bluuebunny/crossref_metadata_2025 huggingface dataset:
Percepta Genomic Sequencing Classifier and decision-making in patients with high-risk lung nodules: a decision impact study
Authors: Sethi Sonali , Oh Scott , Chen Alexander , Bellinger Christina , Lofaro Lori , Johnson Marla , Huang Jing , Bhorade Sangeeta Maruti , Bulman William , Kennedy Giulia C.
Published: January 2022

Background

Incidental and screening-identified lung nodules are common, and a bronchoscopic evaluation is frequently nondiagnostic. The Percepta Genomic Sequencing Classifier (GSC) is a genomic classifier developed in current and former smokers which can be used for further risk stratification in these patients. Percepta GSC has the capability of up-classifying patients with a pre-bronchoscopy risk that is high (> 60%) to “very high risk” with a positive predictive value of 91.5%. This prospective, randomized decision impact survey was designed to test the hypothesis that an up-classification of risk of malignancy from high to very high will increase the rate of referral for surgical or ablative therapy without additional intervening procedures while increasing physician confidence.

Methods

Data were collected from 37 cases from the Percepta GSC validation cohort in which the pre-bronchoscopy risk of malignancy was high (> 60%), the bronchoscopy was nondiagnostic, and the patient was up-classified to very high risk by Percepta GSC. The cases were randomly presented to U.S pulmonologists in three formats: a pre-post cohort where each case is presented initially without and then with a GSG result, and two independent cohorts where each case is presented either with or without with a GSC result. Physicians were surveyed with respect to subsequent management steps and confidence in that decision.

Results

One hundred and one survey takers provided a total of 1341 evaluations of the 37 patient cases across the three different cohorts. The rate of recommendation for surgical resection was significantly higher in the independent cohort with a GSC result compared to the independent cohort without a GSC result (45% vs. 17%, p < 0.001) In the pre-post cross-over cohort, the rate increased from 17 to 56% (p < 0.001) following the review of the GSC result. A GSC up-classification from high to very high risk of malignancy increased Pulmonologists’ confidence in decision-making following a nondiagnostic bronchoscopy.

Conclusions

Use of the Percepta GSC classifier will allow more patients with early lung cancer to proceed more rapidly to potentially curative therapy while decreasing unnecessary intervening diagnostic procedures following a nondiagnostic bronchoscopy.
Outcomes of acute pulmonary embolism in hospitalized patients with cancer
Authors: Shalaby Khalid , Kahn Adriana , Silver Elizabeth S. , Kim Min Jung , Balakumaran Kathir , Kim Agnes S.
Published: January 2022

Background

Cancer-associated pulmonary embolism (PE) places a significant burden on patients and health care systems.

Methods

A retrospective cross-sectional analysis of the National Inpatient Sample (NIS) database was performed in patients with acute PE from 2002 to 2014. Among patients hospitalized with PE, we investigated the differences in clinical outcomes and healthcare utilization in patients with and without cancer. A multivariate logistic regression model was applied to calculate adjusted odds ratios (OR) to estimate the impact of cancer on clinical outcomes. Wilcoxon rank sum tests were used to determine the differences in healthcare utilization between the two cohorts.

Results

Among 3,313,044 patients who were discharged with a diagnosis of acute PE, 84.2% did not have cancer, while 15.8% had cancer as a comorbidity (56% metastatic cancer, 35% solid tumor without metastasis, and 9% lymphoma). Patients with cancer had a higher mean age but lower rates of common comorbidities except for coagulation deficiency than patients without a cancer diagnosis. In patients with cancer, the rate of IVC filter placement was higher (21.7% vs. 13.11%, OR 1.76 (95% CI 1.73–1.79); p < 0.0001) and thrombolytic use lower (1.34% vs. 2.15%, OR 0.68 (95% CI 0.64–0.72); p < 0.0001). Patients with cancer hospitalized for PE had a higher all-cause in-hospital mortality (11.8% vs. 6.6%, OR 1.79 (95% CI 1.75–1.83); p < 0.0001), longer length of stay (6 vs. 5 days; p < 0.0001), higher total charge per hospitalization ($30,885 vs. $27,273; p < 0.0001), and higher rates of home health services upon discharge (35.8% vs. 23.2%; p < 0.0001) compared with those without cancer.

Conclusion

Concurrent cancer diagnosis in patients hospitalized for acute PE was associated with a 90% increase in all-cause mortality, longer length of stay, higher total charge per hospitalization, and higher rates of home health services upon discharge. The majority (56%) of patients with cancer had metastatic disease. Furthermore, there were identifiable differences in the intervention for acute PE between the two groups.
Periarticular screws: what’s in and what’s out of the joint?
Authors: Sridhar Michael S. , Hunter Michael D. , Colello Michael J.
Published: January 2022

