bluuebunny/crossref_metadata_2025 huggingface dataset:
Down-regulation of PBK inhibits proliferation of human endometrial stromal cells in thin endometrium
Authors: Zhu Qi , Yao Simin , Dong Yishan , Liu Dan , Wang Huiyan , Jiang Peipei , Dai Chenyan , Lv Haining , Cao Chenrui , Zhou Zhenhua , Wang Limin , Gou Wenjing , Zhang Xiwen , Zhao Guangfeng , Hu Yali
Published: February 2022

Background

Thin endometrium (TE) is a challenging clinical issue in the reproductive medicine characterized by inadequate endometrial thickness, poor response to estrogen and no effective treatments currently. At present, the precise pathogenesis of thin endometria remains to be elucidated. We aimed to explore the related molecular mechanism of TE by comparing the transcriptome profiles of late-proliferative phase endometria between TE and matched controls.

Methods

We performed a bulk RNA-Seq (RNA-sequencing) of endometrial tissues in the late-proliferative phase in 7 TE and 7 matched controls for the first time. Differential gene expression analysis, gene ontology enrichment analysis and protein-protein interactions (PPIs) network analysis were performed. Immunohistochemistry was used for molecular expression and localization in endometria. Human endometrial stromal cells (HESCs) were isolated and cultured for verifying the functions of hub gene.

Results

Integrative data mining of our RNA-seq data in endometria revealed that most genes related to cell division and cell cycle were significantly inhibited, while inflammation activation, immune response and reactive oxygen species associated genes were upregulated in TE. PBK was identified as a hub of PPIs network, and its expression level was decreased by 2.43-fold in endometria of TE patients, particularly reduced in the stromal cells, which was paralleled by the decreased expression of Ki67. In vitro experiments showed that the depletion of PBK reduced the proliferation of HESCs by 50% and increased the apoptosis of HESCs by 1 time, meanwhile PBK expression was inhibited by oxidative stress (reduced by 76.2%), hypoxia (reduced by 51.9%) and inflammatory factors (reduced by approximately 50%). These results suggested that the insufficient expression of PBK was involved in the poor endometrial thickness in TE.

Conclusions

The endometrial transcriptome in late-proliferative phase showed suppressed cell proliferation in women with thin endometria and decreased expression of PBK in human endometrial stromal cells (HESCs), to which inflammation and reactive oxygen species contributed.
Transdisciplinarity of India’s master’s level public health programmes: evidence from admission criteria of the programmes offered since 1995
Authors: Ilangovan Kumaravel , Muthappan Sendhilkumar , Govindarajan Keerthiga , Vairamani Vignesh , Venkatasamy Vettrichelvan , Ponnaiah Manickam
Published: February 2022

Introduction

In the Indian subcontinent, Master’s-level Public Health (MlPH) programmes attract graduates of diverse academic disciplines from health and non-health sciences alike. Considering the current and futuristic importance of the public health cadre, we described them and reviewed their transdisciplinarity status based on MlPH admissibility criteria 1995 to 2021.

Methods

Using a search strategy, we abstracted information available in the public domain on MlPH programmes and their admissibility criteria. We categorized the admission criteria based on specified disciplines into Health science, Non-health science and Non-health non-science categories. We described the MlPH programmes by location, type of institution, course duration, curriculum, pedagogical methods, specializations offered, and nature of admission criteria statements. We calculated descriptive statistics for eligible educational qualifications for MlPH admission.

Results

Overall, 76 Indian institutions (Medical colleges—21 and Non-medical coleges—55) offered 92 MlPH programmes (Private—58 and Public—34). We included 89 for review. These programmes represent a 51% increase (n = 47) from 2016 to 2021. They are mostly concentrated in 21 Indian provinces. These programmes stated that they admit candidates of but not limited to “graduation in any life sciences”, “3-year bachelor’s degree in any discipline”, “graduation from any Indian universities”, and “graduation in any discipline”. Among the health science disciplines, Modern medicine (n = 89; 100%), Occupational therapy (n = 57; 64%) is the least eligible. Among the non-health science disciplines, life sciences and behavioural sciences (n = 53; 59%) and non-health non-science disciplines, humanities and social sciences (n = 62; 72%) are the topmost eligible disciplines for admission in the MPH programmes.

Conclusion

Our review suggests that India’s MlPH programmes are less transdisciplinary. Relatively, non-medical institutions offer admission to various academic disciplines than the medical institutions in their MlPH programmes. India’s Master’s level public health programmes could be more inclusive by opening to graduates from trans-disciplinary backgrounds.
Effects of high-intensity interval training on improving arterial stiffness in Chinese female university students with normal weight obese: a pilot randomized controlled trial
Authors: Hu Jingyun , Liu Min , Yang Ruoyu , Wang Liyan , Liang Leichao , Yang Yuanyuan , Jia Shihao , Chen Ruiyi , Liu Qianle , Ren Yu , Zhu Lei , Cai Ming
Published: February 2022

Background

High intensity interval training (HIIT) has been reported to exert better effects on cardiovascular fitness in obesity, but little known about the arterial stiffness (AS) in female university students with normal weight obesity (NWO). Thus, this study aimed to investigate the effects of HIIT on the body composition, heart rate (HR), blood pressure (BP), blood lipids metabolism as well as the novel parameters of propensity for AS (arterial velocity pulse index [AVI], arterial pressure volume index [API]) for female university students with NWO.

Methods

Forty female university students with NWO were randomly assigned to control group (n = 20) and HIIT group (3 bouts of 9‑min intervals at 90% of the maximal heart rate [HRmax], interspersed by 1 min rest, 5 days a week, n = 20). Tests were performed before and after 4 weeks of training. Repeated measures ANOVA and simple effect test analysis were used to analyze dependent variable changes.

