can also conclude that the CCE showed a significant increasing trend change at the three hospital levels after the intervention. The drug proportion showed a significant decreasing trend change in secondary and tertiary hospitals.

Conclusions

Beijing healthcare reform does have an impact on the CCE of NCDs.
Adiponectin ameliorates lung ischemia–reperfusion injury through SIRT1-PINK1 signaling-mediated mitophagy in type 2 diabetic rats
Authors: Jiang Tao , Liu Tianhua , Deng Xijin , Ding Wengang , Yue Ziyong , Yang Wanchao , Lv Xiangqi , Li Wenzhi
Published: October 2021

Background

Diabetes mellitus (DM) is a key contributing factor to poor survival in lung transplantation recipients. Mitochondrial dysfunction is recognized as a critical mediator in the pathogenesis of diabetic lung ischemia–reperfusion (IR) injury. The protective effects of adiponectin have been demonstrated in our previous study, but the underlying mechanism remains unclear. Here we demonstrated an important role of mitophagy in the protective effect of adiponectin during diabetic lung IR injury.

Methods

High-fat diet-fed streptozotocin-induced type 2 diabetic rats were exposed to adiponectin with or without administration of the SIRT1 inhibitor EX527 following lung transplantation. To determine the mechanisms underlying the action of adiponectin, rat pulmonary microvascular endothelial cells were transfected with SIRT1 small-interfering RNA or PINK1 small-interfering RNA and then subjected to in vitro diabetic lung IR injury.

Results

Mitophagy was impaired in diabetic lungs subjected to IR injury, which was accompanied by increased oxidative stress, inflammation, apoptosis, and mitochondrial dysfunction. Adiponectin induced mitophagy and attenuated subsequent diabetic lung IR injury by improving lung functional recovery, suppressing oxidative damage, diminishing inflammation, decreasing cell apoptosis, and preserving mitochondrial function. However, either administration of 3-methyladenine (3-MA), an autophagy antagonist or knockdown of PINK1 reduced the protective action of adiponectin. Furthermore, we demonstrated that APN affected PINK1 stabilization via the SIRT1 signaling pathway, and knockdown of SIRT1 suppressed PINK1 expression and compromised the protective effect of adiponectin.

Conclusion

These data demonstrated that adiponectin attenuated reperfusion-induced oxidative stress, inflammation, apoptosis and mitochondrial dysfunction via activation of SIRT1- PINK1 signaling-mediated mitophagy in diabetic lung IR injury.
Dietary fructose and risk of metabolic syndrome in Chinese residents aged 45 and above: results from the China National Nutrition and Health Survey
Authors: Pang Shaojie , Song Pengkun , Sun Xueqian , Qi Wentao , Yang Chun , Song Ge , Wang Yong , Zhang Jian
Published: October 2021

Background

A growing number of researches supported that dietary fructose was associated with most of the key features of metabolic syndrome (MetS). However, there was no related epidemiological studies among Chinese population, despite the sharp increase in MetS cases. This study explores the relationship between dietary fructose and MetS among Chinese residents aged 45 and above.

Methods

A total of 25,528 participants (11,574 males and 13,954 females) were included in this nationwide representative cross-sectional study of China National Nutrition and Health Survey. Dietary fructose intake was assessed by 3-day 24-h dietary records. MetS was defined by the International Diabetes Federation and Chinese Diabetes Society criteria.

Results

The consumption of dietary fructose was 11.6 g/day for urban residents and 7.6 g/day for rural residents. Fruits and vegetables as well as their products were the main sources of fructose intake. There was no association between dietary fructose intake and the odds of having MetS in both urban (P = 0.315) and rural residents (P = 0.230) after adjustment for confounding factors. Moreover, for urban residents participating physical activities, the odds of having MetS in the fourth quartiles (OR: 0.67; 95%CI: 0.52-0.87) was lower than that in the first quartile. In the sensitivity analysis, a significant reduction in the odds of having MetS was also found in the fourth quartiles (OR, 95%CI: 0.68, 0.51-0.90; 0.67, 0.49-0.91; 0.74, 0.56-0.99) compared with the first quartile when excluding smokers, alcohol users, and underweight/obesity, respectively. And there was no association between dietary fructose intake and the odds of having MetS after multivariate adjustment stratified by gender, smoking and alcohol use.

Conclusions

Under the current dietary fructose intake status, there was no association between dietary fructose intake and the odds of having MetS among Chinese residents aged 45 and above. Physical activity and relatively low fructose intake may have a beneficial synergistic effect on MetS.
Intra-population differences of apolipoproteins in the aqueous humor
Authors: Patel Parth A. , Lee Tae Jin , Kodeboyina Sai Karthik , Jones Garrett , Bollinger Kathryn , Ulrich Lane , Bogorad David , Estes Amy , Zhi Wenbo , Sharma Shruti , Sharma Ashok
Published: October 2021

Background

Evidence suggests that proteins related to lipid metabolism, such as apolipoproteins, play an important role in the maintenance of normal vision. While several members of the apolipoprotein family are abundant in human aqueous humor (AH), their study remains difficult due to the AH’s small volume, low protein concentration, and the invasive nature of sample collection. In this study, we report the use of Liquid Chromatography Tandem Mass Spectrometry (LC-MS/MS) to discover associations between AH apolipoproteins and race, gender, and ocular structure in patients with and without primary open angle glaucoma (POAG).