Periarticular hardware placement can be challenging and a source of angst for orthopaedic surgeons due to fear of penetrating the articular surface and causing undue harm to the joint. In recent years, many surgeons have turned to computed tomography (CT) and other intraoperative or postoperative modalities to determine whether hardware is truly extraarticular in areas of complex anatomy. Yet, these adjuncts are expensive, time consuming, and often unnecessary given the advancement in understanding of intraoperative fluoroscopy. We present a review article with the goal of empowering surgeons to leave the operating room, with fluoroscopy alone, assured that all hardware is beneath the articular surface that is being worked on. By understanding a simple concept, surgeons can extrapolate the information in this article to any joint and bony surface in the body. While targeted at both residents and surgeons who may not have completed a trauma fellowship, this review can benefit all orthopaedic surgeons alike.
The effect of parathyroidectomy compared to non-surgical surveillance on kidney function in primary hyperparathyroidism: a nationwide historic cohort study
Authors: Matzen Josephine , Bislev Lise Sofie , Sikjær Tanja , Rolighed Lars , Hitz Mette Friberg , Eiken Pia , Hermann Anne Pernille , Jensen Jens-Erik Beck , Abrahamsen Bo , Rejnmark Lars
Published: January 2022

Background

Patients with primary hyperparathyroidism (pHPT) and impaired kidney function (estimated glomerular filtration rate (eGFR) < 60 mL/min) are offered parathyroidectomy (PTX) to protect them from further complications. Surprisingly, two recent uncontrolled cohort studies have suggested a further decrease in kidney function following PTX. We aimed to examine the effects of PTX compared to non-surgical surveillance on kidney function in pHPT patients.

Methods

Historic cohort study. From the Danish National Patient Registry (NPR) and major medical biochemistry laboratories in Denmark, we identified 3585 patients with biochemically confirmed pHPT among whom n = 1977 (55%) were treated with PTX (PTX-group) whereas n = 1608 (45%) were followed without surgery (non-PTX group). Baseline was defined as time of diagnosis and kidney function was re-assessed 9–15 months after PTX (PTX group) or 9–15 months after diagnosis (non-PTX group).

Results

At follow-up, eGFR had decreased significantly in the PTX- compared to the non-PTX-group (median − 4% vs. − 1%, p < 0.01). Stratification by baseline eGFR showed that the decrease was significant for those with a baseline eGFR value of 80–89 and > 90 mL/min, but not for those with lower eGFR values. Findings did not differ between patients with mild compared to moderate/severe hypercalcemia. However, after mutual adjustments, we identified baseline levels of calcium, PTH, and eGFR as well as age and treatment (PTX vs. no-PTX) as independent predictors for changes in kidney function.

Conclusion

Compared to non-surgical surveillance, PTX is associated with a small but significant decrease in kidney function in pHPT patients with an initial normal kidney function.
Digital decision aid for prenatal counseling in imminent extreme premature labor: development and pilot testing
Authors: van den Heuvel Josephus F. M. , Hogeveen Marije , Lutke Holzik Margo , van Heijst Arno F. J. , Bekker Mireille N. , Geurtzen Rosa
Published: January 2022

Background

In case of extreme premature delivery at 24 weeks of gestation, both early intensive care and palliative comfort care for the neonate are considered treatment options. Prenatal counseling, preferably using shared decision making, is needed to agree on the treatment option in case labor progresses. This article described the development of a digital decision aid (DA) to support pregnant women, partners and clinicians in prenatal counseling for imminent extreme premature labor.

Methods

This DA is developed following the International Patient Decision Aid Standards. The Dutch treatment guideline and the Dutch recommendations for prenatal counseling in extreme prematurity were used as basis. Development of the first prototype was done by expert clinicians and patients, further improvements were done after alpha testing with involved clinicians, patients and other experts (n = 12), and beta testing with non-involved clinicians and patients (n = 15).

Results

The final version includes information, probabilities and figures depending on users’ preferences. Furthermore, it elicits patient values and provides guidance to aid parents and professionals in making a decision for either early intensive care or palliative comfort care in threatening extreme premature delivery.

Conclusion

A decision aid was developed to support prenatal counseling regarding the decision on early intensive care versus palliative comfort care in case of extreme premature delivery at 24 weeks gestation. It was well accepted by parents and healthcare professionals. Our multimedia, digital DA is openly available online to support prenatal counseling and personalized, shared decision-making in imminent extreme premature labor.
The clinical back pain courses described by information available in Danish central registries
Authors: Iachina Maria , Garvik Olav S. , Ljungdalh Pernille S. , Wod Mette , Schiøttz-Christensen Berit
Published: January 2022

Background

Patients with back pain are often in contact with 2–4 hospital departments when receiving a back pain diagnosis and treatment. This complicates the entire clinical course description. There is, currently, no model that describes the course across departments for patients with back pain. This study aims to construct an interdisciplinary clinical course using the central register’s information.

Methods

All patients with back pain referred for diagnosis and treatment at the Spine Center of Southern Denmark from 1 January 2011 until 31 December 2017 were included. By means of information available in central registers, we described the interdisciplinary clinical course for the individual patient, including information on all contacts at different departments, and proposed three different models to define the index and final date. The index date was defined as the first visit without a previous contact to the Spine Center for 6 months for model I, 1 year for model II, and 2 years for model III. The final date was defined as the last visit without following contacts for 6 months, 1 year, and 2 years, respectively, for models I, II, and III.

Results

A total of 69,564 patients (male: n = 30,976) with back pain diagnosis were identified. The three models all leave the information on the entire course at the hospital. In model I (64,757 clinical back pain courses), the time span to a possible previous clinical course is too short to secure the start of a new course (14% had two or more). With at least 1 year between a possible previous contact, model II (60,914 courses) fits the everyday clinical practice (9% had two or more clinical back pain courses). In model III (60,173 courses) it seems that two independent courses might be connected in the same course as only 5% had two or more clinical back pain courses.

