bluuebunny/crossref_metadata_2025 huggingface dataset:
Safety of house dust mite subcutaneous immunotherapy in preschool children with respiratory allergic diseases
Authors: Yang Yaqi , Ma Dongxia , Huang Nan , Li Wenjing , Jiang Qing , Wang Yin , Wang Xiaolong , Yang Lin , Zhu Rongfei
Published: April 2021

Background

Allergen immunotherapy (AIT) is the only causal therapy for IgE-mediated allergy. There is less evidence about the safety and efficacy of AIT especially subcutaneous immunotherapy (SCIT) in children under 5 years old. We aimed to investigate the side effects and associated risk factors of house dust mite (HDM) SCIT in preschool children with respiratory allergic diseases.

Methods

The preschool children who had HDM-related allergic rhinitis with/without asthma were enrolled and undergone standardized HDM SCIT in our department from June 2013 to December 2019. Local reactions (LRs) and systemic reactions (SRs) were recorded and categorized according to World Allergy Organization recommendations. Demographic data and other therapeutic-related parameters were also recorded to investigate potential risk factors for these side effects.

Results

A total of 91 children (60 boys, 65.93%; 31 girls, 34.07%; mean age 4.13 years old) were included in the study. Among the 91 patients, 3109 SCIT injections were recorded, 62/91 (68.13%) experienced 186 immediate LRs, 4 /91(4.40%) experienced 6 delayed LRs, 11/91 (12.09%) children experienced 44 immediate SRs, 21/44 (47.73%) were grade 1 SRs, 21/44 (47.73%) were grade 2, 2/44 (4.55%) were grade 3, no grade 4 or 5 SRs occurred. Furthermore, 1/91 (1.10%) experienced 1 delayed SRs, manifested by urticaria 2 days later after allergen injection. 9/91 (9.89%) experienced 2 or more times SRs. Multivariable logistic regression analysis showed BMI (OR 1.506; 95%CI 1.091 to 2.079; p < 0.05) and sIgE against HDM (OR 1.497; 95%CI 1.082 to 2.071; p < 0.05) were risk factors for LRs. No variable was found to correlate with SRs (all p > 0.05).

Conclusions

HDM subcutaneous immunotherapy is considered to be safe in preschool children with respiratory allergic diseases. Higher BMI and HDM sIgE level in children are risk factors for developing LRs. The incidence of SRs and the rate of severe SRs are low in preschool children.
Identification of ZBTB18 as a novel colorectal tumor suppressor gene through genome-wide promoter hypermethylation analysis
Authors: Bazzocco Sarah , Dopeso Higinio , Martínez-Barriocanal Águeda , Anguita Estefanía , Nieto Rocío , Li Jing , García-Vidal Elia , Maggio Valentina , Rodrigues Paulo , de Marcondes Priscila Guimarães , Schwartz Simo , Aaltonen Lauri A. , Sánchez Alex , Mariadason John M. , Arango Diego
Published: April 2021

Background

Cancer initiation and progression are driven by genetic and epigenetic changes. Although genome/exome sequencing has significantly contributed to the characterization of the genetic driver alterations, further investigation is required to systematically identify cancer driver genes regulated by promoter hypermethylation.

Results

Using genome-wide analysis of promoter methylation in 45 colorectal cancer cell lines, we found that higher overall methylation levels were associated with microsatellite instability (MSI), faster proliferation and absence of APC mutations. Because epigenetically silenced genes could represent important oncogenic drivers, we used mRNA expression profiling of colorectal cancer cell lines and primary tumors to identify a subset of 382 (3.9%) genes for which promoter methylation was negatively associated with gene expression. Remarkably, a significant enrichment in zinc finger proteins was observed, including the transcriptional repressor ZBTB18. Re-introduction of ZBTB18 in colon cancer cells significantly reduced proliferation in vitro and in a subcutaneous xenograft mouse model. Moreover, immunohistochemical analysis revealed that ZBTB18 is frequently lost or reduced in colorectal tumors, and reduced ZBTB18 expression was found to be associated with lymph node metastasis and shorter survival of patients with locally advanced colorectal cancer.

Conclusions

We identified a set of 382 genes putatively silenced by promoter methylation in colorectal cancer that could significantly contribute to the oncogenic process. Moreover, as a proof of concept, we demonstrate that the epigenetically silenced gene ZBTB18 has tumor suppressor activity and is a novel prognostic marker for patients with locally advanced colorectal cancer.
Nivolumab-induced hypophysitis followed by acute-onset type 1 diabetes with renal cell carcinoma: a case report
Authors: Kikuchi Fumi , Saheki Takanobu , Imachi Hitomi , Kobayashi Toshihiro , Fukunaga Kensaku , Ibata Tomohiro , Sato Seisuke , Ban Natsuki , Lyu Jingya , Japar Salimah , Murao Koji
Published: April 2021

Background

Immune checkpoint inhibitors have recently become widely used for the management of advanced cancer patients. During the development of immune checkpoint inhibitors (ICPIs), it was quickly recognized that they are associated with autoimmune or autoinflammatory side effects. These toxicities are known as immune-related adverse events (irAEs): common endocrine irAEs include hypophysitis and thyroid dysfunction, and uncommon irAEs include type 1 diabetes mellitus (T1DM).