Methods

AH samples were collected from 231 patients undergoing phacoemulsification or glaucoma incisional surgery at the Medical College of Georgia, Augusta University and subsequently analyzed via LC-MS/MS. The number of peptide spectrum matches (PSMs) for each protein was used as a semi-quantitative measure of relative protein levels. Parameters related to ocular structure were determined using Optical Coherence Tomography (OCT) and Heidelberg Retinal Tomography (HRT). These data sets were probed for relationships between apolipoprotein levels and POAG, demographics (gender and race), and ocular structure.

Results

A total of ten apolipoproteins were detected in the 231 collected AH samples, with six detected in 100% of the samples, one detected in almost 57% of the samples and three detected in less than 10% of the samples. The levels of APOA1, APOC3, and APOD were higher among POAG subjects. Stratification by gender and race revealed demographic-specific variations. The levels of five apolipoproteins (APOA1, APOA2, APOA4, APOC3, and APOD) were higher in female POAG patients, whereas no apolipoprotein levels were altered in male POAG patients. The levels of APOA1, APOA2, APOA4, and APOD were increased in glaucomatous African American patients, whereas APOE and APOH levels were decreased in glaucomatous Caucasian patients. We also found distinct associations between apolipoprotein levels and OCT and HRT parameters in patients with and without POAG.

Conclusions

The intra-population variation in apolipoprotein levels highlights the heterogeneity of glaucoma as a disease, suggesting the importance of personalized treatments. Gender and race-specific alterations may be associated with higher risks of POAG in females and members of the African American population.
Metabolic dysfunction associated fatty liver disease and coronavirus disease 2019: clinical relationship and current management
Authors: Xu Yanlan , Yang Xinyu , Bian Hua , Xia Mingfeng
Published: October 2021

The coronavirus disease 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2). At present, the COVID-19 has been prevalent worldwide for more than a year and caused more than four million deaths. Liver injury was frequently observed in patients with COVID-19. Recently, a new definition of metabolic dysfunction associated fatty liver disease (MAFLD) was proposed by a panel of international experts, and the relationship between MAFLD and COVID-19 has been actively investigated. Several previous studies indicated that the patients with MAFLD had a higher prevalence of COVID-19 and a tendency to develop severe type of respiratory infection, and others indicated that liver injury would be exacerbated in the patients with MAFLD once infected with COVID-19. The mechanism underlying the relationship between MAFLD and COVID-19 infection has not been thoroughly investigated, and recent studies indicated that multifactorial mechanisms, such as altered host angiotensin converting enzyme 2 (ACE2) receptor expression, direct viral attack, disruption of cholangiocyte function, systemic inflammatory reaction, drug-induced liver injury, hepatic ischemic and hypoxic injury, and MAFLD-related glucose and lipid metabolic disorders, might jointly contribute to both of the adverse hepatic and respiratory outcomes. In this review, we discussed the relationship between MAFLD and COVID-19 based on current available literature, and summarized the recommendations for clinical management of MAFLD patients during the pandemic of COVID-19.
Atovaquone-HSA nano-drugs enhance the efficacy of PD-1 blockade immunotherapy by alleviating hypoxic tumor microenvironment
Authors: Wang Simeng , Zhou Xinrui , Zeng Zekun , Sui Mengjun , Chen Lihong , Feng Chao , Huang Chen , Yang Qi , Ji Meiju , Hou Peng
Published: October 2021

Background

Hypoxia is inherent character of most solid malignancies, leading to the failure of chemotherapy, radiotherapy and immunotherapy. Atovaquone, an anti-malaria drug, can alleviate tumor hypoxia by inhibiting mitochondrial complex III activity. The present study exploits atovaquone/albumin nanoparticles to improve bioavailability and tumor targeting of atovaquone, enhancing the efficacy of anti-PD-1 therapy by normalizing tumor hypoxia.

Methods

We prepared atovaquone-loaded human serum albumin (HSA) nanoparticles stabilized by intramolecular disulfide bonds, termed HSA-ATO NPs. The average size and zeta potential of HSA-ATO NPs were measured by particle size analyzer. The morphology of HSA-ATO NPs was characterized by transmission electron microscope (TEM). The bioavailability and safety of HSA-ATO NPs were assessed by animal experiments. Flow cytometry and ELISA assays were used to evaluate tumor immune microenvironment.

Results

Our data first verified that atovaquone effectively alleviated tumor hypoxia by inhibiting mitochondrial activity both in vitro and in vivo, and successfully encapsulated atovaquone in vesicle with albumin, forming HSA-ATO NPs of approximately 164 nm in diameter. We then demonstrated that the HSA-ATO NPs possessed excellent bioavailability, tumor targeting and a highly favorable biosafety profile. When combined with anti-PD-1 antibody, we observed that HSA-ATO NPs strongly enhanced the response of mice bearing tumor xenografts to immunotherapy. Mechanistically, HSA-ATO NPs promoted intratumoral CD8+ T cell recruitment by alleviating tumor hypoxia microenvironment, thereby enhancing the efficacy of anti-PD-1 immunotherapy.