Conclusions

Despite contact with different departments, the clinical course for back pain patients can be described by information from the central registers. A one-year time interval fits best the clinicians’ everyday observations.
Atom-precise fluorescent copper cluster for tumor microenvironment targeting and transient chemodynamic cancer therapy
Authors: Yang Zhenzhen , Yang Anli , Ma Wang , Ma Kai , Lv Ya-Kun , Peng Peng , Zang Shuang-Quan , Li Bingjie
Published: January 2022

Background

Reactive oxygen species (ROS) have been widely studied for cancer therapy. Nevertheless, instability and aspecific damages to cellular biomolecules limit the application effect. Recently, significant research efforts have been witnessed in the flourishing area of metal nanoclusters (NCs) with atomically precise structures for targeted release of ROS but few achieved success towards targeting tumor microenvironment.

Results

In this work, we reported an atomically precise nanocluster Cu6(C4H3N2S)6 (Cu6NC), which could slowly break and generate ROS once encountered with acidic. The as-prepared Cu6NC demonstrated high biological safety and efficient chemodynamic anti-tumor properties. Moreover, Cu6NC enabled transient release of ROS and contained targeting behavior led by the tumor microenvironment. Both in vitro and in vivo experiments confirmed that Cu6NC demonstrated a low cytotoxicity for normal cells, while presented high cytotoxicity for tumor cells with a concentration-dependent manner.

Conclusions

This work not only reported a promising candidate for chemodynamic cancer therapy, but also paved the route to address clinical issues at the atomic level.

Graphical Abstract
High-quantum yield alloy-typed core/shell CdSeZnS/ZnS quantum dots for bio-applications
Authors: Kim Jaehi , Hwang Do Won , Jung Heung Su , Kim Kyu Wan , Pham Xuan-Hung , Lee Sang-Hun , Byun Jung Woo , Kim Wooyeon , Kim Hyung-Mo , Hahm Eunil , Ham Kyeong-min , Rho Won-Yeop , Lee Dong Soo , Jun Bong-Hyun
Published: January 2022

Background

Quantum dots (QDs) have been used as fluorophores in various imaging fields owing to their strong fluorescent intensity, high quantum yield (QY), and narrow emission bandwidth. However, the application of QDs to bio-imaging is limited because the QY of QDs decreases substantially during the surface modification step for bio-application.

Results

In this study, we fabricated alloy-typed core/shell CdSeZnS/ZnS quantum dots (alloy QDs) that showed higher quantum yield and stability during the surface modification for hydrophilization compared with conventional CdSe/CdS/ZnS multilayer quantum dots (MQDs). The structure of the alloy QDs was confirmed using time-of-flight medium-energy ion scattering spectroscopy. The alloy QDs exhibited strong fluorescence and a high QY of 98.0%. After hydrophilic surface modification, the alloy QDs exhibited a QY of 84.7%, which is 1.5 times higher than that of MQDs. The QY was 77.8% after the alloy QDs were conjugated with folic acid (FA). Alloy QDs and MQDs, after conjugation with FA, were successfully used for targeting human KB cells. The alloy QDs exhibited a stronger fluorescence signal than MQD; these signals were retained in the popliteal lymph node area for 24 h.

Conclusion

The alloy QDs maintained a higher QY in hydrophilization for biological applications than MQDs. And also, alloy QDs showed the potential as nanoprobes for highly sensitive bioimaging analysis.

Graphical Abstract
Emerging zero-dimensional to four-dimensional biomaterials for bone regeneration
Authors: Fang Haoyu , Zhu Daoyu , Yang Qianhao , Chen Yixuan , Zhang Changqing , Gao Junjie , Gao Youshui
Published: January 2022

Bone is one of the most sophisticated and dynamic tissues in the human body, and is characterized by its remarkable potential for regeneration. In most cases, bone has the capacity to be restored to its original form with homeostatic functionality after injury without any remaining scarring. Throughout the fascinating processes of bone regeneration, a plethora of cell lineages and signaling molecules, together with the extracellular matrix, are precisely regulated at multiple length and time scales. However, conditions, such as delayed unions (or nonunion) and critical-sized bone defects, represent thorny challenges for orthopedic surgeons. During recent decades, a variety of novel biomaterials have been designed to mimic the organic and inorganic structure of the bone microenvironment, which have tremendously promoted and accelerated bone healing throughout different stages of bone regeneration. Advances in tissue engineering endowed bone scaffolds with phenomenal osteoconductivity, osteoinductivity, vascularization and neurotization effects as well as alluring properties, such as antibacterial effects. According to the dimensional structure and functional mechanism, these biomaterials are categorized as zero-dimensional, one-dimensional, two-dimensional, three-dimensional, and four-dimensional biomaterials. In this review, we comprehensively summarized the astounding advances in emerging biomaterials for bone regeneration by categorizing them as zero-dimensional to four-dimensional biomaterials, which were further elucidated by typical examples. Hopefully, this review will provide some inspiration for the future design of biomaterials for bone tissue engineering.