Results

After 4 weeks HIIT statistically significantly improved the body composition by decreasing the body mass index, body fat percent, total body fat mass (BFM), BFM of left arm, measured circumference of left arm, and obesity degree, and increasing the total body skeletal muscle mass, protein content, total body water, fat free mass, body cell mas, and InBody score. HIIT also statistically significantly decreased the HR and BP. As for the lipid profile, HIIT obviously ameliorated the blood lipids metabolism by decreasing the levels of total cholesterol (TC), triglyceride, low-density lipoprotein, and TC/HDL, and increasing the levels of high-density lipoprotein (HDL). In addition, the AVI and API were markedly decreased via HIIT intervention.

Conclusions

HIIT produced significant and meaningful benefits for body composition, HR, BP, and blood lipids metabolism, and could decrease AS in female university students with NWO. This suggests that HIIT may effectively reduce the risk of arteriosclerosis and protect the cardiovascular function for female university students with NWO.

Trial registration ChiCTR2100050711. Registered 3 September 2021. Retrospectively registered.
Catch-up growth of infants born to mothers with autoimmune rheumatic disorders
Authors: Sim Soo Yeun , Choi Hye Yeon , Jung Min Ho , Lee Soo Young , Rhim Jung Woo , Kang Hyun Mi , Jeong Dae Chul
Published: February 2022

Background

In women with autoimmune rheumatic disorders (ARD), pregnancy complications or postpartum events are more frequent compared to the general population. Transplacental autoantibodies or cytokines influence various fetal and neonatal outcomes. We compared the growth patterns of babies born to mothers with ARD versus healthy mothers to assess the long-term growth outcomes of children born to women with ARD.

Methods

This was a retrospective age-matched cohort analyses of babies born to mothers with ARD from the hospitals belonging to the Catholic University of Korea between 2010 and 2017. Demographic and autoimmune laboratory test data of the mothers and newborns were assessed. Neonatal growth was measured in terms of height and weight, measured at birth and follow-up examinations.

Results

We enrolled 142 infants from mothers with ARD and 149 infants from healthy mothers. There was no significant difference between mothers with ARD and healthy mothers in terms of delivery age, parity, abortion, and premature delivery history. The mothers with ARD were diagnosed with systemic lupus erythematosus (81%), Sjogren syndrome (6%), and other autoimmune phenomena (11%). The groups were significantly different in terms of neonatal characteristics such as prematurity, gestational age, birth weight, and height, but not in Apgar score and delivery type. For most neonates, autoimmune laboratory results were normalized within 1 year, except for anti-La/SSB antibody, which remained high in some. The height and weight for age z-score were lower than the normal age groups at birth but showed catch-up growth by 2 years of age.

Conclusions

Low birthweight and prematurity at birth for neonates born to mothers with ARD could be caught up by 2 years of age, and maternal ARD does not affect the growth of their offspring.
Cyclic multiplex fluorescent immunohistochemistry and machine learning reveal distinct states of astrocytes and microglia in normal aging and Alzheimer’s disease
Authors: Muñoz-Castro Clara , Noori Ayush , Magdamo Colin G. , Li Zhaozhi , Marks Jordan D. , Frosch Matthew P. , Das Sudeshna , Hyman Bradley T. , Serrano-Pozo Alberto
Published: February 2022

Background

Astrocytes and microglia react to Aβ plaques, neurofibrillary tangles, and neurodegeneration in the Alzheimer’s disease (AD) brain. Single-nuclei and single-cell RNA-seq have revealed multiple states or subpopulations of these glial cells but lack spatial information. We have developed a methodology of cyclic multiplex fluorescent immunohistochemistry on human postmortem brains and image analysis that enables a comprehensive morphological quantitative characterization of astrocytes and microglia in the context of their spatial relationships with plaques and tangles.

Methods

Single FFPE sections from the temporal association cortex of control and AD subjects were subjected to 8 cycles of multiplex fluorescent immunohistochemistry, including 7 astroglial, 6 microglial, 1 neuronal, Aβ, and phospho-tau markers. Our analysis pipeline consisted of: (1) image alignment across cycles; (2) background subtraction; (3) manual annotation of 5172 ALDH1L1+ astrocytic and 6226 IBA1+ microglial profiles; (4) local thresholding and segmentation of profiles; (5) machine learning on marker intensity data; and (6) deep learning on image features.

Results

Spectral clustering identified three phenotypes of astrocytes and microglia, which we termed “homeostatic,” “intermediate,” and “reactive.” Reactive and, to a lesser extent, intermediate astrocytes and microglia were closely associated with AD pathology (≤ 50 µm). Compared to homeostatic, reactive astrocytes contained substantially higher GFAP and YKL-40, modestly elevated vimentin and TSPO as well as EAAT1, and reduced GS. Intermediate astrocytes had markedly increased EAAT2, moderately increased GS, and intermediate GFAP and YKL-40 levels. Relative to homeostatic, reactive microglia showed increased expression of all markers (CD68, ferritin, MHC2, TMEM119, TSPO), whereas intermediate microglia exhibited increased ferritin and TMEM119 as well as intermediate CD68 levels. Machine learning models applied on either high-plex signal intensity data (gradient boosting machines) or directly on image features (convolutional neural networks) accurately discriminated control vs. AD diagnoses at the single-cell level.