Conclusions

Our data provide strong evidences showing that HSA-ATO NPs can serve as safe and effective nano-drugs to enhance cancer immunotherapy by alleviating hypoxic tumor microenvironment.

Graphic abstract
Risk factors associated with postoperative complications after liver cancer resection surgery in western China
Authors: Hu Yanjie , Zeng Siyu , Li Lele , Fang Yuanchen , He Xiaozhou
Published: October 2021

Objectives

Postoperative complications increase the workload of nursing staff as well as the financial and mental distress suffered by patients. The objective of this study is to identify clinical factors associated with postoperative complications after liver cancer resection surgery.

Methods

Data from liver cancer resections occurring between January 1st, 2019 to December 31st, 2019 was collected from the Department of Liver Surgery in West China Hospital of Sichuan University. The Kruskal–Wallis test and logistic regression were used to perform single-factor analysis. Stepwise logistic regression was used for multivariate analysis. Models were established using R 4.0.2 software.

Results

Based on data collected from 593 cases, the single-factor analysis determined that there were statistically significant differences in BMI, incision type, incision length, duration, incision range, and bleeding between cases that experienced complications within 30 days after surgery and those did not. Stepwise logistic regression models based on Kruskal–Wallis test and single-factor logistic regression determined that BMI, incision length, and duration were the primary factors causing complications after liver resection. The adjust OR of overweight patients and patients with obesity (stage 1) compared to low weight patients were 0.12 (95% CI:0.02–0.72) with p = 0.043 and 0.18 (95% CI:0.03–1.00) with p = 0.04, respectively. An increase of 1 cm in incision length increased the relative risk by 13%, while an increase of 10 min in surgical duration increased the relative risk by 15%.

Conclusions

The risk of postoperative complications after liver resection can be significantly reduced by controlling factors such as bleeding, incision length, and duration of the surgery.
SCO-spondin, a giant matricellular protein that regulates cerebrospinal fluid activity
Authors: Sepúlveda Vania , Maurelia Felipe , González Maryori , Aguayo Jaime , Caprile Teresa
Published: October 2021

Cerebrospinal fluid is a clear fluid that occupies the ventricular and subarachnoid spaces within and around the brain and spinal cord. Cerebrospinal fluid is a dynamic signaling milieu that transports nutrients, waste materials and neuroactive substances that are crucial for the development, homeostasis and functionality of the central nervous system. The mechanisms that enable cerebrospinal fluid to simultaneously exert these homeostatic/dynamic functions are not fully understood. SCO-spondin is a large glycoprotein secreted since the early stages of development into the cerebrospinal fluid. Its domain architecture resembles a combination of a matricellular protein and the ligand-binding region of LDL receptor family. The matricellular proteins are a group of extracellular proteins with the capacity to interact with different molecules, such as growth factors, cytokines and cellular receptors; enabling the integration of information to modulate various physiological and pathological processes. In the same way, the LDL receptor family interacts with many ligands, including β-amyloid peptide and different growth factors. The domains similarity suggests that SCO-spondin is a matricellular protein enabled to bind, modulate, and transport different cerebrospinal fluid molecules. SCO-spondin can be found soluble or polymerized into a dynamic threadlike structure called the Reissner fiber, which extends from the diencephalon to the caudal tip of the spinal cord. Reissner fiber continuously moves caudally as new SCO-spondin molecules are added at the cephalic end and are disaggregated at the caudal end. This movement, like a conveyor belt, allows the transport of the bound molecules, thereby increasing their lifespan and action radius. The binding of SCO-spondin to some relevant molecules has already been reported; however, in this review we suggest more than 30 possible binding partners, including peptide β-amyloid and several growth factors. This new perspective characterizes SCO-spondin as a regulator of cerebrospinal fluid activity, explaining its high evolutionary conservation, its apparent multifunctionality, and the lethality or severe malformations, such as hydrocephalus and curved body axis, of knockout embryos. Understanding the regulation and identifying binding partners of SCO-spondin are crucial for better comprehension of cerebrospinal fluid physiology.
Ceftolozane/tazobactam probability of target attainment and outcomes in participants with augmented renal clearance from the randomized phase 3 ASPECT-NP trial
Authors: Shorr Andrew F. , Bruno Christopher J. , Zhang Zufei , Jensen Erin , Gao Wei , Feng Hwa-Ping , Huntington Jennifer A. , Yu Brian , Rhee Elizabeth G. , De Anda Carisa , Basu Sumit , Kollef Marin H.
Published: October 2021

Background

The randomized, double-blind, phase 3 ASPECT-NP trial evaluated the efficacy of 3 g of ceftolozane/tazobactam (C/T) versus 1 g of meropenem infused every 8 h for 8 to 14 days for treatment of adults with hospital-acquired bacterial pneumonia (HABP) or ventilator-associated bacterial pneumonia (VABP). We assessed the probability of target attainment and compared efficacy outcomes from ASPECT-NP in participants with augmented renal clearance (ARC) versus those with normal renal function.

Methods

Baseline renal function was categorized as normal renal function (creatinine clearance 80–130 mL/min) or ARC (creatinine clearance > 130 mL/min). Population pharmacokinetic models informed Monte Carlo simulations to assess probability of target attainment in plasma and pulmonary epithelial lining fluid. Outcomes included 28-day all-cause mortality and clinical cure and per-participant microbiologic cure rates at the test-of-cure visit.