Case presentation

A 62-year-old Japanese man with metastatic renal cell carcinoma was treated with sunitinib followed by the 10th cycle of treatment with the ICPI nivolumab. He had already had thyroiditis and hypophysitis due to these anti-cancer drugs. On admission, he showed an extremely elevated plasma glucose level (601 mg/dl) and a low C-peptide level, and was diagnosed with acute T1DM. The patient was treated with intravenous fluid infusion and continuous insulin infusion. On the second day, he was switched to multiple daily injections of insulin therapy. Since these treatments, his blood glucose levels have been stable and he has been treated with an additional 10 ICPI treatments for renal cell carcinoma for over a year.

Conclusions

Treatment with ICPIs is expected to increase in the future. There may be cases in which their use for cancer treatment is inevitable despite the side effects. As long as treatment with ICPI continues, multiple side effects can be expected in some cases. It is important to carefully observe the side effects that occur during ICPI treatment and to provide appropriate treatment for each side effect.
Effect of a single, oral administration of selenitetriglycerides, at two dose rates, on blood selenium status and haematological and biochemical parameters in Holstein-Friesian calves
Authors: Żarczyńska Katarzyna , Sobiech Przemysław , Tobolski Dawid , Mee John F. , Illek Josef
Published: April 2021

Background

Selenitetriglycerides are biologically active, organic forms of selenium formed as a result of the modification of selenic acid and sunflower oil. Studies in rats have shown that they are well absorbed and of low toxicity. There are no published studies on selenitetriglycerides supplementation in calves.

Results

In this study, selenitetriglycerides were administered once orally on the 2nd day of life at a dose of 0.5 or 1 mg Se/kg body weight to each of six Holstein-Friesian calves while six control calves were not supplemented. Blood for determination of selenium concentration, glutathione peroxidase activity, haematological parameters, aspartate aminotransferase, creatine kinase, and lactate dehydrogenase activities and glucose, total protein, albumin, triglycerides, cholesterol, urea, and creatinine concentration was collected before supplementation (day 0) and 1, 2, 5, 10 and 14 days after supplementation. Selenitetriglycerides administration increased (P < 0.01) serum selenium concentration in supplemented calves as early as day1, from a mean of 63.4 to 184.22 µg/l in calves receiving selenium at a dose of 0.5 mg/kg BW, and from 63.17 to 200.33 µg/l in calves receiving 1 mg/kg. Serum selenium concentrations remained significantly higher compared to the control group throughout the experiment. Glutathione peroxidase activity was higher in supplemented than control calves, significantly so in animals receiving the 1 mg/kg dose of Se on the 10th and 14th days (P < 0.05). There were no significant differences in the haematological and biochemical parameters between the groups.

Conclusions

This experiment showed that supplementation with selenitetriglycerides could significantly improve blood selenium status in calves without adverse effects on haematological or biochemical parameters. These findings are essential prerequisites for future studies on selenitetriglycerides supplementation to manage clinical selenium deficiency in calves.
Cathelicidin antimicrobial peptide (CAMP) gene promoter methylation induces chondrocyte apoptosis
Authors: Wang Guoliang , Li Yanlin , Yang Guang , Yang Tengyun , He Lu , Wang Yang
Published: April 2021

Objective

The occurrence of osteoarthritis is related to genetic and environmental factors. Among them, the change of chondrocyte gene expression pattern regulated by epigenetic modification is an important participant. This study analyzed the effect of CAMP gene methylation on the level of oxidative stress and inflammation of chondrocytes.

Methods

We analyzed the changes of the transcriptome in the articular cartilage tissue of osteoarthritis (OA) patients from the GSE117999 dataset. The GSE48422 dataset was used to analyze the changes in the methylation level of osteoarthritis cells. Cell Counting Kit-8 (CCK-8) and flow cytometry analysis of short hairpin RNA (shRNA) silencing CAMP gene and 5-μM 5-Aza-2’-Deoxycytidine (AZA) treatment on the proliferation and apoptosis of Human chondrocytes osteoarthritis (HC-OA) cells. The Dichloro-dihydro-fluorescein diacetate (DCFH-DA) assay was used to detect the level of reactive oxygen species (ROS), and the expression level of inflammatory factors was analyzed by Western Blot.

Results

The expression of CAMP in cartilage tissue of OA patients was upregulated, and the level of methylation was downregulated. CAMP was highly expressed in osteoarthritis articular cartilage cells. Silencing CAMP inhibited the proliferation of HC-OA cells and promoted their apoptosis. CAMP gene methylation inhibited ROS levels and tumor necrosis factor-α (TNF-α) expression levels in HC-OA cells, and promoted transforming growth factor beta (TGF-β) expression. CAMP gene methylation inhibited the proliferation of HC-OA cells and promoted their apoptosis.

Conclusion

CAMP gene promoter methylation inhibits ROS levels and inflammation and induces chondrocyte apoptosis.
Can adolescents with eating disorders be treated in primary care? A retrospective clinical cohort study
Authors: Lebow Jocelyn , Mattke Angela , Narr Cassandra , Partain Paige , Breland Renee , Gewirtz O’Brien Janna R. , Geske Jennifer , Billings Marcie , Clark Matthew M. , Jacobson Robert M. , Phelan Sean , Harbeck-Weber Cynthia , Le Grange Daniel , Sim Leslie
Published: April 2021

Background

Family-Based Treatment (FBT) is considered the first-line intervention for adolescent anorexia nervosa. However, access to this treatment is limited. Treatment programs for other pediatric mental health conditions have successfully overcome barriers to accessing evidence-based intervention by integrating mental health services into primary care. This study evaluated the proof-of-concept of a novel modification of FBT, Family-Based Treatment for Primary Care (FBT-PC) for adolescent restrictive eating disorders designed for delivery by primary care providers in their practices.

