bluuebunny/crossref_metadata_2025 huggingface dataset:
Reducing youth suicide: systems modelling and simulation to guide targeted investments across the determinants
Authors: Occhipinti Jo-An , Skinner Adam , Iorfino Frank , Lawson Kenny , Sturgess Julie , Burgess Warren , Davenport Tracey , Hudson Danica , Hickie Ian
Published: March 2021

Background

Reducing suicidal behaviour (SB) is a critical public health issue globally. The complex interplay of social determinants, service system factors, population demographics, and behavioural dynamics makes it extraordinarily difficult for decision makers to determine the nature and balance of investments required to have the greatest impacts on SB. Real-world experimentation to establish the optimal targeting, timing, scale, frequency, and intensity of investments required across the determinants is unfeasible. Therefore, this study harnesses systems modelling and simulation to guide population-level decision making that represent best strategic allocation of limited resources.

Methods

Using a participatory approach, and informed by a range of national, state, and local datasets, a system dynamics model was developed, tested, and validated for a regional population catchment. The model incorporated defined pathways from social determinants of mental health to psychological distress, mental health care, and SB. Intervention scenarios were investigated to forecast their impact on SB over a 20-year period.

Results

A combination of social connectedness programs, technology-enabled coordinated care, post-attempt assertive aftercare, reductions in childhood adversity, and increasing youth employment projected the greatest impacts on SB, particularly in a youth population, reducing self-harm hospitalisations (suicide attempts) by 28.5% (95% interval 26.3–30.8%) and suicide deaths by 29.3% (95% interval 27.1–31.5%). Introducing additional interventions beyond the best performing suite of interventions produced only marginal improvement in population level impacts, highlighting that ‘more is not necessarily better.’

Conclusion

Results indicate that targeted investments in addressing the social determinants and in mental health services provides the best opportunity to reduce SB and suicide. Systems modelling and simulation offers a robust approach to leveraging best available research, data, and expert knowledge in a way that helps decision makers respond to the unique characteristics and drivers of SB in their catchments and more effectively focus limited health resources.
Immunohistochemical expression of β-catenin, Ki67, CD3 and CD18 in canine colorectal adenomas and adenocarcinomas
Authors: Herstad Kristin M. V. , Gunnes Gjermund , Rørtveit Runa , Kolbjørnsen Øyvor , Tran Linh , Skancke Ellen
Published: March 2021

Background

Inflammation is believed to influence human colorectal carcinogenesis and may have an impact on prognosis and survival. The mucosal immunophenotype in dogs with colorectal cancer is poorly described.

The aim of this study was to investigate whether the density, distribution and grade of tumor-infiltrating immune cells (TIIs) are different in normal colonic tissue vs benign stages (adenomas) and malignant stages (adenocarcinomas) of canine colorectal carcinogenesis, and thus, whether they can be considered as prognostic factors in dogs.

This retrospective case-control study was performed on formalin-fixed, paraffin-embedded tissue samples from dogs with histologically confirmed colorectal adenoma (n = 18) and adenocarcinoma (n = 13) collected from archived samples. The samples had been collected by colonoscopy, surgery or during postmortem examination. Healthy colonic tissue obtained post mortem from dogs euthanized for reasons not involving the gastrointestinal tract served as control tissue (n = 9).

Results

The tumor samples had significantly lower numbers of CD3+ T-cells in the epithelium compared to controls (adenocarcinoma vs control, Kruskal-Wallis test, p = 0.0004, and adenoma vs control, p = 0.002). Adenomas had a significantly lower number of CD18+ cells in the lamina propria, compared to control samples (Kruskal-Wallis test, p = 0.008). Colonic samples from control dogs had uniform staining of β-catenin along the cell membrane of epithelial cells. Compared to normal colonic cells, the expression levels of cytoplasmic β-catenin were significantly higher in adenomas and adenocarcinomas (adenoma vs control Kruskal-Wallis test, p = 0.004, and adenocarcinoma vs control, p = 0.002). None of the control samples showed positive staining of β-catenin in the nucleus of colonic cells. In contrast, adenocarcinomas and adenomas showed moderate to strong staining of the cell nucleus. The nuclear β-catenin expression (signal strength and distribution) was significantly higher in adenomas compared to adenocarcinomas (Kruskal-Wallis test, p < 0.05).

Conclusions

β-catenin and Ki67 were not useful markers for demonstrating tumor progression from adenomas to adenocarcinomas. The lower presence of CD18 and CD3+ cells in colorectal tumors compared to controls indicates a reduced presence of histiocytes and T-cells, which may have implications for the pathogenesis and progression of colorectal cancer in dogs.
Exposure to PM2.5 is a risk factor for acute exacerbation of surgically diagnosed idiopathic pulmonary fibrosis: a case–control study
Authors: Tahara Masahiro , Fujino Yoshihisa , Yamasaki Kei , Oda Keishi , Kido Takashi , Sakamoto Noriho , Kawanami Toshinori , Kataoka Kensuke , Egashira Ryoko , Hashisako Mikiko , Suzuki Yuzo , Fujisawa Tomoyuki , Mukae Hiroshi , Suda Takafumi , Yatera Kazuhiro
Published: March 2021

Background

Short-term exposure to ozone and nitrogen dioxide is a risk factor for acute exacerbation (AE) of idiopathic pulmonary fibrosis (AE-IPF). The comprehensive roles of exposure to fine particulate matter in AE-IPF remain unclear. We aim to investigate the association of short-term exposure to fine particulate matter with the incidence of AE-IPF and to determine the exposure-risk time window during 3 months before the diagnosis of AE-IPF.