Results

A > 99% and > 80% probability of target attainment was demonstrated for ceftolozane and tazobactam, respectively, in simulated plasma and epithelial lining fluid. Within treatment arms, 28-day all-cause mortality rates in participants with normal renal function (C/T, n = 131; meropenem, n = 123) and ARC (C/T, n = 96; meropenem, n = 113) were comparable (data comparisons presented as rate; treatment difference [95% CI]) (C/T: normal renal function, 17.6%; ARC, 17.7%; 0.2 [− 9.6 to 10.6]; meropenem: normal renal function, 20.3%; ARC, 17.7%; − 2.6 [− 12.6 to 7.5]). Clinical cure rates at test-of-cure were also comparable across renal function groups within treatment arms (C/T: normal renal function, 57.3%; ARC, 59.4%; − 2.1 [− 14.8 to 10.8]; meropenem: normal renal function, 59.3%; ARC, 57.5%; 1.8 [− 10.6 to 14.2]). Per-participant microbiologic cure rates at test-of-cure were consistent across renal function groups within treatment arms (C/T: normal renal function, 72.2% [n/N = 70/97]; ARC, 71.4% [n/N = 55/77]; 0.7 [− 12.4 to 14.2]; meropenem: normal renal function, 75.0% [n/N = 66/88]; ARC, 70.0% [n/N = 49/70]; 5.0 [− 8.7 to 19.0]).

Conclusions

C/T and meropenem resulted in 28-day all-cause mortality, clinical cure, and microbiologic cure rates that were comparable between participants with ARC or normal renal function. In conjunction with high probability of target attainment, these results confirm that C/T (3 g) every 8 h is appropriate in patients with HABP/VABP and ARC.

Trial registration ClinicalTrials.gov identifier: NCT02070757, registered February 25, 2014; EudraCT: 2012-002862-11.
Phytochemical analysis, antioxidant and in vitro β-galactosidase inhibition activities of Juniperus phoenicea and Calicotome villosa methanolic extracts
Authors: Al-Mustafa Ahmed , Al-Tawarah Mohammad , Al-Sheraideh Mohammed Sharif , Al-Zahrany Fatema Attia
Published: October 2021

Background

Juniperus Phoenicea (JP) and Calicotome Villosa (CV) are used by Jordanian populations as herbal remedies in traditional medicine. Herein, the phytochemical contents of their methanolic extracts were analyzed and their antioxidant as well as in vitro anti- β-Galactosidase activities were evaluated; their effect on β-Galactosidase enzyme kinetics was evaluated and the thermodynamic of the enzyme was determined.

Methods

The antioxidant activity of JP and CV crude methanolic extracts was evaluated using 1,1-diphenyl,2-picrylhydrazyl (DPPH) free radical scavenging and ferric reducing antioxidant power (FRAP) assays; however, the effect of the plants’ crude extracts on β-Galactosidase activity and kinetics was evaluated in vitro. Moreover, total phenolic, flavonoids, and flavonols content in plants’ extracts were determined and expressed in Gallic acid equivalent (mg GAE/g dry extract) or rutin equivalent (mg RE/g dry extract).

Results

Phytochemical screening of the crude extracts of JP and CV leaves revealed the presence of phenols, alkaloids, flavonoids, terpenoids, anthraquinones, and glycosides. Flavonoids and flavonols contents were significantly higher in JP than in CV (p < 0.05). Furthermore, an analogous phenolic content was detected in both JP and CV methanolic extracts (103.6 vs 99.1 mg GAE/g extract). The ability of JP extract to scavenge DPPH radicals was significantly higher than that of CV extract with IC50 = 11.1 μg/ml and 15.6 μg/ml, respectively. However, their extracts revealed relatively similar antioxidant capacities in FRAP assay; their activity was concentration dependent. The JP extract inhibited β—galactosidase enzyme activity with a significant IC50 value compared to CV extract; they exhibited their inhibitory activities at IC50 values 65 µg/ml and 700 µg/ml, respectively. Rutin revealed anti-β-galactosidase activity at IC50 = 75 µg/ml. The mode of inhibition of β-galactosidase by JP, CV, and rutin was non-competitive, mixed, and competitive inhibition, respectively. Thermodynamic and enzyme inactivation kinetics revealed that β-galactosidase has a half-life time of 108 min at 55 °C, activation energy of 208.88 kJ mol−1 and the inactivation kinetics follows a first-order reaction with k-values 0.0023–0.0862 min−1 and positive entropy of inactivation (∆S°) values at various temperatures, indicating non-significant processes of aggregation.