Graphical abstract
The bright future of nanotechnology in lymphatic system imaging and imaging-guided surgery
Authors: Qi Shaolong , Wang Xinyu , Chang Kun , Shen Wenbin , Yu Guocan , Du Jianshi
Published: January 2022

Lymphatic system is identified the second vascular system after the blood circulation in mammalian species, however the research on lymphatic system has long been hampered by the lack of comprehensive imaging modality. Nanomaterials have shown the potential to enhance the quality of lymphatic imaging due to the unparalleled advantages such as the specific passive targeting and efficient co-delivery of cocktail to peripheral lymphatic system, ease molecular engineering for precise active targeting and prolonged retention in the lymphatic system of interest. Multimodal lymphatic imaging based on nanotechnology provides a complementary means to understand the kinetics of lymphoid tissues and quantify its function. In this review, we introduce the established approaches of lymphatic imaging used in clinic and summarize their strengths and weaknesses, and list the critical influence factors on lymphatic imaging. Meanwhile, the recent developments in the field of pre-clinical lymphatic imaging are discussed to shed new lights on the design of new imaging agents, the improvement of delivery methods and imaging-guided surgery strategies.

Graphical Abstract
The impact of preoperative biliary drainage on postoperative outcomes in patients with malignant obstructive jaundice: a retrospective analysis of 290 consecutive cases at a single medical center
Authors: Gao Zhihui , Wang Jie , Shen Sheng , Bo Xiaobo , Suo Tao , Ni Xiaoling , Liu Han , Huang Lihong , Liu Houbao
Published: January 2022

Background

The efficacy of preoperative biliary drainage (PBD) has been debated for several decades, and yet indications for PBD remain controversial. The aim of this study was to compare the postoperative morbidity and mortality in patients with malignant obstructive jaundice undergoing direct surgery versus surgery with PBD.

Methods

All consecutive patients with malignant obstructive jaundice who underwent radical resection between June 2017 and December 2019 at Zhongshan Hospital were analyzed retrospectively. The study population was divided into two groups: PBD group (PG) and direct surgery group (DG). The subgroups were chosen based on the site of obstruction. Perioperative indicators and postoperative complications were compared and analyzed.

Results

A total of 290 patients were analyzed. Postoperative complications occurred in 134 patients (46.4%). Patients in the PG group had a lower overall rate of postoperative complications compared with the DG group, with perioperative total bilirubin (TB) identified as an independent risk factor in multivariate analysis (hazard ratio = 1.004; 95% confidence interval 1.001–1.007; P = 0.017). Subgroup analysis showed that PBD reduced the complication rate in patients with proximal obstruction. In the proximal-obstruction subgroup, a preoperative TB level > 162 μmol/L predicted postoperative complications.

Conclusions

PBD may reduce the overall rate of postoperative complications among patients with proximal malignant obstructive jaundice.

Trial registration

ClinicalTrials.gov, 2018ZSLC 24. Registered May 17, 2018, https://clinicaltrials.gov/.
Preeclampsia at delivery is associated with lower serum vitamin D and higher antiangiogenic factors: a case control study
Authors: Seifer David B. , Lambert-Messerlian Geralyn , Palomaki Glenn E. , Silver Robert M. , Parker Corette , Rowland Hogue Carol J. , Stoll Barbara J. , Saade George R. , Goldenberg Robert L. , Dudley Donald J. , Bukowski Radek , Pinar Halit , Reddy Uma M.
Published: January 2022

Background

Preeclampsia is characterized by decreased trophoblastic angiogenesis leading to abnormal invasion of spiral arteries, shallow implantation and resulting in compromised placentation with poor uteroplacental perfusion. Vitamin D plays an important role in pregnancy influencing implantation, angiogenesis and placental development. The objective of this study was to determine whether there is an association between serum vitamin D levels, and anti-angiogenic factors at the time of delivery and the occurrence of preeclampsia.

Methods

This nested case control study analyzed frozen serum samples at the time of delivery and related clinical data from women with singleton liveborn pregnancies who had participated in studies of the NICHD Stillbirth Collaborative Research Network. Women with a recorded finding of preeclampsia and who had received magnesium sulfate treatment prior to delivery were considered index cases (N = 56). Women without a finding of preeclampsia were controls (N = 341).

Results

Women with preeclampsia had 14.5% lower serum vitamin D levels than women in the control group (16.5 ng/ml vs. 19 ng/ml, p = 0.014) with 64.5% higher sFlt-1 levels (11,600 pg/ml vs. 7050 pg/ml, p < 0.001) and greater than 2 times higher endoglin levels (18.6 ng/ml vs. 8.7 ng/ml, < 0.001). After controlling for gestational age at delivery and maternal BMI, vitamin D levels were 0.88 times lower (P = 0.051), while endoglin levels were 2.5 times higher and sFlt-1 levels were 2.1 times higher than in control pregnancies (P < 0.001).

Conclusions

Women with preeclampsia at time of delivery have higher maternal antiangiogenetic factors and may have lower maternal serum vitamin D levels. These findings may lead to a better understanding of the underlying etiology of preeclampsia as well as possible modifiable treatment options which could include assuring adequate levels of maternal serum vitamin D prior to pregnancy.
The effectiveness of supervision strategies to improve health care provider practices in low- and middle-income countries: secondary analysis of a systematic review
Authors: Rowe Samantha Y. , Ross-Degnan Dennis , Peters David H. , Holloway Kathleen A. , Rowe Alexander K.
Published: January 2022

Background

Although supervision is a ubiquitous approach to support health programs and improve health care provider (HCP) performance in low- and middle-income countries (LMICs), quantitative evidence of its effects is unclear. The objectives of this study are to describe the effect of supervision strategies on HCP practices in LMICs and to identify attributes associated with greater effectiveness of routine supervision.