Methods

This retrospective clinical cohort study evaluated 15 adolescents with restrictive eating disorders receiving FBT-PC and 15 adolescents receiving standard FBT. We examined improvement in BMI percentile, reduction in weight suppression, and clinical benchmarks of eating disorder recovery including weight restoration to > 95% of expected body weight (EBW) and resolution of DSM-5 criteria for eating disorders.

Results

In both groups, effect sizes for increased BMI percentile exceeded Cohen’s convention for a large effect (FBT-PC: d = .94; standard FBT: d = 1.15) as did effect sizes for reduction in weight suppression (FBT-PC: d = 1.83; standard FBT: d = 1.21). At the end of treatment, 80% of the FBT-PC cohort and 87% in the standard FBT group achieved > 95%EBW and 67% in the FBT-PC group and 60% in the standard FBT group no longer met DSM-5 criteria for an eating disorder. There were no cohort differences in the number of treatment drop-outs or referrals to a more intensive level of eating disorder treatment.

Conclusions

Findings suggest that primary care providers have potential to improve weight and clinical status in adolescents with restrictive eating disorders. Based on these results, more rigorous testing of the FBT-PC model is warranted.
Analysis of local habitat selection and large-scale attraction/avoidance based on animal tracking data: is there a single best method?
Authors: Mercker Moritz , Schwemmer Philipp , Peschko Verena , Enners Leonie , Garthe Stefan
Published: April 2021

Background

New wildlife telemetry and tracking technologies have become available in the last decade, leading to a large increase in the volume and resolution of animal tracking data. These technical developments have been accompanied by various statistical tools aimed at analysing the data obtained by these methods.

Methods

We used simulated habitat and tracking data to compare some of the different statistical methods frequently used to infer local resource selection and large-scale attraction/avoidance from tracking data. Notably, we compared spatial logistic regression models (SLRMs), spatio-temporal point process models (ST-PPMs), step selection models (SSMs), and integrated step selection models (iSSMs) and their interplay with habitat and animal movement properties in terms of statistical hypothesis testing.

Results

We demonstrated that only iSSMs and ST-PPMs showed nominal type I error rates in all studied cases, whereas SSMs may slightly and SLRMs may frequently and strongly exceed these levels. iSSMs appeared to have on average a more robust and higher statistical power than ST-PPMs.

Conclusions

Based on our results, we recommend the use of iSSMs to infer habitat selection or large-scale attraction/avoidance from animal tracking data. Further advantages over other approaches include short computation times, predictive capacity, and the possibility of deriving mechanistic movement models.
Chronic opioid use following surgery for head and neck cancer patients undergoing free flap reconstruction
Authors: Hinther Ashley , Rasool Alysha , Nakoneshny Steven C. , Chandarana Shamir P. , Hart Robert , Matthews T. Wayne , Dort Joseph C.
Published: April 2021

Background

Physician opioid-prescribing patterns have significant impacts on the current opioid crisis. Patients who use opioids in the postoperative period are at risk of developing chronic postoperative opioid use. This study determined the rate of chronic postoperative opioid use among head and neck cancer patients undergoing primary surgery with free-flap reconstruction. Additionally, this study identified major risk factors associated with the development of chronic postoperative opioid use.

Methods

A retrospective chart review was performed for all adults (age ≥ 18 years) undergoing primary head and neck surgical resection with free-flap reconstruction between January 2008 and December 2015. Patients were identified from a prospectively collected database, Otobase™. Data from the provincial drug insurance program were used to capture drug dispensing information to determine chronic opioid use at 3- and 12-months postoperatively. Data extracted from Otobase™ included patient demographics, social habits, clinical stage, pathological stage, type of surgery, and adjuvant treatment.

Results

The total cohort was comprised of 212 patients. Chronic opioid use at 3- and 12- months postoperatively was observed in 136 (64%) and 116 (55%) patients, respectively. Of the 212 patients, 85 patients (40%) were identified as preoperative opioid users and 127 were opioid naïve (60%). Of the 85 patients who were preoperative opioid users, 70 (82%) and 63 (77%) patients continued to use opioids 3- and 12-months postoperatively, respectively. The proportion of opioid-naïve patients who were using opioids at 3- and 12-months postoperatively was 52% (66 patients) and 42% (53 patients), respectively. Identified risk factors included preoperative opioid use, prior tobacco use, advanced pathologic T-stage, and adjuvant treatment.

Conclusions

Among head and neck cancer patients that have undergone major resection with free-flap reconstruction, the prevalence of chronic postoperative opioid users was considerable. Identified risk factors included preoperative opioid use, prior tobacco use, tumor stage, and adjuvant treatment.

Graphical Abstract
Mild traumatic brain injury induces microvascular injury and accelerates Alzheimer-like pathogenesis in mice
Authors: Wu Yingxi , Wu Haijian , Zeng Jianxiong , Pluimer Brock , Dong Shirley , Xie Xiaochun , Guo Xinying , Ge Tenghuan , Liang Xinyan , Feng Sudi , Yan Youzhen , Chen Jian-Fu , Sta Maria Naomi , Ma Qingyi , Gomez-Pinilla Fernando , Zhao Zhen
Published: April 2021

Introduction

Traumatic brain injury (TBI) is considered as the most robust environmental risk factor for Alzheimer’s disease (AD). Besides direct neuronal injury and neuroinflammation, vascular impairment is also a hallmark event of the pathological cascade after TBI. However, the vascular connection between TBI and subsequent AD pathogenesis remains underexplored.