Conclusions

The methanolic extracts of JP and CV possess anti-hyperglycemic and antioxidant activities with potential pharmaceutical applications.
Correction to: Epidemiological and entomological studies of malaria transmission in Tibati, Adamawa region of Cameroon 6 years following the introduction of long-lasting insecticide nets
Authors: Feufack-Donfack Lionel Brice , Sarah-Matio Elangwe Milo , Abate Luc Marcel , Tuedom Aline Gaelle Bouopda , Bayibéki Albert Ngano , Ngou Christelle Mafo , Toto Jean-Claude , Sandeu Maurice Marcel , Moukoko Carole Else Eboumbou , Ayong Lawrence , Awono-Ambene Parfait , Morlais Isabelle , Nsango Sandrine Eveline
Published: October 2021

An amendment to this paper has been published and can be accessed via the original article.
Molecular profiling of advanced malignancies guides first-line N-of-1 treatments in the I-PREDICT treatment-naïve study
Authors: Sicklick Jason K. , Kato Shumei , Okamura Ryosuke , Patel Hitendra , Nikanjam Mina , Fanta Paul T. , Hahn Michael E. , De Pradip , Williams Casey , Guido Jessica , Solomon Benjamin M. , McKay Rana R. , Krie Amy , Boles Sarah G. , Ross Jeffrey S. , Lee J. Jack , Leyland-Jones Brian , Lippman Scott M. , Kurzrock Razelle
Published: October 2021

Background

Malignancies are molecularly complex and become more resistant with each line of therapy. We hypothesized that offering matched, individualized combination therapies to patients with treatment-naïve, advanced cancers would be feasible and efficacious. Patients with newly diagnosed unresectable/metastatic, poor-prognosis cancers were enrolled in a cross-institutional prospective study.

Methods

A total of 145 patients were included in the study. Genomic profiling (tissue and/or circulating tumor DNA) was performed in all patients, and PD-L1 immunohistochemistry, tumor mutational burden, and microsatellite status assessment were performed in a subset of patients. We evaluated safety and outcomes: disease-control rate (stable disease for ≥ 6 months or partial or complete response), progression-free survival (PFS), and overall survival (OS).

Results

Seventy-six of 145 patients (52%) were treated, most commonly for non-colorectal gastrointestinal cancers, carcinomas of unknown primary, and hepatobiliary malignancies (53% women; median age, 63 years). The median number of deleterious genomic alterations per patient was 5 (range, 0–15). Fifty-four treated patients (71%) received ≥ 1 molecularly matched therapy, demonstrating the feasibility of administering molecularly matched therapy. The Matching Score, which reflects the percentage of targeted alterations, correlated linearly with progression-free survival (R2 = 0.92; P = 0.01), and high (≥ 60%) Matching Score was an independent predictor of improved disease control rate [OR 3.31 (95% CI 1.01–10.83), P = 0.048], PFS [HR 0.55 (0.28–1.07), P = 0.08], and OS [HR 0.42 (0.21–0.85), P = 0.02]. Serious adverse event rates were similar in the unmatched and matched groups.

Conclusions

Personalized combination therapies targeting a majority of a patient’s molecular alterations have antitumor activity as first-line treatment. These findings underscore the feasibility and importance of using tailored N-of-1 combination therapies early in the course of lethal malignancies.

Trial registration

I-PREDICT (NCT02534675) was registered on August 25, 2015.
Melkersson–Rosenthal syndrome in the context of sarcoidosis: a case report
Authors: Casper J. , Mohammad-Khani S. , Schmidt J. J. , Kielstein J. T. , Lenarz T. , Haller H. , Wagner Annette D.
Published: October 2021

Background

Melkersson–Rosenthal syndrome is a rare disease characterized by the triad of recurrent orofacial swelling with facial paralysis and fissured dorsal tongue. Histologically, noncaseating granulomatous inflammation occurs that confirms the diagnosis. Overlaps between granulomatous diseases such as sarcoidosis and Crohn’s disease are described. Systemic corticosteroid therapy is the treatment of choice for acute attacks.

Case presentation

We here present a case of a 59-year-old White woman suffering from Melkersson–Rosenthal syndrome with a past history of sarcoidosis on therapy with leflunomide in combination with low-dose tacrolimus successfully treated with the anti-leprosy drug clofazimine after failure of systemic steroid therapy.

Conclusions

We propose clofazimine as an alternative treatment in steroid-refractory cases.
Synergy conformal prediction applied to large-scale bioactivity datasets and in federated learning
Authors: Norinder Ulf , Spjuth Ola , Svensson Fredrik
Published: October 2021

Confidence predictors can deliver predictions with the associated confidence required for decision making and can play an important role in drug discovery and toxicity predictions. In this work we investigate a recently introduced version of conformal prediction, synergy conformal prediction, focusing on the predictive performance when applied to bioactivity data. We compare the performance to other variants of conformal predictors for multiple partitioned datasets and demonstrate the utility of synergy conformal predictors for federated learning where data cannot be pooled in one location. Our results show that synergy conformal predictors based on training data randomly sampled with replacement can compete with other conformal setups, while using completely separate training sets often results in worse performance. However, in a federated setup where no method has access to all the data, synergy conformal prediction is shown to give promising results. Based on our study, we conclude that synergy conformal predictors are a valuable addition to the conformal prediction toolbox.
LsrR, the effector of AI-2 quorum sensing, is vital for the H2O2 stress response in mammary pathogenic Escherichia coli
Authors: Wang Hui , Shang Fei , Shen Jiawei , Xu Jingyi , Chen Xiaolin , Ni Jingtian , Yu Lumin , Xue Ting
Published: October 2021