Methods

IPF patients were retrospectively identified from the nationwide registry in Japan. We conducted a case–control study to assess the correlation between AE-IPF incidence and short-term exposure to eight air pollutants, including particulate matter < 2.5 µm (PM2.5). In the time-series data, we compared monthly mean exposure concentrations between months with AE (case months) and those without AE (control months). We used multilevel mixed-effects logistic regression models to consider individual and institutional-level variables, and also adjusted these models for several covariates, including temperature and humidity. An additional analysis with different monthly lag periods was conducted to determine the risk-exposure time window for 3 months before the diagnosis of AE-IPF.

Results

Overall, 152 patients with surgically diagnosed IPF were analyzed. AE-IPF was significantly associated with an increased mean exposure level of nitric oxide (NO) and PM2.5 30 days prior to AE diagnosis. Adjusted odds ratio (OR) with a 10 unit increase in NO was 1.46 [95% confidence interval (CI) 1.11–1.93], and PM2.5 was 2.56 (95% CI 1.27–5.15). Additional analysis revealed that AE-IPF was associated with exposure to NO during the lag periods lag 1, lag 2, lag 1–2, and lag 1–3, and PM2.5 during the lag periods lag 1 and lag 1–2.

Conclusions

Our results show that PM2.5 is a risk factor for AE-IPF, and the risk-exposure time window related to AE-IPF may lie within 1–2 months before the AE diagnosis. Further investigation is needed on the novel findings regarding the exposure to NO and AE-IPF.
Efficient bioconversion of raspberry ketone in Escherichia coli using fatty acids feedstocks
Authors: Chang Chen , Liu Bo , Bao Yihong , Tao Yong , Liu Weifeng
Published: March 2021

Background

Phenylpropanoid including raspberry ketone, is a kind of important natural plant product and widely used in pharmaceuticals, chemicals, cosmetics, and healthcare products. Bioproduction of phenylpropanoid in Escherichia coli and other microbial cell factories is an attractive approach considering the low phenylpropanoid contents in plants. However, it is usually difficult to produce high titer phenylpropanoid production when fermentation using glucose as carbon source. Developing novel bioprocess using alternative sources might provide a solution to this problem. In this study, typical phenylpropanoid raspberry ketone was used as the target product to develop a biosynthesis pathway for phenylpropanoid production from fatty acids, a promising alternative low-cost feedstock.

Results

A raspberry ketone biosynthesis module was developed and optimized by introducing 4-coumarate-CoA ligase (4CL), benzalacetone synthase (BAS), and raspberry ketone reductase (RZS) in Escherichia coli strains CR1–CR4. Then strain CR5 was developed by introducing raspberry ketone biosynthesis module into a fatty acids-utilization chassis FA09 to achieve production of raspberry ketone from fatty acids feedstock. However, the production of raspberry ketone was still limited by the low biomass and unable to substantiate whole-cell bioconversion process. Thus, a process by coordinately using fatty-acids and glycerol was developed. In addition, we systematically screened and optimized fatty acids-response promoters. The optimized promoter Pfrd3 was then successfully used for the efficient expression of key enzymes of raspberry ketone biosynthesis module during bioconversion from fatty acids. The final engineered strain CR8 could efficiently produce raspberry ketone repeatedly using bioconversion from fatty acids feedstock strategy, and was able to produce raspberry ketone to a concentration of 180.94 mg/L from soybean oil in a 1-L fermentation process.

Conclusion

Metabolically engineered Escherichia coli strains were successfully developed for raspberry ketone production from fatty acids using several strategies, including optimization of bioconversion process and fine-tuning key enzyme expression. This study provides an essential reference to establish the low-cost biological manufacture of phenylpropanoids compounds.
Oncological safety of immediate breast reconstruction with skin- or nipple-sparing mastectomy: the value of tumor-to-dermis distance measured by preoperative ultrasonography
Authors: Fujii Takaaki , Nakazawa Yuko , Ogino Misato , Obayashi Sayaka , Yajima Reina , Honda Chikako , Nakamura Hideharu , Makiguchi Takaya , Shirabe Ken
Published: March 2021

Background

Immediate breast reconstruction with skin-sparing (SSM) or nipple-sparing mastectomy (NSM) has become a common procedure. In this study, we evaluated the distance between breast tumor and skin in a series of patients undergoing IBR as it relates to oncologic safety, namely, the incidence of recurrence.

Methods

The distance of the tumor to the dermis, rather than the outer layer of skin, was the key parameter of our preoperative ultrasound measurements. Our data set comprised the cases of 171 patients and 181 breasts with breast cancer that had undergone two-stage breast reconstruction by expander. The median age of the patients was 47 years (25–75 years). The overall median follow-up period was 47.1 months (8.8–125.3 months). Eighty-five breasts underwent IBR with SSM/NSM; the others underwent conventional mastectomy.