Methods

In a closed-head mild TBI (mTBI) model in mice with controlled cortical impact, we examined the time courses of microvascular injury, blood–brain barrier (BBB) dysfunction, gliosis and motor function impairment in wild type C57BL/6 mice. We also evaluated the BBB integrity, amyloid pathology as well as cognitive functions after mTBI in the 5xFAD mouse model of AD.

Results

mTBI induced microvascular injury with BBB breakdown, pericyte loss, basement membrane alteration and cerebral blood flow reduction in mice, in which BBB breakdown preceded gliosis. More importantly, mTBI accelerated BBB leakage, amyloid pathology and cognitive impairment in the 5xFAD mice.

Discussion

Our data demonstrated that microvascular injury plays a key role in the pathogenesis of AD after mTBI. Therefore, restoring vascular functions might be beneficial for patients with mTBI, and potentially reduce the risk of developing AD.
Nontraumatic perforation of the small intestine caused by true primary enteroliths associated with radiation enteritis: a case report
Authors: Hirakawa Yusuke , Shigyo Hirona , Katagiri Yuriko , Hashimoto Kazuaki , Katsumoto Mitsuru , Tomoeda Hiroshi , Nakano Masahiko
Published: April 2021

Background

True primary enterolithiasis is an uncommon condition, and nontraumatic perforation of the small intestine (NTPSI) is also an unusual entity. Therefore, NTPSI due to true primary enteroliths is an exceptionally rare complication. Moreover, enterolithiasis and radiation enteritis are also unique combinations. Herein, we present an exceedingly rare case of NTPSI induced by multiple true primary enteroliths associated with radiation enteritis.

Case presentation

A 92-year-old woman with acute abdominal pain was transferred to our hospital because a computed tomography (CT) scan performed by her family doctor revealed free air and fluid collection within her abdomen. Our initial diagnosis was upper gastrointestinal perforation, and we selected nonoperative management (NOM) with adnominal drainage. Although her general condition was stable, jejunal juice was drained continuously. Given that the CT performed 10 days after onset demonstrated perforation of the small intestine and adjacent concretion, we performed an emergency partial resection of the small intestine and jejunostomy. The resected bowel was 1 m in length and had many strictures that contained multiple enteroliths in their proximal lumens. The patient’s postoperative course was uneventful. The enteroliths were composed of deoxycholic acid (DCA). She was diagnosed with peritonitis due to NTPSI derived from multiple true primary enteroliths associated with radiation enteritis, as she had previously undergone hysterectomy and subsequent internal radiation therapy.

Conclusions

Clinicians should consider the rare entity of true primary enteroliths associated with radiation enteritis in NTPSI cases with unknown etiologies.
Laparoscopic transposition for crossing vessels (vascular hitch) in pure extrinsic pelvic-ureteric junction obstruction: a successful case report of a 2-year-old infant with horseshoe kidney
Authors: Ieiri Satoshi , Nagata Kouji
Published: April 2021

Background

Pediatric hydronephrosis induced by pelvic-ureteric junction obstruction (PUJO) is treated by dismembered pyeloplasty (DP) via open and laparoscopic surgery. The etiology of PUJO involves both intrinsic stenosis and extrinsic compression of crossing vessels (CVs). PUJO owing to CVs is also treated by DP, as there is no consensus concerning this vascular condition. We encountered a 2-year-old infant with pure extrinsic PUJO combined with horseshoe kidney who successfully underwent laparoscopic transposition for CVs (vascular hitch).

Case presentation

A 2-year-old boy was prenatally diagnosed with left multicystic dysplastic kidney (MDCK) and right hydronephrosis and received a definitive diagnosis after birth. At 6 months old, renal scintigraphy revealed a non-functioning pattern in the left kidney and an obstructive pattern in the right, showing no response to furosemide loading. The patient also had recurrent urinary tract infection, and his right hydronephrosis gradually worsened. We decided to perform surgery for the right PUJO. Preoperative enhanced computed tomography detected three right renal vessels independently branching from the abdominal aorta. The middle renal vessels were located at the ventral side of the pelvis and coincident with the site of PUJO. These vessels were suspected of being CVs. The patient underwent laparoscopic surgery electively. A 5-mm trocar was inserted at the umbilicus for a 5-mm, 30° rigid scope. Two additional ports were then inserted under laparoscope inspection. The dilated right pelvis and CVs were detected after ascending colon mobilization. To confirm the pathogenesis of PUJO, the CVs were dissected and taped. After taping the CVs, an intraoperative diuretic test was performed using furosemide loading. Peristalsis of the right ureter was recognized, and the extrinsic PUJO owing to the CVs was definitively confirmed. We therefore performed transposition for the CVs (vascular hitch procedure). The CVs were mobilized in the cranial direction and those were wrapped by dilated pelvis. The post-operative course was uneventful. The renal scintigraphy findings improved and showed a favorable response of furosemide loading.