Mammary pathogenic Escherichia coli (MPEC) is an important causative agent of mastitis in dairy cows that results in reduced milk quality and production, and is responsible for severe economic losses in the dairy industry worldwide. Oxidative stress, as an imbalance between reactive oxygen species (ROS) and antioxidants, is a stress factor that is common in most bacterial habitats. The presence of ROS can damage cellular sites, including iron-sulfur clusters, cysteine and methionine protein residues, and DNA, and may cause bacterial cell death. Previous studies have reported that Autoinducer 2 (AI-2) can regulate E. coli antibiotic resistance and pathogenicity by mediating the intracellular receptor protein LsrR. This study explored the regulatory mechanism of LsrR on the H2O2 stress response in MPEC, showing that the transcript levels of lsrR significantly decreased under H2O2 stress conditions. The survival cell count of lsrR mutant XW10/pSTV28 was increased about 3080-fold when compared with that of the wild-type WT/pSTV28 in the presence of H2O2 and overexpression of lsrR (XW10/pUClsrR) resulted in a decrease in bacterial survival rates under these conditions. The β-galactosidase reporter assays showed that mutation of lsrR led to a remarkable increase in expression of the promoters of ahpCF, katG and oxyR, while lsrR-overexpressing significantly reduced the expression of ahpCF and katG. The electrophoretic mobility shift assays confirmed that LsrR could directly bind to the promoter regions of ahpCF and katG. These results revealed the important role played by LsrR in the oxidative stress response of MPEC.
Handgrip strength to predict extubation outcome: a prospective multicenter trial
Authors: Cottereau Guillaume , Messika Jonathan , Megarbane Bruno , Guérin Laurent , da Silva Daniel , Bornstain Caroline , Santos Matilde , Ricard Jean-Damien , Sztrymf Benjamin
Published: October 2021

Background

ICU-acquired weakness (ICUAW) has been shown to be associated with prolonged duration of mechanical ventilation and extubation failure. It is usually assessed through Medical Research Council (MRC) score, a time-consuming score performed by physiotherapists. Handgrip strength (HG) can be monitored very easily at the bedside. It has been shown to be a reproducible and reliable marker of global muscular strength in critical care patients. We sought to test if muscular weakness, as assessed by handgrip strength, was associated with extubation outcome.

Methods

Prospective multicenter trial over an 18 months period in six mixed ICUs. Adults receiving mechanical ventilation for at least 48 h were eligible. Just before weaning trial, HG, Maximal Inspiratory Pressure (MIP), Peak Cough Expiratory Flow (PCEF) and Medical Research Council (MRC) score were registered. The attending physicians were unaware of the tests results and weaning procedures were conducted according to guidelines. Occurrence of unscheduled reintubation, non-invasive ventilation (NIV) or high-flow nasal continuous oxygen (HFNC) because of respiratory failure within 7 days after extubation defined extubation failure. The main outcome was the link between HG and extubation outcome.

Results

233 patients were included. Extubation failure occurred in 51 (22.5%) patients, 39 (17.2%) required reintubation. Handgrip strength was 12 [6–20] kg and 12 [8–20] kg, respectively, in extubation success and failure (p = 0.85). There was no association between extubation outcome and MRC score, MIP or PCEF. Handgrip strength was well correlated with MRC score (r = 0.718, p < 0.0001). ICU and hospital length of stay were significantly higher in the subset of patients harboring muscular weakness as defined by handgrip performed at the first weaning trial (respectively, 15 [10–25] days vs. 11 [7–17] days, p = 0.001 and 34 [19–66] days vs. 22 [15–43] days, p = 0.002).

Conclusion

No association was found between handgrip strength and extubation outcome. Whether this was explained by the appropriateness of the tool in this specific setting, or by the precise impact of ICUAW on extubation outcome deserves to be further evaluated.

Trial registration Clinical Trials; NCT02946502, 10/27/2016, URL: https://clinicaltrials.gov/ct2/results?cond=&term=gripwean&cntry=&state=&city=&dist=
A reinforcement learning-based computing offloading and resource allocation scheme in F-RAN
Authors: Jiang Fan , Ma Rongxin , Gao Youjun , Gu Zesheng
Published: October 2021

This paper investigates a computing offloading policy and the allocation of computational resource for multiple user equipments (UEs) in device-to-device (D2D)-aided fog radio access networks (F-RANs). Concerning the dynamically changing wireless environment where the channel state information (CSI) is difficult to predict and know exactly, we formulate the problem of task offloading and resource optimization as a mixed-integer nonlinear programming problem to maximize the total utility of all UEs. Concerning the non-convex property of the formulated problem, we decouple the original problem into two phases to solve. Firstly, a centralized deep reinforcement learning (DRL) algorithm called dueling deep Q-network (DDQN) is utilized to obtain the most suitable offloading mode for each UE. Particularly, to reduce the complexity of the proposed offloading scheme-based DDQN algorithm, a pre-processing procedure is adopted. Then, a distributed deep Q-network (DQN) algorithm based on the training result of the DDQN algorithm is further proposed to allocate the appropriate computational resource for each UE. Combining these two phases, the optimal offloading policy and resource allocation for each UE are finally achieved. Simulation results demonstrate the performance gains of the proposed scheme compared with other existing baseline schemes.
Objectively measured preoperative physical activity is associated with time to functional recovery after hepato-pancreato-biliary cancer surgery: a pilot study
Authors: Mylius Caspar F. , Krijnen Wim P. , Takken Tim , Lips Daan J. , Eker Hasan , van der Schans Cees P. , Klaase Joost M.
Published: October 2021

Background

Surgical resection is currently the cornerstone of hepato-pancreato-biliary (HPB) cancer treatment. A low preoperative aerobic fitness level has been identified as a modifiable risk factor associated with complications after major abdominal surgery. A person’s aerobic fitness is influenced by performing moderate to vigorous physical activity (MVPA). This study aims to determine the activity monitor measured levels of MVPA performed among patients on the waiting list for HPB cancer surgery and their association with postoperative outcomes.