Results

Among the total of 181 reconstructed breast mounds, the locoregional recurrence rate was 1.1% (2 breasts) with no cases of skin flap recurrence or skin flap necrosis. The tumor-to-dermis distance of cases with skin preservation (NSM/SSM) was significantly less than that of cases with conventional mastectomy (3.8 ± 2.7 mm vs 5.2 ± 2.4 mm). In cases with invasive carcinoma, all cases whose tumor-to-dermis distance was less than 2 mm underwent resection of the skin immediately overlying the tumor.

Conclusions

Our results suggested that a 2-mm distance between the dermis and tumor on ultrasound evaluation is sufficient for the use of this tissue as a skin flap in SSM/NSM procedures. Our study indicated that immediate breast reconstruction with SSM/NSM can be an oncologically safe surgical option for breast cancer. However, we recommend that resection of the skin overlying the tumor be performed in cases with invasive breast cancer in which the tumor-to-dermis distance is less than 2 mm.

Trial registration

Patients in this study were retrospectively registered. This study design was approved by our Clinical Ethics Committee (No 1297) (http://ciru.dept.showa.gunma-u.ac.jp/guidance/storage-sample/list.html).
ADAMTS13 activity decreases in the early phase of trauma associated with coagulopathy and systemic inflammation: a prospective observational study
Authors: Matsumoto Hironori , Takeba Jun , Umakoshi Kensuke , Kikuchi Satoshi , Ohshita Muneaki , Annen Suguru , Moriyama Naoki , Nakabayashi Yuki , Sato Norio , Aibiki Mayuki
Published: March 2021

Background

We conducted a prospective observational study for investigating the changes in the 13th member of a disintegrin-like and metalloprotease with thrombospondin type 1 motif (ADAMTS13) and its association with the coagulofibrinolytic response in adult trauma patients.

Methods

In 39 trauma patients hospitalized for longer than 7 days, time-course changes in biomarkers of coagulofibrinolysis and systemic inflammation along with ADAMTS13 activity were examined. The patients were stratified into three groups based on ADAMTS13 activities on admission (day 0): normal group (≥70%), mildly decreased group (≥50 and < 70%) and moderately decreased group (< 50%).

Results

Among 39 patients with a median Injury Severity Score (ISS) of 20, 11 patients developed disseminated intravascular coagulation (DIC) and 16 patients required transfusion. Six of 39 patients (15.4%) showed moderate decreased ADAMTS13 activity to < 50%, and 20 patients (51.3%) showed mild drops (≥50 and < 70%). These changes in ADAMTS13 activity on day 0 were significantly correlated with changes in IL-6 and other coagulofibrinolytic markers such as platelet counts, prothrombin time and fibrin/fibrinogen degradation product (FDP). Antithrombin activity (AT) and serum albumin (Alb) level showed significantly positive linear correlations with ADAMTS13 activity (AT: r = 0.513, p < 0.001; Alb: r = 0.647, p < 0.001). Simple logistic regression analyses showed that ADAMTS13 activity, if less than 50%, was significantly correlated with the development of DIC (OR 7.499, 95%CI 1.121–49.242, p = 0.038) and the need for transfusion of fresh frozen plasma (OR 9.000, 95%CI 1.327–61.025, p = 0.028).

Conclusions

ADAMTS13 activity decreased even in the early phase of trauma, which was complicated by coagulopathy and systemic inflammation. Furthermore, the decrease in ADAMTS13 activity was correlated with DIC and plasma transfusion.
Growth and puberty in children with juvenile idiopathic arthritis
Authors: d’Angelo Debora Mariarita , Di Donato Giulia , Breda Luciana , Chiarelli Francesco
Published: March 2021

Juvenile Idiopathic Arthritis is one of the most prevalent chronic diseases in children, with an annual incidence of 2–20 cases per 100,000 and a prevalence of 16–150 per 100,000. It is associated with several complications that can cause short-term or long-term disability and reduce the quality of life. Among these, growth and pubertal disorders play an important role. Chronic inflammatory conditions are often associated with growth failure ranging from slight decrease in height velocity to severe forms of short stature. The prevalence of short stature in JIA varies from 10.4% in children with polyarticular disease to 41% of patients with the systemic form, while oligoarthritis is mostly associated with localized excessive bone growth of the affected limb, leading to limb dissymmetry. The pathogenesis of growth disorders is multifactorial and includes the role of chronic inflammation, long-term use of corticosteroids, undernutrition, altered body composition, delay of pubertal onset or slow pubertal progression. These factors can exert a systemic effect on the GH/IGF-1 axis and on the GnRH-gonadotropin-gonadic axis, or a local influence on the growth plate homeostasis and function. Although new therapeutic options are available to control inflammation, there are still 10–20% of patients with severe forms of the disease who show continuous growth impairment, ending in a short final stature. Moreover, delayed puberty is associated with a reduction in the peak bone mass with the possibility of concomitant or future bone fragility. Monitoring of puberty and bone health is essential for a complete health assessment of adolescents with JIA. In these patients, an assessment of the pubertal stage every 6 months from the age of 9 years is recommended. Also, linear growth should be always evaluated considering the patient’s bone age. The impact of rhGH therapy in children with JIA is still unclear, but it has been shown that if rhGH is added at high dose in a low-inflammatory condition, post steroids and on biologic therapy, it is able to favor a prepubertal growth acceleration, comparable with the catch-up growth response in GH-deficient patients. Here we provide a comprehensive review of the pathogenesis of puberty and growth disorders in children with JIA, which can help the pediatrician to properly and timely assess the presence of growth and pubertal disorders in JIA patients.
Simultaneous quantification of bioactive components in Chinese herbal spirits by ultra-high performance liquid chromatography coupled to triple-quadrupole mass spectrometry (UHPLC–QQQ–MS/MS)
Authors: Hu Yan , Wang Zhe , Xia Fangbo , Yang Wen , Liu Yuan-Cai , Wan Jian-Bo
Published: March 2021