Conclusions

The laparoscopic vascular hitch procedure is minimally invasive and effective for extrinsic PUJO due to CVs. Anastomotic stricture after Anderson and Hynes DP can be prevented by appropriate patient selection.
Multifocal serous retinopathy with pemigatinib therapy for metastatic colon adenocarcinoma
Authors: Alekseev Oleg , Ojuok Effy , Cousins Scott
Published: April 2021

Background

Pemigatinib is an inhibitor of the fibroblast growth factor receptor (FGFR), recently approved for the treatment of cholangiocarcinoma. FGFR retinopathy is a newly recognized entity, with only two other FGFR inhibitors reported to cause serous retinopathy. Herein, we describe the first published report of a multifocal serous retinopathy secondary to pemigatinib.

Case presentation

A 67-year-old male with stage 4A metastatic colon adenocarcinoma undergoing systemic therapy with pemigatinib was found to have developed bilateral multifocal serous retinopathy. Fundus autofluorescence showed corresponding multifocal hypoautofluorescent foci, whereas fluorescein angiography and indocyanine green angiography were unremarkable. Subretinal fluid resolved rapidly after discontinuation of pemigatinib.

Conclusions

Multifocal serous retinopathy appears to be a class effect of FGFR inhibitors. FGFR retinopathy clinically resembles MEK retinopathy—both feature multifocal subretinal fluid, low visual significance, and quick resolution. However, given that FGFR inhibitors have a broader molecular range than MEK inhibitors, further characterization of FGFR retinopathy is necessary to generate management guidelines.
In vitro and in vivo biological control of the green mold using different bacteria in button mushroom cultivation
Authors: Aydoğdu Mehmet , Sülü Serap Melike , Kurbetli İlker , Sülü Görkem
Published: April 2021

Background

Aggressive biotype (Trichoderma aggressivum f. aggressivum) of green mold is one of the main biotic factors limiting button mushroom (Agaricus bisporus) cultivation. Due to issues such as fungicide resistance, cost, and adverse effects, biological control seems to be an applicable management method against the green mold in button mushroom cultivation.

Results

The objective of the study was to assess biological control of green mold in button mushroom cultivation. Five native bacterial isolates from mushroom compost and 3 commercial biological preparations were tested against two isolates of T. aggressivum f. aggressivum. Dual culture tests were used in vitro experiments. In vivo, compost and casing soil experiments were conducted by comparing yield values of treated plots with negative and positive controls. In vitro, the bacterial isolates inhibited mycelial growth of isolates of T. aggressivum f. aggressivum and A. bisporus up to 46.60 and 56.94%, respectively. In vivo, in the compost experiment, compared with positive control plots, bacterial isolate MSG-5 (Bacillus subtilis) caused the highest yield increase (40.56%) in the treatments. In the casing soil experiment, commercial biological preparation Tic-3 (Ampelomyces quisqualis) caused the highest yield increase (36.15%) in the treated plots. Compared with positive and negative controls, all the treatments caused 30.23% increase but 4.86% decrease in yield of A. bisporus in the compost experiment, respectively. However, they caused 20.25% increase but 17.33% decrease in the yield of A. bisporus in the casing soil experiment, respectively.

Conclusions

Results suggested that biological control of the green mold in compost can be more efficient than casing soil in button mushroom cultivation.
Optimizing Implementation in Cancer Control (OPTICC): protocol for an implementation science center
Authors:   OPTICC Consortium, represented by Bryan J. Weiner, Lewis Cara C. , Hannon Peggy A. , Klasnja Predrag , Baldwin Laura-Mae , Hawkes Rene , Blackmer Janell , Johnson Ashley
Published: April 2021

Background

Evidence-based interventions (EBIs) could reduce cervical cancer deaths by 90%, colorectal cancer deaths by 70%, and lung cancer deaths by 95% if widely and effectively implemented in the USA. Yet, EBI implementation, when it occurs, is often suboptimal. This manuscript outlines the protocol for Optimizing Implementation in Cancer Control (OPTICC), a new implementation science center funded as part of the National Cancer Institute Implementation Science Consortium. OPTICC is designed to address three aims. Aim 1 is to develop a research program that supports developing, testing, and refining of innovative, efficient methods for optimizing EBI implementation in cancer control. Aim 2 is to support a diverse implementation laboratory of clinical and community partners to conduct rapid, implementation studies anywhere along the cancer care continuum for a wide range of cancers. Aim 3 is to build implementation science capacity in cancer control by training new investigators, engaging established investigators in cancer-focused implementation science, and contributing to the Implementation Science Consortium in Cancer.

Methods

Three cores serve as OPTICC’s foundation. The Administrative Core plans coordinates and evaluates the Center’s activities and leads its capacity-building efforts. The Implementation Laboratory Core (I-Lab) coordinates a network of diverse clinical and community sites, wherein studies are conducted to optimize EBI implementation, implement cancer control EBIs, and shape the Center’s agenda. The Research Program Core conducts innovative implementation studies, measurement and methods studies, and pilot studies that advance the Center’s theme. A three-stage approach to optimizing EBI implementation is taken—(I) identify and prioritize determinants, (II) match strategies, and (III) optimize strategies—that is informed by a transdisciplinary team of experts leveraging multiphase optimization strategies and criteria, user-centered design, and agile science.