Methods

We performed a secondary analysis of data on HCP practice outcomes (e.g., percentage of patients correctly treated) from a systematic review on improving HCP performance. The review included controlled trials and interrupted time series studies. We described distributions of effect sizes (defined as percentage-point [%-point] changes) for each supervision strategy. To identify attributes associated with supervision effectiveness, we performed random-effects linear regression modeling and examined studies that directly compared different approaches of routine supervision.

Results

We analyzed data from 81 studies from 36 countries. For professional HCPs, such as nurses and physicians, primarily working at health facilities, routine supervision (median improvement when compared to controls: 10.7%-points; IQR: 9.9, 27.9) had similar effects on HCP practices as audit with feedback (median improvement: 10.1%-points; IQR: 6.2, 23.7). Two attributes were associated with greater mean effectiveness of routine supervision (p < 0.10): supervisors received supervision (by 8.8–11.5%-points), and supervisors participated in problem-solving with HCPs (by 14.2–20.8%-points). Training for supervisors and use of a checklist during supervision visits were not associated with effectiveness. The effects of supervision frequency (i.e., number of visits per year) and dose (i.e., the number of supervision visits during a study) were unclear. For lay HCPs, the effect of routine supervision was difficult to characterize because few studies existed, and effectiveness in those studies varied considerably. Evidence quality for all findings was low primarily because many studies had a high risk of bias.

Conclusions

Although evidence is limited, to promote more effective supervision, our study supports supervising supervisors and having supervisors engage in problem-solving with HCPs. Supervision’s integral role in health systems in LMICs justifies a more deliberate research agenda to identify how to deliver supervision to optimize its effect on HCP practices.
Contested notions of challenges affecting Community Health Workers in low- and middle-income countries informed by the Silences Framework
Authors: Musoke David , Nyashanu Mathew , Bugembe Henry , Lubega Grace Biyinzika , O’Donovan James , Halage Abdullah Ali , Gibson Linda
Published: January 2022

Despite increasing evidence of the challenges affecting Community Health Workers (CHWs) such as those related to training, supportive supervision and remuneration, there is a need to explore concerns and challenges from the perspective of CHWs themselves. This commentary highlights some of the contested and unexplored notions of challenges affecting CHWs in low- and middle-income countries (LMICs) informed by the Silences Framework. This framework defines experiences that are under-explored, misunderstood or difficult to share because of the often invisible power relations within communities, but also in setting the research agenda. These challenges include the heavy workload imposed by several stakeholders, dealing with religious and cultural practices, and gendered barriers of care. The workload of CHWs is a major source of stress and anxiety as they have to balance both government and other stakeholders’ agendas to deliver interventions with their own need to provide for their families for those whose work is unpaid. The tensions of CHWs carrying out their work among members of the community whose religious or cultural beliefs are different from theirs also needs to be considered. Gender issues are an impediment to the work of CHWs, particularly with community members of the opposite sex around sensitive health issues. Lastly, CHWs have found themselves victims of domestic suspicion while fulfilling their duties in communities, such as when seen having conversations with spouses of other individuals in the community. Solutions to these challenges need to be co-produced with CHWs to both to strengthen their relationship with the communities they serve and shape more sustainable interventions for delivery of healthcare in LMICs.
Estimating the impact of donor programs on child mortality in low- and middle-income countries: a synthetic control analysis of child health programs funded by the United States Agency for International Development
Authors: Weiss William , Piya Bhumika , Andrus Althea , Ahsan Karar Zunaid , Cohen Robert
Published: January 2022

Background

Significant levels of funding have been provided to low- and middle-income countries for development assistance for health, with most funds coming through direct bilateral investment led by the USA and the UK. Direct attribution of impact to large-scale programs funded by donors remains elusive due the difficulty of knowing what would have happened without those programs, and the lack of detailed contextual information to support causal interpretation of changes.

Methods

This study uses the synthetic control analysis method to estimate the impact of one donor’s funding (United States Agency for International Development, USAID) on under-five mortality across several low- and middle-income countries that received above average levels of USAID funding for maternal and child health programs between 2000 and 2016.

Results

In the study period (2000–16), countries with above average USAID funding had an under-five mortality rate lower than the synthetic control by an average of 29 deaths per 1000 live births (year-to-year range of − 2 to − 38). This finding was consistent with several sensitivity analyses.

Conclusions

The synthetic control method is a valuable addition to the range of approaches for quantifying the impact of large-scale health programs in low- and middle-income countries. The findings suggest that adequately funded donor programs (in this case USAID) help countries to reduce child mortality to significantly lower rates than would have occurred without those investments.
CTPS1 promotes malignant progression of triple-negative breast cancer with transcriptional activation by YBX1
Authors: Lin Yuxiang , Zhang Jie , Li Yan , Guo Wenhui , Chen Lili , Chen Minyan , Chen Xiaobin , Zhang Wenzhe , Jin Xuan , Jiang Meichen , Xiao Han , Wang Chuan , Song Chuangui , Fu Fangmeng
Published: January 2022

Background

Cytidine nucleotide triphosphate synthase 1 (CTPS1) is a CTP synthase which play critical roles in DNA synthesis. However, its biological regulation and mechanism in triple-negative breast cancer (TNBC) has not been reported yet.