Conclusions

Cyclic multiplex fluorescent immunohistochemistry combined with machine learning models holds promise to advance our understanding of the complexity and heterogeneity of glial responses as well as inform transcriptomics studies. Three distinct phenotypes emerged with our combination of markers, thus expanding the classic binary “homeostatic vs. reactive” classification to a third state, which could represent “transitional” or “resilient” glia.
Growth rate of ascending thoracic aortic aneurysms in a non-referral-based population
Authors: Weininger Gabe , Mori Makoto , Yousef Sameh , Hur David J. , Assi Roland , Geirsson Arnar , Vallabhajosyula Prashanth
Published: February 2022

Background

Prior studies on ascending thoracic aortic aneurysm (ATAA) growth rates have reported approximately 1 mm of growth per year but these studies are based on referral-based study populations which are biased towards the highest risk patients who may not represent the true natural history of aortic aneurysm disease. We aimed to characterize the growth rate of ATAAs in a non-referral-based population, using a large institutional database of computed tomography (CT) scans.

Methods

We queried the 21,325 CT scans performed at our institution between 2013 and 2016 on patients ages 50–85 years old for radiologic diagnosis of aortic aneurysm or dilatation. 560 patients were identified to have aortic dilatation > 4 cm, of which 207 had follow-up scan intervals > 6 months. This comprised our non-referral-based study population. Linearized annual aneurysm growth rates were calculated by dividing the change in aortic size by the time interval between CT scans.

Results

The median time interval between scans was 2.7 years (interquartile range [IQR] 1.5–4.2) for the 207 patients included in the study. The median initial aneurysm size was 4.3 cm (IQR 4.1–4.5). 38.2% (n = 79) of patients did not experience aortic dilatation. The median growth rate was 0.13 mm/year (IQR − 0.24 to 0.49). Of patients in the top quartile of growth rates, 26.9% of patients were female whereas 12.9% of patients were female in the bottom three quartiles of growth rates.

Conclusion

While some patients’ ATAAs may grow at previously published rates of around 1 mm/year, this is not the predominant pattern in a non-referral-based population and may over-estimate the overall growth rate of ATAAs.
Impact of progressive familial intrahepatic cholestasis on caregivers: caregiver-reported outcomes from the multinational PICTURE study
Authors: Mighiu Claudia , O’Hara Sonia , Ferri Grazzi Enrico , Murray Karen F. , Schattenberg Jörn M. , Ventura Emily , Karakaidos Melanie , Taylor Alison , Brrang Harpreet , Dhawan Anil , Willemse Jose , Finnegan Alan
Published: February 2022

Background

Progressive familial intrahepatic cholestasis (PFIC) is a spectrum of rare genetic diseases characterized by inadequate bile secretion that requires substantial ongoing care, though little research is published in this area. We report health-related quality of life (HRQoL) and work productivity outcomes from the retrospective, cross-sectional PICTURE study investigating the burden of PFIC on caregivers. Information from caregivers of patients with PFIC 1 or 2 in Germany, the United Kingdom and the United States from September 2020 to March 2021 was included.

Results

The PICTURE study sample comprised HRQoL responses from 22 PFIC caregivers. Patients were on average 8.2 years old; most caregivers were 30–49 years old (68%) and mothers (77%). Median CarerQoL-7D score was 67.7/100; mean CarerQoL-VAS score for general happiness was 5.7/10 (SD 2.1). Most caregivers reported fulfilment in their caregiving responsibilities, but problems with mental and physical health, finances, and relationships. When stratified by patient’s PFIC type, mean CarerQoL-7D and CarerQoL-VAS scores suggested worse HRQoL outcomes with PFIC2 versus PFIC1 (59.4 vs. 71.2, and 5.3 vs. 6.5, respectively). Additionally, more caregivers reported impact on sleep in the PFIC2 versus PFIC1 subgroup (93% vs. 75%). When stratified by history of PFIC-related surgeries, mean CarerQoL-7D and VAS scores were higher among those whose children had no specified surgeries (67.7 vs. 59.0/100 and 6.2 vs. 5.2/10, respectively). Nearly all caregivers reported an impact of caregiving responsibilities on sleeping (86%) and on personal relationships (82%). No caregivers reported having formal care support. Most caregivers were employed (73%); a third reported mean productivity loss of 12.9 days (SD 19.3) over the last 3 months, and a mean of 2.8 (SD 9.5) missed years of employment during their career. A higher number of workdays were missed by PFIC 2 caregivers compared to PFIC1 over last 3 months (16 days vs. 3 days).

Conclusions

The PICTURE study has demonstrated the prevalent, comprehensive, and meaningful burden that caring for an individual with PFIC has on caregivers. Despite fulfilment from caregiving, the breadth and depth of these responsibilities reduced caregiver reported HRQoL including mental and physical health, productivity, career prospects, sleep, relationships and finances.
Adult-onset CblC deficiency: a challenging diagnosis involving different adult clinical specialists
Authors: Kalantari Silvia , Brezzi Brigida , Bracciamà Valeria , Barreca Antonella , Nozza Paolo , Vaisitti Tiziana , Amoroso Antonio , Deaglio Silvia , Manganaro Marco , Porta Francesco , Spada Marco
Published: February 2022

Background

Methylmalonic aciduria and homocystinuria, CblC type (OMIM #277400) is the most common disorder of cobalamin intracellular metabolism, an autosomal recessive disease, whose biochemical hallmarks are hyperhomocysteinemia, methylmalonic aciduria and low plasma methionine. Despite being a well-recognized disease for pediatricians, there is scarce awareness of its adult presentation. A thorough analysis and discussion of cobalamin C defect presentation in adult patients has never been extensively performed. This article reviews the published data and adds a new case of the latest onset of symptoms ever described for the disease.