Discussion

OPTICC will develop, test, and refine efficient and economical methods for optimizing EBI implementation by building implementation science capacity in cancer researchers through applications with our I-Lab partners. Once refined, OPTICC will disseminate its methods as toolkits accompanied by massive open online courses, and an interactive website, the latter of which seeks to simultaneously accumulate knowledge across OPTICC studies.
Current status and challenges in drug discovery against the globally important zoonotic cryptosporidiosis
Authors: Zhu Guan , Yin Jigang , Cuny Gregory D.
Published: April 2021

The zoonotic cryptosporidiosis is globally distributed, one of the major diarrheal diseases in humans and animals. Cryptosporidium oocysts are also one of the major environmental concerns, making it a pathogen that fits well into the One Health concept. Despite its importance, fully effective drugs are not yet available. Anti-cryptosporidial drug discovery has historically faced many unusual challenges attributed to unique parasite biology and technical burdens. While significant progresses have been made recently, anti-cryptosporidial drug discovery still faces a major obstacle: identification of systemic drugs that can be absorbed by patients experiencing watery diarrhea and effectively pass through electron-dense (ED) band at the parasite-host cell interface to act on the epicellular parasite. There may be a need to develop an in vitro assay to effectively screen hits/leads for their capability to cross ED band. In the meantime, non-systemic drugs with strong mucoadhesive properties for extended gastrointestinal exposure may represent another direction in developing anti-cryptosporidial therapeutics. For developing both systemic and non-systemic drugs, a non-ruminant animal model exhibiting diarrheal symptoms suitable for routine evaluation of drug absorption and anti-cryptosporidial efficacy may be very helpful.
Strategies for preventing occupational stress in healthcare workers: past evidence, current problems
Authors: De Giorgi Riccardo , Dinkelaar Bianca M.
Published: April 2021

The problem of occupational stress in healthcare workers is hardly new, but effective interventions in this area are lacking despite being sorely needed – especially in the ongoing COVID-19 pandemic. The results of a Cochrane review suggest that cognitive–behavioural therapy and mental and physical relaxation reduce stress more than no intervention but not more than alternative interventions, and that changing work schedules may lead to a reduction of stress. Other organisational interventions showed no effect on stress levels. However, the evidence is of low quality owing to risk of bias and lack of precision. This commentary critically appraises the review and attempts to put its findings into the current real-world context.
Genetic interactions with stressful environments in depression and addiction
Authors: Burmeister Margit , Sen Srijan
Published: April 2021

Stress is the most important proximal precipitant of depression, yet most large genome-wide association studies (GWAS) do not include stress as a variable. Here, we review how gene × environment (G × E) interaction might impede the discovery of genetic factors, discuss two examples of G × E interaction in depression and addiction, studies incorporating high-stress environments, as well as upcoming waves of genome-wide environment interaction studies (GWEIS). We discuss recent studies which have shown that genetic distributions can be affected by social factors such as migrations and socioeconomic background. These distinctions are not just academic but have practical consequences. Owing to interaction with the environment, genetic predispositions to depression should not be viewed as unmodifiable destiny. Patients may genetically differ not just in their response to drugs, as in the now well-recognised field of pharmacogenetics, but also in how they react to stressful environments and how they are affected by behavioural therapies.
Investigating smoking and nicotine dependence among people with severe mental illness during the COVID-19 pandemic: analysis of linked data from a UK Closing the Gap cohort
Authors: Peckham Emily , Allgar Victoria , Crosland Suzanne , Heron Paul , Johnston Gordon , Newbronner Elizabeth , Ratschen Elena , Spanakis Panagiotis , Wadman Ruth , Walker Lauren , Gilbody Simon
Published: April 2021

Smoking rates are higher for people who use mental health services, which contributes substantially to health inequalities. Smoking can lead to worse COVID-19 outcomes, yet it remains unclear whether smoking has changed for people who use mental health services. We examined smoking patterns in a large clinical cohort of people with severe mental illness, before and during the pandemic. We found high levels of nicotine dependence and heavier patterns of smoking. Although some people had reported quitting, it is likely that smoking inequalities have become further entrenched. Mental health services should seek to mitigate this modifiable risk and source of poor health.
Building External Control Arms From Patient-Level Electronic Health Record Data to Replicate the Randomized IMblaze370 Control Arm in Metastatic Colorectal Cancer
Authors: Schröder Carsten , Lawrance Marcus , Li Chen , Lenain Christelle , Mhatre Shivani K. , Fakih Marwan , Reyes-Rivera Irmarie , Bretscher Michael T.
Published: April 2021

PURPOSE

External control (EC) arms derived from electronic health records (EHRs) can provide appropriate comparison groups when randomized control arms are not feasible, but have not been explored for metastatic colorectal cancer (mCRC) trials. We constructed EC arms from two patient-level EHR-derived databases and evaluated them against the control arm from a phase III, randomized controlled mCRC trial.

METHODS

IMblaze370 evaluated atezolizumab with or without cobimetinib versus regorafenib in patients with mCRC. EC arms were constructed from the Flatiron Health (FH) EHR-derived de-identified database and the combined FH/Foundation Medicine Clinico-Genomic Database (CGDB). IMblaze370 eligibility criteria were applied to the EC cohorts. Propensity scores and standardized mortality ratio weighting were used to balance baseline characteristics between the IMblaze370 and EC arms; balance was assessed using standardized mean differences. Kaplan-Meier method estimated median overall survival (OS). Cox proportional hazards models estimated hazard ratios with bootstrapped 95% CIs to compare differences in OS between study arms.

RESULTS

The FH EC included 184 patients; the CGDB EC included 108 patients. Most characteristics were well-balanced (standardized mean difference < 0.1) between each EC arm and the IMblaze370 population. Median OS was similar between the IMblaze370 control arm (8.5 months [95% CI, 6.41 to 10.71]) and both EC arms: FH (8.5 months [6.93 to 9.92]) and CGDB (8.8 months [7.85 to 9.92]). OS comparisons between the IMblaze370 experimental arm and the FH EC (hazard ratio, 0.85 [0.64 to 1.14]) and CGDB EC (0.86 [0.65 to 1.18]) yielded similar results as the comparison with the IMblaze370 control arm (1.01 [0.75 to 1.37]).