Background

The Chinese medicinal wine made from herbal medicines became prevalent among Chinese people. The Chinese herbal spirit is composed of several herbal extracts, and has the certain health functions, such as anti-fatigue and immune regulation. The quality evaluation of Chinese herbal spirit is greatly challenged by the enormous and complex components with great structural diversity and wide range of concentration distribution.

Methods

An ultra-high performance liquid chromatography coupled to triple quadrupole mass spectrometry (UHPLC-QQQ-MS/MS) with multiple reaction monitoring (MRM) method was developed to simultaneously determine forty-three bioactive components in the Chinese herbal spirits produced by year 2014 and 2018.

Results

Quantitative results showed that 11 components, i.e.., puerarin (5), purpureaside C (7), daidzin (8), echinacoside (9), acteoside (15), epimedin B (22), epimedin C (23), icariin (24), eugenol (27), chikusetsusaponin iva (30) and Z-ligustilide (40), significantly decreased along with the increasing years of storage, while 5 compounds, i.e.., geniposidic acid (1), protocatechuic acid (2), crustecdysone (14), daidzein (18) and icariside I (35), were basically stable in all samples across the years.

Concusion

The established method allowing to simultaneously determined 43 components with wide structural diversity and trace amounts will facilitate the quality control research of Chinese herbal spirits.
First French study relative to preconception genetic testing: 1500 general population participants’ opinion
Authors: Bonneau Valérie , Nizon Mathilde , Latypova Xenia , Gaultier Aurélie , Hoarau Eugénie , Bézieau Stéphane , Minguet Guy , Turrini Mauro , Jourdain Maud , Isidor Bertrand
Published: March 2021

Background

Until very recently, preconception genetic testing was only conducted in particular communities, ethnic groups or families for which an increased risk of genetic disease was identified. To detect in general population a risk for a couple to have a child affected by a rare, recessive or X-linked, genetic disease, carrier screening is proposed in several countries. We aimed to determine the current public opinion relative to this approach in France, using either a printed or web-based questionnaire.

Results

Among the 1568 participants, 91% are favorable to preconception genetic tests and 57% declare to be willing to have the screening if the latter is available. A medical prescription by a family doctor or a gynecologist would be the best way to propose the test for 73%, with a reimbursement from the social security insurance. However, 19% declare not to be willing to use the test because of their ethic or moral convictions, and the fear that the outcome would question the pregnancy. Otherwise, most participants consider that the test is a medical progress despite the risk of an increased medicalization of the pregnancy.

Conclusion

This first study in France highlights a global favorable opinion for the preconception genetic carrier testing under a medical prescription and a reimbursement by social security insurance. Our results emphasize as well the complex concerns underpinned by the use of this screening strategy. Therefore, the ethical issues related to these tests include the risk of eugenic drift mentioned by more than half of the participants.
Haematological findings in 158 cows with acute toxic mastitis with a focus on the leukogram
Authors: Braun Ueli , Gerspach Christian , Riond Barbara , Oschlies Carina , Corti Sabrina , Bleul Ulrich
Published: March 2021

Background

In cows with acute toxic mastitis (ATM), the leukogram aids in the assessment of the severity of disease. The goal of our study was to compare the leukogram of 158 cows with ATM (cases) and 168 clinically healthy cows (controls). We hypothesised that the leukograms of surviving and non-surviving cows differ and that there are variables of the leukogram with sufficient prognostic potential to be used in the decision to treat or not to treat a cow with ATM. The cows were examined clinically and underwent haematological and biochemical examination of blood and bacteriological culture of milk samples.

Results

All cows with ATM had a poor appetite or anorexia, and 34 cows (21.5%) were recumbent. A single quarter was affected in 119 cows (75.3%), two quarters in 37 cows (23.4%) and three quarters in two cows (1.3%). Bacteriological culture showed Gram-negative pathogens in 100 cows (63.3%), Gram-positive in 15 (9.5%) and yeast in 4 (2.5%). The median total leukocyte count of cases was 4300 cells/µL (interquartile range = 2300–8200/µL), which was significantly lower than 8000 cells/µL (6525–9300/µL) in controls. Except for band neutrophils and metamyelocytes, the counts of all components of the leukogram were lower in cases compared with controls. Significantly more cows with ATM had leukopenia (60.1 vs. 4.1%) or leukocytosis (10.1 vs. 3.0%) than controls. Diseased cows had significantly lower segmented neutrophil counts than controls (860 vs. 2598 cells/µL), and 69.5 and 17.3%, respectively, had counts below the reference interval. Cases had increased band (77.3%) and metamyelocyte (25.0%) counts compared with controls (0.6 and 0%, respectively). In diseased cows, eosinopenia occurred in 66.4% (controls, 1.8%), monocytopenia in 40.6% (4.2%) and lymphopenia in 60.2% (1.8%). Twenty-one diseased cows (16.4%) had a regenerative and 57 (44.5%) had a degenerative left shift. The median neutrophil-to-lymphocyte ratio was 0.97 in diseased cows and 0.63 in controls. Toxic changes in neutrophils including cytoplasmic basophilia and vacuolisation were seen in 101 (91.8%) of 110 blood smears of diseased cows. The leukogram of the surviving and non-surviving cows did not differ significantly, and the hypothesis was rejected.