Results

We present the emblematic case of a 45-year-old male, describing the diagnostic odyssey he ventured through to get to the appropriate treatment and molecular diagnosis. Furthermore, available clinical, biochemical and molecular data from 22 reports on cases and case series were collected, resulting in 45 adult-onset CblC cases, including our own. We describe the onset of the disease in adulthood, encompassing neurological, psychiatric, renal, ophthalmic and thromboembolic symptoms. In all cases treatment with intramuscular hydroxycobalamin was effective in reversing symptoms. From a molecular point of view adult patients are usually compound heterozygous carriers of a truncating and a non-truncating variant in the MMACHC gene.

Conclusion

Adult onset CblC disease is a rare disorder whose diagnosis can be delayed due to poor awareness regarding its presenting insidious symptoms and biochemical hallmarks. To avoid misdiagnosis, we suggest that adult onset CblC deficiency is acknowledged as a separate entity from pediatric late onset cases, and that the disease is considered in the differential diagnosis in adult patients with atypical hemolytic uremic syndromes and/or slow unexplained decline in renal function and/or idiopathic neuropathies, spinal cord degenerations, ataxias and/or recurrent thrombosis and/or visual field defects, maculopathy and optic disc atrophy. Plasma homocysteine measurement should be the first line for differential diagnosis when the disease is suspected. To further aid diagnosis, it is important that genes belonging to the intracellular cobalamin pathway are included within gene panels routinely tested for atypical hemolytic uremic syndrome and chronic kidney disorders.
Seroprevalence of Encephalitozoon cuniculi and Toxoplasma gondii antibodies and risk-factor assessment for Encephalitozoon cuniculi seroprevalence in Finnish pet rabbits (Oryctolagus cuniculus)
Authors: Mäkitaipale Johanna , Järvenpää Emmi , Bruce Anne , Sankari Satu , Virtala Anna-Maija , Näreaho Anu
Published: February 2022

Background

Neurological signs, such as head tilt, torticollis, paralysis, and seizures, are common in rabbits. Differential diagnoses include two zoonotic infections caused by the microsporidial fungi Encephalitozoon cuniculi and the apicomplexan protozoa Toxoplasma gondii. Both infections are mainly latent in rabbits but may cause severe or even fatal disease. Although several international studies have reported the seroprevalence of these pathogens in different commercial rabbit populations, similar prevalence studies and risk-factor analyses among family-owned pet rabbits are uncommon and lacking in Scandinavia. We sought to estimate the seroprevalence and possible risk factors for E. cuniculi and T. gondii among Finnish pet rabbits. We used ELISA to measure E. cuniculi IgG seroprevalence of 247 rabbits and modified direct agglutination test for T. gondii seroprevalence of 270 rabbits. Samples were collected as part of the Finnish Pet Rabbit Health Research project. Internet-based questionnaires (n = 231) completed by the rabbit owners were used for risk-factor analysis.

Results

The apparent seroprevalence of E. cuniculi was 29.2% and true seroprevalence of T. gondii 3.9%. Risk factors were analysed only for E. cuniculi due to the low T. gondii seroprevalence. The final multivariable logistic regression model revealed that rabbits spending the whole summer outdoors had a higher risk of being E. cuniculi seropositive than rabbits with limited outdoor access. Additionally, rabbits living in households with only one or two rabbits had higher risk of being E. cuniculi seropositive than those in multi-rabbit households.

Conclusions

Nearly one third of Finnish pet rabbits participating in this study had E. cuniculi IgG antibodies, indicating previous exposure to this pathogen. The prevalence is similar to that reported previously in clinically healthy rabbit populations in UK and Korea. While the seroprevalence of T. gondii was low (3.9%), antibodies were detected. Therefore, these zoonotic parasitic infections should be considered as differential diagnoses when treating rabbits.
Autophagic Schwann cells promote perineural invasion mediated by the NGF/ATG7 paracrine pathway in pancreatic cancer
Authors: Zhang Wunai , He Rui , Yang Wenbin , Zhang Yan , Yuan Qinggong , Wang Jixin , Liu Yang , Chen Shuo , Zhang Simei , Zhang Weifan , Zhu Zeen , Zhang Jing , Wang Zheng , Li Junhui
Published: February 2022

Background

Perineural invasion (PNI) and autophagy are two common features in the tumor microenvironment of pancreatic cancer (PanCa) and have a negative effect on prognosis. Potential mediator cells and the molecular mechanism underlying their relationships need to be fully elucidated.

Methods

To investigate the autophagy of Schwann cells (SCs) in PNI, we reproduced the microenvironment of PNI by collecting clinical PNI tissue, performing sciatic nerve injection of nude mice with cancer cells and establishing a Dorsal root ganglion (DRG) coculture system with cancer cell lines. Autophagy was detected by IHC, IF, transmission electron microscopy (TEM) and western blotting assays. Apoptosis was detected by IF, TEM and western blotting. NGF targeting molecular RO 08–2750(RO) and the autophagy inhibitor Chloroquine (CQ) were utilized to evaluate the effect on autophagy and apoptosis in SCs and PanCa cells in PNI samples.

Results

SC autophagy is activated in PNI by paracrine NGF from PanCa cells. Autophagy-activated Schwann cells promote PNI through a) enhanced migration and axon guidance toward PanCa cells and b) increased chemoattraction to PanCa cells. The NGF-targeting reagent RO and autophagy inhibitor CQ inhibited Schwann cell autophagic flux and induced Schwann cell apoptosis. Moreover, RO and CQ could induce PanCa cell apoptosis and showed good therapeutic effects in the PNI model.