Methods

A prospective, observational multi-center cohort pilot study was conducted. Patients enlisted for resection surgery on suspicion of HPB (pre)malignancy were enrolled. Performed MVPA was measured by an Actigraph wGT3X-BT. Additionally, aerobic fitness was measured via the Incremental Shuttle Walk Test, and (post)operative variables were collected from the electronic patient files. The association between MVPA and the pre- and postoperative variables was determined by univariate and multivariable (logistic) robust regression.

Results

A total of 38 participants, median age 66.0 (IQR 58.25–74.75) years, were enrolled. The median daily MVPA was 10.7 (IQR 6.9–18.0) min; only 8 participants met the Dutch MVPA guidelines. Participant’s age and aerobic fitness were associated with MVPA by multivariable statistical analysis. Time to functional recovery was 8 (IQR 5–12) days and was associated with MVPA and type of surgery (major/minor) in multivariable analysis.

Conclusion

Seventy-six percent of patients enlisted for resection of HPB (pre)malignancy performed insufficient MVPA. A higher level of MVPA was associated with a shorter time to functional recovery.
Strategies for large bone defect reconstruction after trauma, infections or tumour excision: a comprehensive review of the literature
Authors: Migliorini Filippo , La Padula Gerardo , Torsiello Ernesto , Spiezia Filippo , Oliva Francesco , Maffulli Nicola
Published: October 2021

Large bone defects resulting from musculoskeletal tumours, infections, or trauma are often unable to heal spontaneously. The challenge for surgeons is to avoid amputation, and provide the best functional outcomes. Allograft, vascularized fibular or iliac graft, hybrid graft, extracorporeal devitalized autograft, distraction osteogenesis, induced-membrane technique, and segmental prostheses are the most common surgical strategies to manage large bone defects. Given its optimal osteogenesis, osteoinduction, osteoconduction, and histocompatibility properties, along with the lower the risk of immunological rejection, autologous graft represents the most common used strategy for reconstruction of bone defects. However, the choice of the best surgical technique is still debated, and no consensus has been reached. The present study investigated the current reconstructive strategies for large bone defect after trauma, infections, or tumour excision, discussed advantages and disadvantages of each technique, debated available techniques and materials, and evaluated complications and new perspectives.
Distinct B cell subsets in Peyer’s patches convey probiotic effects by Limosilactobacillus reuteri
Authors: Liu Hao-Yu , Giraud Antoine , Seignez Cedric , Ahl David , Guo Feilong , Sedin John , Walden Tomas , Oh Jee-Hwan , van Pijkeren Jan Peter , Holm Lena , Roos Stefan , Bertilsson Stefan , Phillipson Mia
Published: October 2021

Background

Intestinal Peyer’s patches (PPs) form unique niches for bacteria-immune cell interactions that direct host immunity and shape the microbiome. Here we investigate how peroral administration of probiotic bacterium Limosilactobacillus reuteri R2LC affects B lymphocytes and IgA induction in the PPs, as well as the downstream consequences on intestinal microbiota and susceptibility to inflammation.

Results

The B cells of PPs were separated by size to circumvent activation-dependent cell identification biases due to dynamic expression of markers, which resulted in two phenotypically, transcriptionally, and spatially distinct subsets: small IgD+/GL7−/S1PR1+/Bcl6, CCR6-expressing pre-germinal center (GC)-like B cells with innate-like functions located subepithelially, and large GL7+/S1PR1−/Ki67+/Bcl6, CD69-expressing B cells with strong metabolic activity found in the GC. Peroral L. reuteri administration expanded both B cell subsets and enhanced the innate-like properties of pre-GC-like B cells while retaining them in the sub-epithelial compartment by increased sphingosine-1-phosphate/S1PR1 signaling. Furthermore, L. reuteri promoted GC-like B cell differentiation, which involved expansion of the GC area and autocrine TGFβ-1 activation. Consequently, PD-1-T follicular helper cell-dependent IgA induction and production was increased by L. reuteri, which shifted the intestinal microbiome and protected against dextran-sulfate-sodium induced colitis and dysbiosis.

Conclusions

The Peyer’s patches sense, enhance and transmit probiotic signals by increasing the numbers and effector functions of distinct B cell subsets, resulting in increased IgA production, altered intestinal microbiota, and protection against inflammation.
Anti-inflammatory efficacy of Berberine Nanomicelle for improvement of cerebral ischemia: formulation, characterization and evaluation in bilateral common carotid artery occlusion rat model
Authors: Azadi Roza , Mousavi Seyyedeh Elaheh , Kazemi Negar Motakef , Yousefi-Manesh Hasan , Rezayat Seyed Mahdi , Jaafari Mahmoud Reza
Published: October 2021

Background

Berberine (BBR) is a plant alkaloid that possesses anti-inflammatory and anti-oxidant effects with low oral bioavailability. In this study, micelle formulation of BBR was investigated to improve therapeutic efficacy and examined its effect on the secretion of inflammatory cytokines in cerebral ischemia in the animal model.