CONCLUSION

EC arms constructed from the FH database and the CGDB closely replicated the control arm from IMblaze370. EHR-derived EC arms can provide meaningful comparators in mCRC trials when recruiting a randomized control arm is not feasible.
Advancing Breast Cancer Advocacy in Eastern Europe and Central Asia: Findings From Women’s Empowerment Cancer Advocacy Network (WE CAN) Summits
Authors: Antone Nicoleta , Kizub Darya , Gralow Julie , Zujewski Jo Anne , Dvaladze Allison
Published: April 2021

PURPOSE

Breast cancer civil society organizations have emerged in Eastern Europe and Central Asia to raise awareness about cancer as a survivable disease and provide patient support. We explored the experiences and priorities of these organizations with the goal of making recommendations to advance cancer advocacy and improve cancer care.

METHODS

We conducted in-depth interviews and focus group discussions with representatives of civil society organizations attending the 7th Women’s Empowerment Cancer Advocacy Network Summit in Romania in 2015. Interviews were audiorecorded, transcribed, coded, and analyzed for key themes. Findings were discussed at the 8th Women’s Empowerment Cancer Advocacy Network Summit in Ukraine in 2017 to ensure accuracy.

RESULTS

We conducted nine in-depth interviews and three focus group discussions with a total of 36 participants. Survivor- and oncologist-led organizations played an important role in filling existing gaps in public health care systems through awareness raising, patient support, and advocacy to improve early detection and access to treatment. Barriers to these efforts included persistent stigma, mistrust of patients toward the public health care system, limited access to evidence-based guidelines, difficulty adapting existing best practices to their setting, and insufficient involvement of policymakers. Key facilitators of advocacy efforts included effective local and international partnerships with physicians, like-minded organizations, and policymakers to facilitate access to educational resources, improve breast cancer early detection and care, and catalyze meaningful policy change.

CONCLUSION

Our findings highlight the value of providing opportunities for advocates to connect and share experiences. To advance cancer advocacy and improve cancer care, the following needs were identified: dissemination of resource-adapted information for improving outcomes; needs assessments; improved program-monitoring practices; and fostering and promotion of collaboration between advocates, medical professionals, and local governments.
Efficacy of an Online Curriculum for Perioperative Goals of Care and Code Status Discussions: A Randomized Controlled Trial
Authors: Robertson Amy C. , Fowler Leslie C. , Kimball Thomas S. , Niconchuk Jonathan A. , Kreger Michael T. , Brovman Ethan Y. , Rickerson Elizabeth , Sadovnikoff Nicholas , Hepner David L. , McEvoy Matthew D. , Bader Angela M. , Urman Richard D.
Published: April 2021

BACKGROUND:

Preoperative goals of care (GOC) and code status (CS) discussions are important in achieving an in-depth understanding of the patient’s care goals in the setting of a serious illness, enabling the clinician to ensure patient autonomy and shared decision making. Past studies have shown that anesthesiologists are not formally trained in leading these discussions and may lack the necessary skill set. We created an innovative online video curriculum designed to teach these skills. This curriculum was compared to a traditional method of learning from reading the medical literature.

METHODS:

In this bi-institutional randomized controlled trial at 2 major academic medical centers, 60 anesthesiology trainees were randomized to receive the educational content in 1 of 2 formats: (1) the novel video curriculum (video group) or (2) journal articles (reading group). Thirty residents were assigned to the experimental video curriculum group, and 30 were assigned to the reading group. The content incorporated into the 2 formats focused on general preoperative evaluation of patients and communication strategies pertaining to GOC and CS discussions. Residents in both groups underwent a pre- and postintervention objective structured clinical examination (OSCE) with standardized patients. Both OSCEs were scored using the same 24-point rubric. Score changes between the 2 OSCEs were examined using linear regression, and interrater reliability was assessed using weighted Cohen’s kappa.

RESULTS:

Residents receiving the video curriculum performed significantly better overall on the OSCE encounter, with a mean score of 4.19 compared to 3.79 in the reading group. The video curriculum group also demonstrated statistically significant increased scores on 8 of 24 rubric categories when compared to the reading group.

CONCLUSIONS:

Our novel video curriculum led to significant increases in resident performance during simulated GOC discussions and modest increases during CS discussions. Further development and refinement of this curriculum are warranted.
Differential expression of a muscle actin gene in muscle cell lineages of ascidian embryos
Authors: Tomlinson Craig R. , Beach Rebecca L. , Jeffery William R.
Published: April 2021