Conclusions

PanCa cells can induce autophagy in SCs through paracrine pathways such as the NGF/ATG7 pathway. Autophagic SCs exert a “nerve-repair like effect”, induce a high level of autophagy of cancer cells, provide a “beacon” for the invasion of cancer cells to nerve fibers, and induce directional growth of cancer cells. Targeting NGF and autophagy for PNI treatment can block nerve infiltration and is expected to provide new directions and an experimental basis for the research and treatment of nerve infiltration in pancreatic cancer.
Efficacy and safety of Qushi Huayu granule for hyperlipidemia: study protocol for a randomized, double-blind, placebo-controlled trial
Authors: Sun Yuanlong , Hu Na , Chen Gaofeng , Wang Yanjie , Hu Yiyang , Ge Maojun , Zhao Yu
Published: February 2022

Background

Hyperlipidemia has become a common chronic disease worldwide in recent years. Studies have shown that hyperlipidemia patients, especially those with a high level of serum low-density lipoprotein cholesterol (LDL-C), have a significantly higher prevalence of atherosclerosis, leading to coronary heart disease. Previous basic experiments and clinical studies have shown that Qushi Huayu granules (QSHY) reduce blood lipids in patients with non-alcoholic fatty liver disease (NAFLD) accompanied by hyperlipidemia. However, the clinical efficacy of QSHY in patients with hyperlipidemia is still lacking. This study aims to investigate the effect and safety of QSHY for hyperlipidemia.

Methods

This is a randomized, double-blind, placebo-controlled trial. A total of 210 participants will be enrolled and randomized into the QSHY or placebo granules groups in equal proportions, who will receive treatment for 24 weeks. The primary outcome will be the change in LDL-C from baseline to week 12. Secondary outcomes will be changes in other serum lipids markers, life quality measuring health surveys, and traditional Chinese medicine (TCM) pattern scale. All related tests will be measured at baseline, week 12, and week 24 after enrollment. Adverse events and the safety of intervention will be monitored and evaluated.

Discussion

We designed a clinical trial of hyperlipidemia management with QSHY, a TCM prescription. The results of this trial will present the efficacy and safety of QSHY in patients with hyperlipidemia.

Trial registration

Chinese Clinical Trial Registry ChiCTR2000034125. Registered on June 25, 2019
Implementation of an in situ simulation-based training adapted from Morbidity and Mortality conference cases: effect on the occurrence of adverse events—study protocol of a cluster randomised controlled trial
Authors: Michel Nicolas , Bui-Xuan Bernard , Bapteste Lionel , Rimmele Thomas , Lilot Marc , Chollet François , Favre Hélène , Duclos Antoine , Michel Philippe
Published: February 2022

Background

Morbidity and Mortality conference provides the necessary improvement measures for patient safety. However, they are an underused resource mainly because the conclusions to be drawn from the discussion and their implications for practice are not always well integrated by inpatient care teams. We therefore propose in this study two interventions to optimise their effectiveness: a passive feedback with wide dissemination by e-mail and/or on paper of the results of the Morbidity and Mortality conference to inpatient care teams and an active feedback with in situ inter-professional simulation-training programme in which scenarios will be based on cases studied in Morbidity and Mortality conference. In the present study, we hypothesise that the greatest reduction the occurrence of adverse event will be in the active feedback arm.

Methods

A cluster randomised controlled study will be performed at four study sites. The unit of randomisation is wards within the study sites. Fifteen wards will be randomly assigned to passive feedback, active feedback, or a standard MMC (control arm). Passive feedback and active feedback arms will be compared to standard arm in terms of occurrence of adverse events. The trigger tool methodology used to identify adverse events is a retrospective review of inpatient records using “triggers”: an adverse event is defined as a patient’s stay with at least one positive trigger.

Discussion

The in situ simulation training based on cases processed in Morbidity and Mortality conference is built according to the main topics identified for the successful implementation of healthcare simulation in patient safety programmes: technical skills, nontechnical skills, assessment, effectiveness, and system probing. The in situ simulation-training programme conducted as part of the study has the potential to improve patient safety during hospitalisation. We therefore expect the greatest reduction in the occurrence of adverse events in patients hospitalised in the active feedback arm. This expected result would have a direct impact on patient safety and would place in situ simulation at the highest level of the Kirkpatrick model.

Trial registration

Clinicaltrials.gov NCT02771613. Registered on May 12, 2016. All items from the WHO Trial Registration Data Set can be found within the protocol.
Dietary calcium requirements of broilers fed a conventional corn-soybean meal diet from 1 to 21 days of age
Authors: Bai Shiping , Yang Yunfeng , Ma Xuelian , Liao Xiudong , Wang Runlian , Zhang Liyang , Li Sufen , Luo Xugang , Lu Lin
Published: February 2022

Background

The current calcium (Ca) recommendation for broilers is primarily based on studies conducted more than 30 years ago with birds of markedly different productive potentials from those which exist today. And the response indicators in these studies are mainly growth performance and bone ash percentage. Therefore, the present study was carried out to investigate the effect of dietary Ca level on growth performance, serum parameters, bone characteristics and Ca metabolism-related gene expressions, so as to estimate dietary Ca requirements of broilers fed a conventional corn-soybean meal diet from 1 to 21 days of age.

Methods

A total of 420 1-day-old Arbor Acres male broilers were randomly assigned to 1 of 7 treatments with 6 replicates (10 birds per cage) and fed the corn-soybean meal diets containing 0.60%, 0.70%, 0.80%, 0.90%, 1.00%, 1.10% or 1.20% Ca for 21 days. Each diet contained the constant non-phytate phosphorus content of about 0.39%.