Conclusions

ATM results in severe changes in the leukogram particularly leukopenia, lymphopenia, and degenerative left shift. The hypothesis that the leukograms of surviving and non-surviving cows differ was rejected. The leukogram has not sufficient prognostic potential to be used in the decision to treat or not to treat a cow with ATM.
Study factors associated with the incompletion of clinical trials that include pediatric patients: a retrospective analysis of the European Clinical Trials Database and a lesson from the European region
Authors: Tanemura Nanae , Sasaki Tsuyoshi , Sato Junko , Urushihara Hisashi
Published: March 2021

Background

Incomplete clinical trials for pediatric drug development result in a lack of adequate scientific evidence for providing appropriate medication to pediatric populations; this is especially true for Japan. Thus, using the European Clinical Trials Database (EudraCT), this study aimed to identify the factors related to the study design and administration that lead to incompletion of clinical trials that included pediatric patients.

Methods

We focused on clinical trials that included patients under the age of 18 registered in the database, named as the European Clinical Trials Database between January 1, 2014, and December 31, 2018. Two groups of trials were identified: “all cases completed” and “not all cases completed,” reflecting whether they were completed in all participating countries/regions or not. To identify the factors of the occurrence of “not all cases completed,” a logistic regression analysis was performed to calculate the odds ratios and 95% confidence intervals. In total, 142 clinical trials (95 “all cases completed” and 47 “not all cases completed”) were analyzed.

Results

The logistic regression analysis showed the number of countries in which a clinical trial was conducted to be the only significant factor (odds ratio: 1.3; 95% confidence interval: 1.1-1.5); this was identified as the primary factor for the occurrence of “not all cases completed” in the clinical trials that included pediatric patients.

Conclusion

Our findings suggest that the feasibility of clinical trials that include pediatric patients, such as whether the countries in which the trial is to be conducted are suitable, must be considered prior to the trial.
Clinical research and burnout syndrome in Italy – only a physicians’ affair?
Authors: Cagnazzo Celeste , Filippi Roberto , Zucchetti Giulia , Cenna Rosita , Taverniti Cristiana , Guarrera Agata Sue Ellen , Stabile Stefano , Federici Irene , Monti Manuela , Pirondi Sara , Testoni Sara , Fagioli Franca
Published: March 2021

Background

The burnout phenomenon has been extensively investigated among health care professionals, particularly focusing on physicians and nurses. However, literature concerning burnout in clinical research is poor and often neglects the other professional categories involved.

Methods

In March 2019, all members of Italian Group of Clinical Research Coordinator were invited to participate to a web survey, consisting of three sections: general information and workload; Maslach Burnout Inventory (MBI) test; subjective perception of oneself’s work stress and possible causes.

Results

The majority of respondents felt a form of distress. The main source was contract type (31.2%), followed by workload (20.5%) and lack of skills recognition (17.8%).

Results from MBI test confirmed the interviewees’ subjective perception: an intermediate level of emotional exhaustion (19.1 points) and a very high sense of reduced professional achievement (26.8 points) were observed. Both depersonalization and sense of reduced professional achievement showed weak to moderate correlations with emotional exhaustion. Emotional exhaustion was associated with contract type with high significance.

Conclusion

It is necessary to act on those qualitative factors that are greatly increasing the level of perceived stress, jeopardizing the quality of clinical research coordinators work and significantly amplifying the phenomenon of migration towards the private sector.
A novel preference-informed complementary trial (PICT) design for clinical trial research influenced by strong patient preferences
Authors: Ali Samina , Hopkin Gareth , Poonai Naveen , Richer Lawrence , Yaskina Maryna , Heath Anna , Klassen Terry Paul , McCabe Chris ,   on behalf of the KidsCAN PERC Innovative Pediatric Clinical Trials No OUCH Study Group, Drendel Amy , Hopkin Gareth , Round Jeff , Offringa Martin , Pechlivanoglou Petros , Pullenayegum Eleanor , Rios David , Auclair Marie-Christine , Kim Kelly , Bourrier Lise , Dawson Lauren , DaSilva Kamary Coriolano , Marples Pamela , Watts Rick , Thull-Freedman Jennifer , McGrath Patrick , Graham Timothy A. D. , Hartling Lisa , Erickson Tannis , Foot Brendon , Schreiner Kurt , Leung Julie ,   the KidsCAN PERC Innovative Pediatric Clinical Trials Methods Core, Offringa Martin , Pechlivanoglou Petros , Pullenayegum Eleanor , Rios Juan David , Round Jeff
Published: March 2021

Background

Patients and their families often have preferences for medical care that relate to wider considerations beyond the clinical effectiveness of the proposed interventions. Traditionally, these preferences have not been adequately considered in research. Research questions where patients and families have strong preferences may not be appropriate for traditional randomized controlled trials (RCTs) due to threats to internal and external validity, as there may be high levels of drop-out and non-adherence or recruitment of a sample that is not representative of the treatment population. Several preference-informed designs have been developed to address problems with traditional RCTs, but these designs have their own limitations and may not be suitable for many research questions where strong preferences and opinions are present.