Methods

The expression of CTPS1 in TNBC tissues was determined by GEO, TCGA databases and immunohistochemistry (IHC). The effect of CTPS1 on TNBC cell proliferation, migration, invasion, apoptosis and tumorigenesis were explored in vivo and in vitro. In addition, the transcription factor Y-box binding protein 1 (YBX1) was identified by bioinformatics methods, dual luciferase reporter and chromatin immunoprecipitation (CHIP) assays. Pearson correlation analysis was utilized to assess the association between YBX1 and CTPS1 expression.

Results

CTPS1 expression was significantly upregulated in TNBC tissues and cell lines. Higher CTPS1 expression was correlated with a poorer disease-free survival (DFS) and overall survival (OS) in TNBC patients. Silencing of CTPS1 dramatically inhibited the proliferation, migration, invasion ability and induced apoptosis of MDA-MB-231 and HCC1937 cells. Xenograft tumor model also indicated that CTPS1 knockdown remarkably reduced tumor growth in mice. Mechanically, YBX1 could bind to the promoter of CTPS1 to promote its transcription. Furthermore, the expression of YBX1 was positively correlated with CTPS1 in TNBC tissues. Rescue experiments confirmed that the enhanced cell proliferation and invasion ability induced by YBX1 overexpression could be reversed by CTPS1 knockdown.

Conclusion

Our data demonstrate that YBX1/CTPS1 axis plays an important role in the progression of TNBC. CTPS1 might be a promising prognosis biomarker and potential therapeutic target for patients with triple-negative breast cancer.
Identification of COPA as a potential prognostic biomarker and pharmacological intervention target of cervical cancer by quantitative proteomics and experimental verification
Authors: Bao Huiqiong , Li Xiaobin , Cao Zhixing , Huang Zhihong , Chen Li , Wang Mingbing , Hu Jiali , Li Wenting , Sun Hongwei , Jiang Xue , Mei Ping , Li Huawen , Lu Ligong , Zhan Meixiao
Published: January 2022

Background

Cervical cancer is the most fatal gynecological carcinoma in the world. It is urgent to explore novel prognostic biomarkers and intervention targets for cervical cancer.

Methods

Through integrated quantitative proteomic strategy,we investigated the protein expression profiles of cervical cancer; 28 fresh frozen tissue samples (11 adenocarcinoma (AC), 12 squamous cell carcinoma (SCC) and 5 normal cervixes (HC)) were included in discover cohort; 45 fresh frozen tissue samples (19 AC, 18 SCC and 8 HC) were included in verification cohort; 140 paraffin-embedded tissues samples of cervical cancer (85 AC and 55 SCC) were used for immunohistochemical evaluation (IHC) of coatomer protein subunit alpha (COPA) as a prognostic biomarker for cervical cancer; how deficiency of COPA affects cell viability and tumorigenic ability of cervical cancer cells (SiHa cells and HeLa cells) were evaluated by cell counting kit-8 and clone formation in vitro.

Results

We identified COPA is a potential prognostic biomarker for cervical cancer in quantitative proteomics analysis. By retrospective IHC analysis, we additionally verified the proteomics results and demonstrated moderate or strong IHC staining for COPA is an unfavourable independent prognostic factor for cervical cancer. We also identified COPA is a potential pharmacological intervention target of cervical cancer by a series of in vitro experiments.

Conclusion

This study is the first to demonstrate that COPA may contribute to progression of cervical cancer. It can serve as a potential prognostic biomarker and promising intervention target for cervical cancer.
FOXA1 can be modulated by HDAC3 in the progression of epithelial ovarian carcinoma
Authors: Lou Tong , Liu Chongdong , Qu Hong , Zhang Zhiqiang , Wang Shuzhen , Zhuang Huiyu
Published: January 2022

FOXA1 is associated with malignant tumors, but the function of FOXA1 in EOC is unclear. HDAC3 can influence the proliferation, migration and invasion ability of EOC. In this study, we wanted to explore the function of FOXA1 in ovarian cancer and the relationship between HDAC3 and FOXA1.The expression of HDAC3 and FOXA1 was detected by immunohistochemical staining of primary lesions from 127 epithelial ovarian carcinoma patients. A proliferation assay, a Transwell assay, an apoptosis assay and animal experiments were used to assess the proliferation, invasion and apoptosis abilities of ovarian cancer cells before and after transfection with FOXA1. The relevance of the in vitro findings was confirmed in xenografts. The H-scores for FOXA1 and HDAC3 staining in FIGO stage III-IV were noticeably higher and predicted adverse clinical outcomes in patients with ovarian cancer. The expression level of HDAC3 was significantly correlated with the expression level of FOXA1. Invasion, proliferation and apoptosis capacity and tumor formation were decreased in the FOXA1-knockdown cells. Experiments in xenografts confirmed that HDAC3 mediated tumor formation. In conclusion, FOXA1 can be modulated by HDAC3 through the Wnt/β-catenin signaling pathway, and FOXA1 plays essential roles in the proliferation, apoptosis and invasion of EOC cell lines and xenograft experiments.
Management skin manifestation of multisystem inflammatory syndrome associated with SARS-CoV-2
Authors: Bayram Yeter Eylul , Yildiz-Sevgi Dilek , Yavuz Ayse , Cancetin Merve , Gurler Mehmet Yavuz
Published: January 2022

Background

Multisystem inflammatory syndrome (MIS), which develops after a past covid-19 infection. MIS can be described in different tissue inflammation, including the heart, lung, kidney, brain, skin, eye, and or gastrointestinal organs at the presence of COVID-19. Initially, MIS was described in Europe in children infected with SARS-CoV-2, then it was recently seen in the USA in 2020. MIS is a rare but serious disease condition associated with COVID-19 that can affect children (MIS-C) and adults (MIS-A).