Results

The average daily gain decreased linearly (P < 0.001) as dietary Ca level increased. The serum and tibia alkaline phosphatase (ALP) activities, tibia bone mineral density (BMD), middle toe BMD, tibia ash percentage, tibia breaking strength, and tibia ALP protein expression level were affected (P < 0.05) by dietary Ca level, and showed significant quadratic responses (P < 0.02) to dietary Ca levels. The estimates of dietary Ca requirements were 0.80 to 1.00% based on the best fitted broken-line or quadratic models (P < 0.03) of the above serum and bone parameters, respectively.

Conclusions

The results from the present study indicate that the Ca requirements would be about 0.60% to obtain the best growth rate, and 1.00% to meet all of the Ca metabolisms and bone development of broilers fed a conventional corn-soybean meal diet from 1 to 21 days of age.
Novel approach for treating challenging implant-borne maxillary dental rehabilitation cases of cleft lip and palate: a retrospective study
Authors: Rahlf Björn , Korn Philippe , Zeller Alexander-Nicolai , Spalthoff Simon , Jehn Philipp , Lentge Fritjof , Gellrich Nils-Claudius
Published: February 2022

Purpose

Dental restoration in cleft lip and palate (CLP) patients is demanding and often results in bone loss and dental implant failure. Furthermore, unfavorable conditions of hard and soft tissues as well as skeletal deformities aggravate surgical and dental treatment. Therefore, this study was designed to assess the feasibility of using a new type of patient-specific implant (IPS-preprosthetic®) in CLP patients.

Methods

Of the 63 patients who received a IPS-preprosthetic® implant in the Department of Oral and Maxillofacial Surgery at the Hannover Medical School, Germany, six patients were treated for a CLP deformity with significant soft and hard tissue impairment. Two patients were partially edentulous, whereas four patients were edentulous for the maxilla. All implants were inserted in a single-step outpatient surgery and were followed up for up to 40 months.

Results

Within the observation period, no implant failed and no screw loosening or change in stability of the implant to recipient site occurred (mean number of screws: 21). This study demonstrates, for the first time, the efficient use of a one-piece multivector screw primarily retained a stable patient-specific implant for implant-borne prosthodontic rehabilitation of CLP patients with deformities and challenging initial situations.

Conclusions

IPS-preprosthetic® implants offer a novel approach to implant dentistry treatment protocols, especially in difficult cases of unusual anatomy, even when previous conventional treatment fails.
Risk factors for interstitial lung disease induced by gemcitabine plus albumin-bound paclitaxel therapy in pancreatic ductal adenocarcinoma patients
Authors: Ueda Rikako , Yamamoto Naho , Hori Yuki , Yoshida Kouji , Ohtsubo Koushiro , Terashima Takeshi , Shimada Tsutomu , Sai Yoshimichi
Published: February 2022

Background

Gemcitabine plus nab-paclitaxel (GnP) therapy is used for unresectable pancreatic ductal adenocarcinoma, but may cause interstitial lung disease (ILD) as a serious side effect. However, the risk factors for ILD in patients receiving GnP therapy are not well established. Here, we retrospectively investigated the incidence of GnP-induced ILD in pancreatic ductal adenocarcinoma patients, and the risk factors.

Methods

We investigated the patients’ background, laboratory data, previous treatment history, concomitant medications, number of doses of GnP, cumulative dosage and administration period, and occurrence of side effects.

Results

Of the 105 patients included in this study, ILD occurred in 10 (9.5%). Patients with ILD had a significantly higher frequency of concomitant treatment with Kampo medicines, especially goshajinkigan, which is considered to help prevent chemotherapy-induced peripheral neuropathy (CIPN) (odds ratio: 11.5, 95% confidence interval: 2.67–49.38). No significant differences were observed in other clinical characteristics. Notably, the severity of CIPN in patients who used goshajinkigan for prevention was not significantly different from that in patients who did not use goshajinkigan in this study.

Conclusions

These results suggest that administration of goshajinkigan to patients receiving GnP therapy for prevention of CIPN may need to be reconsidered.
Anti-inflammatory and analgesic activities of black cumin (BC, Nigella sativa L.) extracts in in vivo model systems
Authors: Shaheen Nazma , Azam Afiatul , Ganguly Amlan , Anwar Saeed , Parvez Md. Sorwer Alam , Punyamurtula Ujwal , Hasan Md. Kamrul
Published: February 2022

Background

Black cumin (Nigella sativa) is a widely used ingredient of traditional medicine for its broad-spectrum pharmacological actions, including analgesic, bronchial asthma, anti-inflammatory properties, and others. We sought to evaluate BC extracts' efficacy for the anti-inflammatory and analgesic properties using a comprehensive in vivo and in silico experimental setup. To investigate whether BC extract has anti-inflammatory and analgesic therapeutic potentials in vivo anti-inflammatory activity by carrageenan-induced rat paw edema, analgesic activity by acetic acid-induced writhing test and ingenuity analysis of the BC extracts in inflammation control.

Results

The acetic acid-induced writhing test had shown a dose-dependent reduction of writhing number following BC administration. Rat paw edema test showed the dose-dependent reduction of paw edema volume following BC administration. Ingenuity Pathway Analysis (IPA) suggested BC extracts containing ferulic acid, p-coumaric acid, kaempferol, and quercetin can inhibit inflammation.

Conclusions

This study suggests that bioactive compounds in BC extract act as an anti-inflammatory and analgesic agent by regulating several downstream and upstream inflammation pathways.
High Plasma Oxytocin Levels in Men With Hypersexual Disorder
Authors: Flanagan John , Chatzittofis Andreas , Boström Adrian Desai E , Hallberg Jonas , Öberg Katarina Görts , Arver Stefan , Jokinen Jussi
Published: February 2022

Context

Hypersexual disorder (HD) involves excessive, persistent sexual behaviors related to various mood states and the diagnosis compulsive sexual behavior disorder is included as an impulse control disorder in the 11th revision of the International Classification of Diseases. Although the neurobiology behind the disorder is not clear, some studies suggest dysregulated hypothalamic-pituitary-adrenal axis. Oxytocin acts as counterregulatory neuroendocrine hormone to cortisol and is also involved in sexual behavior.