Methods

In this paper, we propose a novel and innovative preference-informed complementary trial (PICT) design which addresses key weaknesses with both traditional RCTs and available preference-informed designs. In the PICT design, complementary trials would be operated within a single study, and patients and/or families would be given the opportunity to choose between a trial with all treatment options available and a trial with treatment options that exclude the option which is subject to strong preferences. This approach would allow those with strong preferences to take part in research and would improve external validity through recruiting more representative populations and internal validity. Here we discuss the strengths and limitations of the PICT design and considerations for analysis and present a motivating example for the design based on the use of opioids for pain management for children with musculoskeletal injuries.

Conclusions

PICTs provide a novel and innovative design for clinical trials with more than two arms, which can address problems with existing preference-informed trial designs and enhance the ability of researchers to reflect shared decision-making in research as well as improving the validity of trials of topics with strong preferences.
The effect of opioid-free anesthesia on the quality of recovery after gynecological laparoscopy: study protocol for a prospective randomized controlled trial
Authors: Song Jae Yen , Choi Hoon , Chae Minsuk , Ko Jemin , Moon Young Eun
Published: March 2021

Background

Because of the indiscriminate use of opioids during the perioperative period, opioid-free anesthesia (OFA) has been increasingly required. Nevertheless, the studies on the detailed techniques and effects of OFA are not sufficient. The Quality of Recovery-40 (QoR-40) questionnaire is a validated assessment tool for measuring recovery from general anesthesia. However, no study has used the QoR-40 to determine if OFA leads to better recovery than standard general anesthesia. Therefore, we aim to perform this study to determine the effects of OFA using dexmedetomidine and lidocaine on the quality of recovery as well as the various postoperative outcomes.

Methods

The participants (n = 78) will be allocated to one of the two groups; the study group will receive bolus and infusion of dexmedetomidine and lidocaine, and the control group will receive remifentanil infusion during general anesthesia for gynecological laparoscopy. The other processes including anesthetic and postoperative care will be performed similarly in the two groups. Intraoperative hemodynamic, anesthetic, and nociceptive variables will be recorded. Postoperative outcomes such as QoR-40, pain severity, and opioid-related side effects will be assessed. Additionally, an ancillary cytokine study (inflammatory cytokine, stress hormone, and reactive oxygen species) will be performed during the study period.

Discussion

This will be the first study to determine the effect of OFA, using the combination of dexmedetomidine and lidocaine, on the quality of recovery after gynecological laparoscopy compared with standard general anesthesia using remifentanil. The findings from this study will provide scientific and clinical evidence on the efficacy of OFA.

Trial registration

ClinicalTrials.govNCT04409964. Registered on 28 May 2020
Some remarks on the sparse dominations for commutators of multi(sub)linear operator
Authors: Wang Zhidan
Published: March 2021

We establish pointwise sparse dominations for the iterated commutators of multi(sub)linear operators satisfying the$W_{q}$Wqcondition. As consequences, we present some quantitative weighted estimates for the commutators. In addition, we also obtain the Fefferman–Stein inequality, the Coifman–Fefferman inequality, and the local decay estimates regarding the iterated commutators.
Bupivacaine inhibits a small conductance calcium‐activated potassium type 2 channel in human embryonic kidney 293 cells
Authors: Chen Hongfei , Jin Zhousheng , Xia Fangfang , Fu Zhijian
Published: March 2021

Background

Bupivacaine blocks many ion channels in the heart muscle, causing severe cardiotoxicity. Small-conductance calcium-activated potassium type 2 channels (SK2 channels) are widely distributed in the heart cells and are involved in relevant physiological functions. However, whether bupivacaine can inhibit SK2 channels is still unclear. This study investigated the effect of bupivacaine on SK2 channels.

Methods

The SK2 channel gene was transfected into human embryonic kidney 293 cells (HEK-293 cells) with Lipofectamine 2000. The whole-cell patch-clamp technique was used to examine the effect of bupivacaine on SK2 channels. The concentration–response relationship of bupivacaine for inhibiting SK2 currents (0 mV) was fitted to a Hill equation, and the half-maximal inhibitory concentration (IC50) value was determined.

Results

Bupivacaine inhibited the SK2 channels reversibly in a dose-dependent manner. The IC50 value of bupivacaine, ropivacaine, and lidocaine on SK2 currents was 16.5, 46.5, and 77.8µM, respectively. The degree of SK2 current inhibition by bupivacaine depended on the intracellular concentration of free calcium.

Conclusions

The results of this study suggested the inhibitory effect of bupivacaine on SK2 channels. Future studies should explore the effects of SK2 on bupivacaine cardiotoxicity.
Association between physical restraint requirement and unfavorable neurologic outcomes in subarachnoid hemorrhage
Authors: Akiyama Kyoko , Inoue Akihiko , Hifumi Toru , Nakamura Kentaro , Taira Takuya , Nakagawa Shun , Jinno Keisuke , Manabe Arisa , Kinugasa Sayaka , Matsumura Hikaru , Shishido Hajime , Yokoyama Shota , Okazaki Tomoya , Hamaya Hideyuki , Takano Koshiro , Kiridume Kazutaka , Shinohara Natsuyo , Kawakita Kenya , Kuroda Yasuhiro
Published: March 2021

Background

Physical restraint has been commonly indicated to patients with brain dysfunction in neurocritical care. The effect of physical restraints on outcomes of critically ill adults remains controversial as no randomized controlled trials have compared its safety and efficacy, and the association between physical restraint requirement and neurological outcome in patients with subarachnoid hemorrhage (SAH) has not been fully examined. The aim of this study was to examine the association between physical restraint requirement and neurological outcomes in patients with SAH.