Case presentation

A 44-year-old male who showed MIS-A in 59-day after his first covid-19 contact history. The patient presented to our emergency department with complaints of high fever, nausea, weakness, redness of the eyes, headache, and joint pain. On the second day of his hospitalization, a maculopapular skin lesion was seen in most of the skin. His fever could not be controlled even given paracetamol and broad effective antibiotics. His clinical, radiological, and laboratory findings showed that he had MIS-A. The patient was given intravenous pulse methylprednisolone and intravenous immunoglobulin (IVIG). These treatments, then, resulted in improvement of his clinical conditions, including fever and skin lesions, on the second day of the treatment. The patient was discharged in 14 days after the treatment.

Conclusion

This report indicated that diagnosis and treatment of MIS-A could result in reducing patient morbidity and mortality.
Progress on the roles of MEF2C in neuropsychiatric diseases
Authors: Zhang Zhikun , Zhao Yongxiang
Published: January 2022

Myocyte Enhancer Factor 2 C (MEF2C), one of the transcription factors of the MADS-BOX family, is involved in embryonic brain development, neuronal formation and differentiation, as well as in the growth and pruning of axons and dendrites. MEF2C is also involved in the development of various neuropsychiatric disorders, such as autism spectrum disorders (ASD), epilepsy, schizophrenia and Alzheimer’s disease (AD). Here, we review the relationship between MEF2C and neuropsychiatric disorders, and provide further insights into the mechanism of these diseases.
AHSA1 is a promising therapeutic target for cellular proliferation and proteasome inhibitor resistance in multiple myeloma
Authors: Gu Chunyan , Wang Yajun , Zhang Lulin , Qiao Li , Sun Shanliang , Shao Miaomiao , Tang Xiaozhu , Ding Pinggang , Tang Chao , Cao Yuhao , Zhou Yanyan , Guo Mengjie , Wei Rongfang , Li Nianguang , Xiao Yibei , Duan Jinao , Yang Ye
Published: January 2022

Background

Currently, multiple myeloma (MM) is still an incurable plasma cell malignancy in urgent need of novel therapeutic targets and drugs.

Methods

Bufalin was known as a highly toxic but effective anti-cancer compound. We used Bufalin as a probe to screen its potential targets by proteome microarray, in which AHSA1 was the unique target of Bufalin. The effects of AHSA1 on cellular proliferation and drug resistance were determined by MTT, western blot, flow cytometry, immunohistochemistry staining and xenograft model in vivo. The potential mechanisms of Bufalin and KU-177 in AHSA1/HSP90 were verified by co-immunoprecipitation, mass spectrometry, site mutation and microscale thermophoresis assay.

Results

AHSA1 expression was increased in MM samples compared to normal controls, which was significantly associated with MM relapse and poor outcomes. Furthermore, AHSA1 promoted MM cell proliferation and proteasome inhibitor (PI) resistance in vitro and in vivo. Mechanism exploration indicated that AHSA1 acted as a co-chaperone of HSP90A to activate CDK6 and PSMD2, which were key regulators of MM proliferation and PI resistance respectively. Additionally, we identified AHSA1-K137 as the specific binding site of Bufalin on AHSA1, mutation of which decreased the interaction of AHSA1 with HSP90A and suppressed the function of AHSA1 on mediating CDK6 and PSMD2. Intriguingly, we discovered KU-177, an AHSA1 selective inhibitor, and found KU-177 targeting the same site as Bufalin. Bufalin and KU-177 treatments hampered the proliferation of flow MRD-positive cells in both primary MM and recurrent MM patient samples. Moreover, KU-177 abrogated the cellular proliferation and PI resistance induced by elevated AHSA1, and decreased the expression of CDK6 and PSMD2.

Conclusions

We demonstrate that AHSA1 may serve as a promising therapeutic target for cellular proliferation and proteasome inhibitor resistance in multiple myeloma.
M1-like tumor-associated macrophages cascade a mesenchymal/stem-like phenotype of oral squamous cell carcinoma via the IL6/Stat3/THBS1 feedback loop
Authors: You Yuanhe , Tian Zhuowei , Du Zhong , Wu Kailiu , Xu Guisong , Dai Meilu , Wang Yan’an , Xiao Meng
Published: January 2022

Background

Tumor-associated macrophages (TAMs) have a leading position in the tumor microenvironment. Previously, we have demonstrated that M1-like TAMs activated by exosome-transferred THBS1 promote malignant migration in oral squamous cell carcinoma (OSCC). However, the functional roles and associated molecular mechanisms of the activated M1-like TAMs need to be further clarified in OSCC.

Methods

Conditioned Media (CM) were harvested from the exosome activated M1-like TAMs. We measured the malignant behaviors of OSCC under the treatment of CM from M1-like TAMs by performing colony forming assays, invasion assays, wound-healing assays, spheroid forming assays and in vivo xenograft experiments. The underlying mechanisms were investigated by RNA-seq, cytokines analysis, intracellular signaling pathway analysis, ChIP assays, bioinformatics analysis and validation.