Objective

We hypothesized that oxytocin may play a role in the pathophysiology of HD with compensatory actions to cortisol.

Design

Longitudinal.

Setting

ANOVA clinic (Karolinska University Hospital).

Patients or other participants

64 males with HD and 38 age-matched healthy volunteers.

Main Outcome Measures

Plasma oxytocin levels, measured with radioimmunoassay; Hypersexual Disorder Screening Inventory; and Hypersexual Disorder: Current Assessment Scale for assessing hypersexual symptoms.

Interventions

A patient subgroup (n = 30) completed the manual-based group-administered cognitive-behavioral therapy (CBT) program for HD, and posttreatment oxytocin levels were measured.

Results

Hypersexual men (n = 64) exhibited significantly higher oxytocin plasma levels (mean ± SD: 31.0 ± 9.9 pM) compared with healthy volunteers (16.9 ± 3.9 pM; P < 0.001). There were significant positive correlations between oxytocin levels and the rating scales measuring hypersexual behavior. Patients who completed CBT treatment (n = 30) had a significant reduction of oxytocin plasma levels from pretreatment (30.5 ± 10.1 pM) to posttreatment (20.2 ± 8.0 pM; P < 0.001).

Conclusions

The results suggest that the hyperactive oxytocinergic system in hypersexual men may be a compensatory mechanism to attenuate hyperactive stress.
Safety, Efficacy, and Pharmacokinetics of HP501 in Healthy Volunteers and Hyperuricemic Patients: A Phase I/IIa Study
Authors: Wang Zhenlei , Li Xinghai , Jin Ying , Liu Runhan , Di Xiangjie , Zhou Yi , Wang Ying , Fan Lei , Chen Yuanwei , Wang Yongsheng , Zheng Li
Published: February 2022

Context

Uricosuric agents are the typical approach to the control of hyperuricemia; however, their use has been eclipsed by adverse reactions, and a safer uricosuric drug is badly needed.

Objective

HP501 is a novel renal urate transporter 1 inhibitor for the treatment of hyperuricemia. In this first-in-human study, we investigated the safety, efficacy, and pharmacokinetics of HP501 in healthy volunteers and hyperuricemic patients.

Methods

The placebo-controlled, double-blind, randomized, 3-part, phase I/IIa study consists of a single ascending dose (SAD) part with 32 participants, a multiple ascending dose part with 48 participants, and a drug-drug interaction part with 20 participants. Effects of food in healthy volunteers administered 45 mg HP501 in the fed state were also assessed in the SAD part.

Results

A total of 68 healthy volunteers and 32 hyperuricemic patients were enrolled. HP501 appeared to be safe and well tolerated in both groups. In hyperuricemic patients dosed with 45 mg HP501 over 10 days, 2/10 and 3/10 patients had elevated AST (< 2 times upper limit of normal [ULN]) and ALT (< 2.5 times ULN), respectively. No dose-limiting adverse events were observed. Across doses of HP501 from 5 to 60 mg, the concentrations of serum uric acid (sUA) are reduced by a maximum of about 50%. HP501 exhibited predictable pharmacokinetics across different dose levels in healthy volunteers or hyperuricemic patients. HP501 and febuxostat have obvious synergistic sUA-lowering effects with no apparent pharmacokinetics interaction.

Conclusion

HP501 was effective at reducing sUA in healthy volunteers and hyperuricemic patients with a tolerable safety profile, warranting further development.
Population-based Assessment of Cardiometabolic-related Diagnoses in Youth With Klinefelter Syndrome: A PEDSnet Study
Authors: Davis Shanlee M , Nokoff Natalie J , Furniss Anna , Pyle Laura , Valentine Anna , Fechner Patricia , Ikomi Chijioke , Magnusen Brianna , Nahata Leena , Vogiatzi Maria G , Dempsey Amanda
Published: February 2022

Context

Diabetes and cardiovascular diseases are common among men with Klinefelter syndrome (KS) and contribute to high morbidity and mortality.

Objective

To determine if cardiometabolic-related diagnoses are more prevalent among youth with KS than matched controls in a large population-based cohort.

Methods

Secondary data analysis of electronic health records from 6 pediatric institutions in the United States (PEDSnet). Patients included all youth with KS in the database (n = 1080) and 4497 youth without KS matched for sex, age (mean 13 years at last encounter), year of birth, race, ethnicity, insurance, site, and duration of care (mean 7 years). The main outcome measures were prevalence of 5 cardiometabolic-related outcomes: overweight/obesity, dyslipidemia, dysglycemia, hypertension, and liver dysfunction.

Results

The odds of overweight/obesity (OR 1.6; 95% CI 1.4-1.8), dyslipidemia (3.0; 2.2-3.9), and liver dysfunction (2.0; 1.6-2.5) were all higher in KS than in controls. Adjusting for covariates (obesity, testosterone treatment, and antipsychotic use) attenuated the effect of KS on these outcomes; however, boys with KS still had 45% greater odds of overweight/obesity (95% CI 1.2-1.7) and 70% greater odds of liver dysfunction (95% CI 1.3-2.2) than controls, and both dyslipidemia (1.6; 1.1-2.4) and dysglycemia (1.8; 1.1-3.2) were higher in KS but of borderline statistical significance when accounting for multiple comparisons. The odds of hypertension were not different between groups.