Methods

A single-center, retrospective study was conducted on patients with acute phase SAH treated for > 72 h in the intensive care unit from 2014 to 2020. Patients were divided into three groups based on the amount of time required for physical restraint during the first 24–72 h after admission: no, intermittent, and continuous use of physical restraint. Unfavorable neurologic outcome, assessed using the modified Rankin scale upon hospital discharge, has been considered as primary end point.

Results

Overall, 101 patients were included in the study, with 52 patients (51.5%) having unfavorable neurological outcomes. Among them, 46 patients (45.5%) did not use physical restraint, and 55 (54.5%) patients used physical restraint during the first 24–72 h after admission: 26 (25.7%) intermittent and 29 (28.7%) continuous. Multivariable logistic regression analysis showed that continuous use of physical restraint during the first 24–72 h after admission was significantly associated with unfavorable neurological outcomes in patients with SAH (odds ratio, 3.54; 95% confidence interval, 1.05–13.06; p = 0.042) compared with no physical restraint.

Conclusions

Continuous use of physical restraint during the first 24–72 h after admission was more significantly associated with unfavorable neurological outcomes than no physical restraint among patients with SAH during the acute phase.
Self-reported infertility diagnoses and treatment history approximately 20 years after fertility treatment initiation
Authors: Jung Alesia M. , Missmer Stacey A. , Cramer Daniel W. , Ginsburg Elizabeth S. , Terry Kathryn L. , Vitonis Allison F. , Farland Leslie V.
Published: March 2021

Background

Infertility history may have important implications for clinical practice and scientific discovery. Previous research on the validity of self-reported infertility measurements has been limited in scope and duration (< 5 years). In this study, we validated self-reported infertility history measures 15–23 years after fertility treatment initiation among women who utilized assisted reproductive technology (ART).

Methods

Women who received ART treatments from three Boston infertility clinics and who enrolled in a prior study (1994–2003) were re-contacted in 2018 for the AfteR Treatment Follow-up Study (ART-FS). Infertility history was collected from clinical records and two self-report questionnaires (at ART initiation and at ART-FS enrollment). Treatment history included specific details (fresh or frozen embryo transfers, number of cycles) and treatment recall prior to ART initiation. Self-reported infertility diagnoses included polycystic ovary syndrome (PCOS), endometriosis, uterine factor infertility, tubal factor infertility, diminished ovarian reserve/advanced maternal age, male factor infertility, and other/unknown. We compared self-reported measures from 2018 to self-reported and clinical data from prior study initiation, using Cohen’s kappa, sensitivity, specificity, and 95% confidence intervals.

Results

Of 2644 women we attempted to recontact, 808 completed the ART-FS, with an average follow-up of 19.6 years (standard deviation: 2.7). Recall of fertility treatment usage had moderate sensitivity (IVF = 0.85, Clomiphene/Gonadotropin = 0.81) but low specificity across different infertility treatment modalities (IVF = 0.63, Clomiphene/Gonadotropin = 0.55). Specific IVF details had low to moderate validity and reliability with clinical records. Reliability of recalled infertility diagnosis was higher when compared to self-report at ART initiation (PCOS K = 0.66, Endometriosis K = 0.76, Tubal K = 0.73) than when compared to clinical records (PCOS K = 0.31, Endometriosis K = 0.48, Tubal K = 0.62) and varied by diagnosis.

Conclusions

The ability of women to recall specific IVF treatment details was moderately accurate and recall of self-reported infertility diagnosis varied by diagnosis and measurement method.
Military medical research on internal diseases in modern warfare: new concepts, demands, challenges, and opportunities
Authors: Liu Guang-Dong , Wang Nan , Wang Hai-Ming , Li Xin , Shao Jun-Jie , Liu Zi-Fan , Jiang Min , Wang Lin , Wang Zi-Kai , Li Meng , Cao Xue-Ying , Wang Jiang , Zhang Ran , Chen Yun-Dai
Published: March 2021

Battlefield internal medicine aims at the treatment of combatants and noncombatants with various internal diseases on the battlefield. The military medical research on battlefield internal diseases focuses on the pathogenesis, clinical management, and prevention of internal diseases under military war conditions. In both wartime and peacetime, the soldiers suffer from more internal diseases than surgical wounds. With the introduction of high-tech weapons, including chemical, physical, and biological agents, a large number of special internal illnesses and casualties will appear in future wars. The battles often occur in special environments, such as high or low temperatures, plateau or polar areas, and micro- or hyper-gravity. The current theories of battlefield internal medicine are mainly derived from wars decades ago and cannot meet the needs of military medical support under the conditions of modern warfare. Therefore, the military medical research on battlefield internal medicine should be based on contemporary military situations, focus on the purpose of treating battlefield internal diseases, and adhere to the actual needs of the troops in peacetime and wartime. We should investigate the pathogenesis of battlefield internal diseases and explore the threats that may arise in future wars to ensure the advancement of battlefield internal medicine. This review highlights new concepts, demands, challenges, and opportunities for the further development of military medical research on battlefield internal medicine.
Dichloroacetate as a possible treatment for endometriosis-associated pain: a single-arm open-label exploratory clinical trial (EPiC)
Authors: Leow H. W. , Koscielniak M. , Williams L. , Saunders P. T. K. , Daniels J. , Doust A. M. , Jones M-C , Ferguson G. D. , Bagger Y. , Horne A. W. , Whitaker L. H. R.
Published: March 2021