Results

M1-like TAMs significantly promoted the epithelial-mesenchymal transition (EMT) process, and induced the cancer-stem like cells (CSCs) by upregulating the expression of MME and MMP14 in OSCC cells. Cytokine analysis revealed a shark increase of IL6 secretion from M1-like TAMs. Blocking IL6 in the CM from M1-like TAMs could significantly weaken its effects on the colony forming, invasion, migration, microsphere forming and xenograft forming abilities of OSCC cells. Cellular signaling assays indicated the activation of Jak/Stat3 pathway in the OSCC cells treated by the CM from M1-like TAMs. Blocking the activation of the Jak/Stat3 pathway could significantly weaken the effects of M1-like TAMs on the colony forming, invasion, migration, microsphere forming and xenograft forming abilities of OSCC cells. Further RNA-seq analysis and bioinformatics analysis revealed an increased expression of THBS1 in the OSCC cells treated by M1-like TAMs. Bioinformatics prediction and ChIP assays revealed the activation of Stat3 by CM from M1-like TAMs could directly promote the transcription of THBS1 in OSCC cells.

Conclusions

We proposed that M1-like TAMs could cascade a mesenchymal/stem-like phenotype of OSCC via the IL6/Stat3/THBS1 feedback loop. A better understanding on the functional roles and associated molecular mechanisms of M1-like TAMs might facilitate the development of novel therapies for supplementing the current treatment strategies for OSCC patients.
Comparison of the kinematics, repeatability, and reproducibility of five different multi‐segment foot models
Authors: Yoo Hyo Jeong , Park Hye Sun , Lee Dong‐Oh , Kim Seong Hyun , Park Gil Young , Cho Tae‐Joon , Lee Dong Yeon
Published: January 2022

Background

Multi‐segment foot models (MFMs) for assessing three‐dimensional segmental foot motions are calculated via various analytical methods. Although validation studies have already been conducted, we cannot compare their results because the experimental environments in previous studies were different from each other. This study aims to compare the kinematics, repeatability, and reproducibility of five MFMs in the same experimental conditions.

Methods

Eleven healthy males with a mean age of 26.5 years participated in this study. We created a merged 29‐marker set including five MFMs: Oxford (OFM), modified Rizzoli (mRFM), DuPont (DFM), Milwaukee (MiFM), and modified Shriners Hospital for Children Greenville (mSHCG). Two operators applied the merged model to participants twice, and then we analysed two relative angles of three segments: shank‐hindfoot (HF) and hindfoot‐forefoot (FF). Coefficients of multiple correlation (CMC) and mean standard errors were used to assess repeatability and reproducibility, and statistical parametric mapping (SPM) of the t‐value was employed to compare kinematics.

Results

HF varus/valgus of the MiFM and mSHCG models, which rotated the segment according to radiographic or goniometric measurements during the reference frame construction, were significantly more repeatable and reproducible, compared to other models. They showed significantly more dorsiflexed HF and plantarflexed FF due to their static offset angles. DFM and mSHCG showed a greater range of motion (ROM), and some models had significantly different FF points of peak angle.

Conclusions

Under the same conditions, rotating the segment according to the appropriate offset angle obtained from radiographic or goniometric measurement increased reliability, but all MFMs had clinically acceptable reliability compared to previous studies. Moreover, in some models, especially HF varus/valgus, there were differences in ROM and points of peak angle even with no statistical difference in SPM curves. Therefore, based on the results of this study, clinicians and researchers involved in the evaluation of foot and ankle dysfunction need an understanding of the specific features of each MFM to make accurate decisions.
Modulatory effects of R10 fraction of garlic (Allium sativum L.) on hormonal levels, T cell polarization, and fertility-related genes in mice model of polycystic ovarian syndrome
Authors: Falahatian Somaye , Haddad Raheem , Pakravan Nafiseh
Published: January 2022

Polycystic ovary syndrome (PCOS) is an inflammatory endocrine-metabolic disorder related to reproductive system characterized by polycystic ovarian morphology, androgen excess, and chronic anovulation. Current treatments haven’t been very successful in PCOS treatment and the problem still remains as a challenge. Therefore, new approaches should be applied to overcome the disease. Previous studies demonstrated immunomodulatory effects of R10 fraction of garlic in the treatment of inflammatory conditions such as cancer. Considering previous studies suggesting immunomodulatory therapy for PCOS, therapeutic effects of R10 fraction was evaluated in a mouse model of PCOS. To do so, PCOS was developed by intramuscular injection of estradiol valerate. Treatment with R10 fraction, isolated from garlic, was performed and the alterations in hormonal levels (estradiol, progesterone, and testosterone), T cell polarization markers (IFN-γ, IL-4, and IL-17), and expression of fertility-related genes (Gpx3 and Ptx3) were evaluated. The results showed that hormonal levels were elevated in PCOS model comparing to normal animals but were markedly modulated after treatment with R10 fraction. Moreover, a severe disturbance in T cell polarization with a significant reduction of fertility-related genes expression were detected in PCOS-induced ovaries. Treatment with R10 fraction also represented modulatory effects on T cell polarization by increasing IL-4 and decreasing IL-17 and IFN-γ levels. Accordingly, fertility-related genes were also modulated following treatment with R10 fraction in PCOS. Our study elucidated that R10 fraction of garlic possess immunomodulatory effects alleviating PCOS symptoms. This approach could be adjusted to give rise the optimum therapeutic results and considered as a candidate therapeutic approach for PCOS.