Specific probes were used to examine the accumulation of muscle actin mRNA during embryonic development of the ascidian Styela. Clones of a muscle actin gene were obtained from an adult mantle cDNA library. Four lines of evidence indicate that these clones correspond to a muscle actin gene. First, their coding regions share 11 of 14 diagnostic amino acid positions with mammalian smooth and skeletal muscle actins. Second, subclones that contain only the 3’ noncoding region of the gene select mRNA coding for muscle actin, while subclones that include the coding region of the gene select mRNA coding for muscle and nonmuscle actins. Third, a probe that contains only the 3’ noncoding region detects a single band, corresponding to a 2 kb transcript, while a probe that includes the coding region detects the 2 kb transcript and at least one other band, presumably a cytoplasmic actin transcript. Fourth, the 3’ noncoding region probe detects transcripts only in muscle cells and their precursors, while the coding region probe detects transcripts in muscle and nonmuscle cells. The muscle actin transcript is present at very low levels in eggs and early embryos, begins to accumulate between the early gastrula and tailbud stages, and by the tadpole stage attains a level about 25-fold higher than in the egg. In situ hybridization showed that embryonic muscle actin transcripts are restricted to the muscle cell lineages. These transcripts were initially observed in primary muscle lineage cells (descendants of the B4.1 blastomeres) at the early gastrula stage and continued to be present in these cells throughout embryonic development. In contrast, muscle actin transcripts did not appear in secondary muscle lineage cells (descendants of b4.2 and A4.1 blastomeres) until the mid-tailbud stage, and were not detected in mesenchyme cells, the presumptive adult muscle cell precursors, at any time during embryonic development. The results suggest that muscle actin gene expression is subject to spatial and temporal regulation in the muscle cell lineages.
Differential accumulation of oocyte nuclear proteins by embryonic nuclei ofXenopus
Authors: Dreyer Christine
Published: April 2021

Oocyte nuclear proteins of Xenopus are distributed into the cytoplasm of the maturing egg after germinal vesicle breakdown. Later they are found in all cell nuclei of the embryo. At early stages of development, different nuclear proteins behave differently. A class of’early shifting’ antigens is accumulated by pronuclei and cleavage nuclei, whereas others appear to be excluded from the nuclei at early stages but are shifted into the nuclei at blastula or during and after gastrulation. Accumulation of ‘late-shifting’ nuclear antigens is a gradual process and occurs during a period characteristic of each protein. Multiple artificial pronuclei can be formed after injection of sperm nuclei, erythrocyte nuclei or pure λ-DNA into unfertilized eggs. The artificial pronuclei accumulate early-but not late-shifting proteins. Early-migrating proteins rapidly accumulate into the germinal vesicle after de novo synthesis in the oocyte, indicating that the efficiency of translocation into nuclei is an intrinsic property of each protein. Artificial extension of the length of the cell cycle before midblastula transition does not lead to accumulation of the late-shifting nuclear antigens investigated.

Abbreviations: mAB: monoclonal antibody; GV: germinal vesicle; DAPI: 4’,6-diamidino-2-phenyl-indol-dihydro-chloride; FITC: fluoresceinisothiocyanate; TCA: trichloroacetic acid; MBS-H: modified Barth’s solution.
Abnormally high variability in the uncrossed retinofugal pathway of mice with albino mosaicism
Authors: Jeffery R. W. , Jeffery Glen , Cattanach B. M.
Published: April 2021

Female mice showing albino mosaicism due to an X-autosome translocation [Is(In7;X)Ct] have been studied in order to investigate the relationship between the distribution of melanin and the formation, early in development, of the abnormally small uncrossed retinofugal pathway characteristically found in all albino mammals. Earlier evidence indicates that cells normally bearing melanin play a role in producing the abnormality. In the mosaic mice, the albino gene is expressed in only about half of the cells due to random X-inactivation apd the patches of normal and albino cells are extremely small relative to total retinal size (<l/50). We argued that if all the cells that would normally bear melanin play a role in producing the albino abnormality then the mosaic mice would have a pathway abnormality, about half the size of that in the albino mice. If, however, only a small patch of these cells plays a role, as has been proposed in earlier studies, then one would expect the size of the uncrossed pathway to be highly variable in the mosaic mice.

The size of the uncrossed pathway was assessed by placing horseradish peroxidase in the region of the optic tract and lateral geniculate nucleus unilaterally and then counting the number of retrogradely labelled retinal ganglion cells on the same side. The mosaic mice showed a highly variable uncrossed pathway. In some of the mosaic mice, it was the same size as in the albinos and, in others, it was the same size as in normally pigmented mice. Surprisingly, in a small number of mosaic mice, the uncrossed pathway was larger than normal. Whether this relatively rare occurrence of a supernormal uncrossed pathway is due to the higher gene dosage or to the translocation itself remains an open question.
Nuclear cytoplasmic interactions following nuclear transplantation in mouse embryos
Authors: Howlett Sarah K. , Barton Sheila C. , Surani M. Azim
Published: April 2021

We have investigated the development of reconstituted embryos in which enucleated 1- or 2-cell embryos received various advanced nuclei. Enucleated 1-cells developed to the blastocyst stage only when an early 2cell donor nucleus was transferred but very rarely if the donor nucleus was derived from a late 2-cell, early 4-cell or mid 8-cell embryo. Although an 8-cell nucleus could only support development of an enucleated zygote to the 2-cell stage, it did express the hsp 68/70 × 103Mr proteins that are characteristic of the first embryonic gene activity. These polypeptides were absent in enucleated zygotes that did not receive a donor nucleus. Moreover, an 8-cell nucleus transferred to an enucleated late 2-cell blastomere could also support preimplantation development provided that the nuclear: cytoplasmic ratio was maintained as in intact 2-cell blastomeres. 8-cell nuclei transferred to zygotes that retained at least one pronucleus were able to support development to the blastocyst stage provided that the pronucleus was both fully transcriptionally active and present beyond the late 1-cell stage. This study suggests an active and continued helper role of the resident pronucleus for the participation by an 8-cell nucleus in reconstituted eggs.