Background

Endometriosis (where endometrial-like tissue is found outside the uterus) affects ~ 176 million women worldwide and can lead to debilitating pelvic pain. There is an unmet need for new medical treatment options for endometriosis. Pelvic peritoneal mesothelial cells of women with endometriosis exhibit detrimental metabolic reprogramming that creates an environment favouring the formation and survival of endometriosis lesions. We have generated powerful preclinical proof-of-concept data to show that it is possible to correct this metabolic phenotype using dichloroacetate (DCA), a non-hormonal compound previously used to treat rare metabolic disorders in children. We plan a single-arm, open-label, single site exploratory clinical trial to inform the design of a future randomised controlled trial (RCT) to determine the efficacy of DCA for the treatment of endometriosis-associated pain.

Methods

We will recruit 30 women with endometriosis-associated pain over a 6-month period. All participants will receive approximately 6.25 mg/kg oral DCA capsules twice daily for 6 weeks, with a dose increase to approximately 12.5 mg/kg twice daily for a further 6 weeks if their pain has not been adequately controlled on this dose regime and side-effects are acceptable. If pain is adequately controlled with minimal side-effects, the lower dose will be continued for a further 6 weeks. The primary objective is to determine whether it is possible to achieve acceptable recruitment and retention rates within the defined exclusion and inclusion criteria. Secondary objectives are to determine the acceptability of the trial to participants, including the proposed methods of recruitment, treatment, follow-up frequency and number of questionnaires. The recruitment rate will be determined by the proportion of patients recruited from the pool of eligible women. The retention rate will be determined by the proportion of participants who attended the final trial visit.

Discussion

This is a feasibility study to explore effectiveness and acceptability of the proposed field methodology (recruitment, retention, study processes and compliance with treatment). The results will be used to inform the design of a future RCT.

Trial registration

ClinicalTrials.gov, NCT04046081 Registered 6 August 2019
Visual search under physical effort is faster but more vulnerable to distractor interference
Authors: Park Hyung-Bum , Ahn Shinhae , Zhang Weiwei
Published: March 2021

Cognition and action are often intertwined in everyday life. It is thus pivotal to understand how cognitive processes operate with concurrent actions. The present study aims to assess how simple physical effort operationalized as isometric muscle contractions affects visual attention and inhibitory control. In a dual-task paradigm, participants performed a singleton search task and a handgrip task concurrently. In the search task, the target was a shape singleton among distractors with a homogeneous but different shape. A salient-but-irrelevant distractor with a unique color (i.e., color singleton) appeared on half of the trials (Singleton distractor presentcondition), and its presence often captures spatial attention. Critically, the visual search task was performed by the participants with concurrent hand grip exertion, at 5% or 40% of their maximum strength (low vs. high physical load), on a hand dynamometer. We found that visual search under physical effort is faster, but more vulnerable to distractor interference, potentially due to arousal and reduced inhibitory control, respectively. The two effects further manifest in different aspects of RT distributions that can be captured by different components of the ex-Gaussian model using hierarchical Bayesian method. Together, these results provide behavioral evidence and a novel model for two dissociable cognitive mechanisms underlying the effects of simple muscle exertion on the ongoing visual search process on a moment-by-moment basis.
Categorized wetland preference and life forms of the vascular plants in the Korean Peninsula
Authors: Choung Yeonsook , Min Byeong Mee , Lee Kyu Song , Cho Kang-Hyun , Joo Kwang Yeong , Hyun Jin-Oh , Na Hye Ryun , Oh Hyun Kyung , Nam Gi-Heum , Kim Jin-Seok , Cho Soyeon , Lee Jongsung , Jung Sangyeop , Lee Jaeyeon
Published: March 2021

Background

In 2020, a categorized list of wetland preferences, major habitats, and life forms of 4145 vascular plant taxa occurring in the Korean Peninsula was published by the National Institute of Biological Resources. We analyzed the list and explored the distribution patterns of the five categorized groups according to wetland preference, along with the information on the major habitats and the life forms of the plants belonging to those categories.

Results

Out of 4145 taxa, we found that 729 wetland plant taxa (18%) occur in Korea: 401 obligate wetland plants and 328 facultative wetland plants. Among the 729 wetland taxa, the majority (73%) was hygrophytes and the remaining 27% was aquatic macrophytes. Furthermore, almost all of the wetland taxa are herbs; so, woody plants are only 4.7%. The 16 carnivorous taxa distributed in Korea were characterized as obligate wetland plants.

Conclusions

We expect the categorized information would promote understanding of the characteristics of the plant species and would be an important source for understanding, conservation, and restoration of wetland ecosystems.