Conclusion

This large, population-based cohort of youth with KS had a higher odds of most cardiometabolic-related diagnoses than matched controls.
Association of Antithyroid Antibodies in Checkpoint Inhibitor–Associated Thyroid Immune–Related Adverse Events
Authors: Muir Christopher A , Wood Cameron C G , Clifton-Bligh Roderick J , Long Georgina V , Scolyer Richard A , Carlino Matteo S , Menzies Alexander M , Tsang Venessa H M
Published: February 2022

Context

The significance of thyroid peroxidase (TPOAb) and thyroglobulin antibody (TgAb) in the pathogenesis of thyroid immune-related adverse events (irAEs) is unknown.

Objective

To characterize the association of anti-thyroid antibodies with the development of thyroid immune related adverse events.

Methods

A retrospective cohort study was conducted of patients with melanoma receiving immune checkpoint inhibitor (ICI) treatment. TPOAb, TgAb, and interleukin-6 (IL-6) were measured retrospectively using tumor-banked samples at baseline and at time of diagnosis of a thyroid irAE. In euthyroid patients (without thyroid irAEs) measures were repeated 30 to 60 days after ICI commencement, which was similar to the median time to onset of thyroid irAEs in other patients.

Results

A total of 122 patients were included—31 remained euthyroid, 47 developed subclinical thyrotoxicosis, 37 developed overt thyrotoxicosis, and 7 developed overt hypothyroidism without preceding thyrotoxicosis. Baseline elevation of TPOAb or TgAb was present in 19 (16%) and 28 (23%) patients, respectively. Positive TPOAb or TgAb at baseline was 97% and 100% specific for eventual development of a thyroid irAE, respectively. During ICI treatment, overt thyrotoxicosis, but not other subtypes of thyroid irAE, was associated with statistically significant increases in the titer of TgAb and TPOAb. Baseline IL-6 levels were not associated with thyroid irAE onset but statistically significantly increased during treatment in patients who developed overt hypothyroidism.

Conclusions

TPOAb and TgAb positivity at baseline was more prevalent in patients who developed thyroid irAEs. Statistically significant increases or new antibody positivity was observed in association with overt thyrotoxicosis. TPOAb and TgAb positivity or increases during ICI treatment may be a useful biomarker to identify patients at increased risk of thyroid irAEs, particularly overt thyrotoxicosis.
Machine Learning Applications of Surgical Imaging for the Diagnosis and Treatment of Spine Disorders: Current State of the Art
Authors: Karandikar Paramesh , Massaad Elie , Hadzipasic Muhamed , Kiapour Ali , Joshi Rushikesh S. , Shankar Ganesh M. , Shin John H.
Published: February 2022

Recent developments in machine learning (ML) methods demonstrate unparalleled potential for application in the spine. The ability for ML to provide diagnostic faculty, produce novel insights from existing capabilities, and augment or accelerate elements of surgical planning and decision making at levels equivalent or superior to humans will tremendously benefit spine surgeons and patients alike. In this review, we aim to provide a clinically relevant outline of ML-based technology in the contexts of spinal deformity, degeneration, and trauma, as well as an overview of commercial-level and precommercial-level surgical assist systems and decisional support tools. Furthermore, we briefly discuss potential applications of generative networks before highlighting some of the limitations of ML applications. We conclude that ML in spine imaging represents a significant addition to the neurosurgeon's armamentarium—it has the capacity to directly address and manifest clinical needs and improve diagnostic and procedural quality and safety—but is yet subject to challenges that must be addressed before widespread implementation.
Single-cell imaging of ERK and Akt activation dynamics and heterogeneity induced by G-protein-coupled receptors
Authors: Chavez-Abiega Sergei , Grönloh Max L. B. , Gadella Theodorus W. J. , Bruggeman Frank J. , Goedhart Joachim
Published: February 2022

Kinases play key roles in signaling networks that are activated by G-protein-coupled receptors (GPCRs). Kinase activities are generally inferred from cell lysates, hiding cell-to-cell variability. To study the dynamics and heterogeneity of ERK and Akt proteins, we employed high-content biosensor imaging with kinase translocation reporters. The kinases were activated with GPCR ligands. We observed ligand concentration-dependent response kinetics to histamine, α2-adrenergic and S1P receptor stimulation. By using G-protein inhibitors, we observed that Gq mediated the ERK and Akt responses to histamine. In contrast, Gi was necessary for ERK and Akt activation in response to α2-adrenergic receptor activation. ERK and Akt were also strongly activated by S1P, showing high heterogeneity at the single-cell level, especially for ERK. Cluster analysis of time series derived from 68,000 cells obtained under the different conditions revealed several distinct populations of cells that display similar response dynamics. ERK response dynamics to S1P showed high heterogeneity, which was reduced by the inhibition of Gi. To conclude, we have set up an imaging and analysis strategy that reveals substantial cell-to-cell heterogeneity in kinase activity driven by GPCRs.
Negotiations with Limited Specifiability
Authors: Fukuda Satoshi , Kamada Yuichiro
Published: February 2022

We study negotiations with limited specifiability—each party may not be able to fully specify a negotiation outcome. We construct a class of negotiation protocols to conduct comparative statics on specifiability as well as move structures. We find that asynchronicity of proposal announcements narrows down the equilibrium payoff set, in particular, leading to a unique prediction in negotiations with a “common interest” alternative. The equilibrium payoff set is not a singleton in general, and depends on the fine details of how limitation on specifiability is imposed. The equilibrium payoff set is weakly larger under limited specifiability than under unlimited specifiability. (JEL C72, D83, D86)