Material and methods

Nano formulation was prepared by thin-film hydration method, and characterized by particle size, zeta potential, morphology, encapsulation efficacy, and drug release in Simulated Gastric Fluid (SGF) and Simulated Intestine Fluid (SIF). Then, Wistar rats were pretreated with the drug (100 mg/kg) and nano-drug (25, 50, 75, 100 mg/kg) for 14 days. Then, on the fourteenth day, stroke induction was accomplished by Bilateral Common Carotid Artery Occlusion (BCCAO); after that, Tumor Necrosis Factor - Alpha (TNF-α), Interleukin – 1 Beta (IL-1ß), and Malondialdehyde (MDA) levels were measured in the supernatant of the whole brain, then the anti-inflammatory effect of BBR formulations was examined.

Result and discussion

Micelles were successfully formed with appropriate characteristics and smaller sizes than 20 nm. The Poly Dispersity Index (PDI), zeta potential, encapsulation efficacy of micelles was 0.227, − 22 mV, 81%, respectively. Also, the stability of nano micelles was higher in SGF as compared to SIF. Our outcomes of TNF-a, IL-1B, and MDA evaluation show a significant ameliorating effect of the Berberine (BBR) and BBR-loaded micelles in pretreated groups.

Conclusion

Our experimental data show that pretreated groups in different doses (nano BBR 100, 75, 50 mg/kg, and BBR 100 mg/kg) successfully showed decreased levels of the inflammatory factors in cerebral ischemia compared with the stroke group and pretreated group with nano BBR in the dose of 25 mg/kg. Nano BBR formulation with a lower dose can be a better candidate than conventional BBR formulation to reduce oxidative and inflammatory factors in cerebral ischemia. Therefore, BBR-loaded micelle formulation could be a promising protective agent on cerebral ischemia.
PFP@PLGA/Cu12Sb4S13-mediated PTT ablates hepatocellular carcinoma by inhibiting the RAS/MAPK/MT-CO1 signaling pathway
Authors: Dong Tianxiu , Jiang Jian , Zhang Hao , Liu Hongyuan , Zou Xiaomeng , Niu Jiamei , Mao Yingxuan , Zhu Mingwei , Chen Xi , Li Zizhuo , Chen Yaodong , Shi Chunying , Yang Xiuhua
Published: October 2021

Hepatocellular carcinoma (HCC) is one of the most malignant tumors in the world, and patients with HCC face a poor prognosis. The conventional therapeutic strategies for HCC have undergone a challenge-riddled evolution owing to side effects and unsatisfactory efficacy. Here, aiming to provide a new method of HCC elimination, we formulated a novel multifunctional nanocapsule (PFP@PLGA/Cu12Sb4S13, PPCu) with applications in contrast-enhanced ultrasound imaging (CEUS) and photothermal therapy (PTT). These PPCu were successfully constructed with an average diameter of 346 nm (polydispersity index, PDI = 0.276). The reinforced contrast ratio of these PPCu was determined by CEUS, revealing their promising applications in image-guided monitoring of HCC treatment. Furthermore, the excellent photoabsorption and biocompatibility indicated by organ H&E staining indicated that PPCu meet quality expectations for use as photothermal transduction agent (PTA). PPCu treatment at 50 °C and higher temperatures efficiently repressed the proliferation, induced the apoptosis and decreased the motility of HCC cells. These effects might have been results of RAS/MAPK/MT-CO1 signaling pathway inhibition. In summary, PPCu were constructed to integrate CEUS and PTT successfully into therapy, which can lead to HCC elimination through RAS/MAPK/MT-CO1 signaling pathway repression.
An Almahata Sitta EL3 fragment: implications for the complex thermal history of enstatite chondrites
Authors: Kimura M. , Weisberg M. K. , Takaki A. , Imae N. , Yamaguchi A.
Published: October 2021

Almahata Sitta is a polymict breccia, consisting of many kinds of clasts. Here we present our mineralogical and petrological results on an EL3 fragment, MS-177 from Almahata Sitta. This fragment shows a typical type 3 chondritic texture, consisting of well-defined chondrules, isolated silicate minerals, and opaque nodules. Most chondrules are enstatite-rich with some having olivine. Although these components are typical of EL3 chondrites, the mineral abundances and compositions are different from the other EL3s. Diopside is unusually abundant in MS-177. On the other hand, perryite and daubreelite were not found. The major pyroxene is orthoenstatite, and the silica phase is quartz. Fe–Ni metal has relatively high P contents. Troilite is enriched in Cr and Mn. Keilite and buseckite are present in MS-177. From the mineralogy and texture, MS-177 experienced a high-temperature event under subsolidus conditions. Shock-induced heating for a short duration might explain this high-temperature event. We suggest that other E3 chondrites also experienced heating events under such subsolidus conditions on their parent bodies. On the other hand, the high abundance of diopside cannot be explained by a secondary thermal event and may have been a primary feature of MS-177, formed before accretion to the parent body.