Coarctation of the aorta (CoA ) is a well-known congenital heart disease (CHD) , which is often associated with several other cardiac and vascular anomalies, such as bicuspid aortic valve (BAV) and ventricular septal defect. BAV is the most common CHD whereas Pacman heart (incomplete muscular ventricular septal defect) is rare congenital deformity. We found a coexistence of Pacman heart, CoA and BAV in a 21- year- old male patient presenting with headache and high blood preesure. This extremely rare combination of these three congenital cardiac abnormalities occurring in the same patient has not been reported yet.

Alpine grasslands are sensitive to grazing and atmospheric deposition of nitrogen (N). With the increase of N deposition, experimental investigations of the effects of grazing on alpine grassland vegetation with the background of N deposition are scarce. In this study, we examined the effects of overgrazing and overgrazing with N deposition on eco-physiologies of alpine grassland plants at the functional group level. We found that both overgrazing and overgrazing with N deposition obviously changed species composition and the dominance of three plant functional groups (PFGs) in alpine meadow and alpine steppe. Under overgrazing and overgrazing with N deposition treatment, forb tended to be predominant in the whole plant community, while grass and sedge dominance was obviously decreased. In addition, we found that the underlying eco-physiological processes that lead to forb-dominant were different under overgrazing and overgrazing with N deposition. Overgrazing with N deposition obviously tended to increase forb dominance both directly by selective herbivory and indirectly by enhancing forb photosynthetic capacity. Our results suggested that long-term overgrazing with N deposition will lead to a more favorable living environment for forbs, making the grassland community of alpine grasslands on the Qinghai-Tibetan Plateau likely shift to forb-dominant in the future.

Rice blast disease caused by the filamentous Ascomycetous fungus Magnaporthe oryzae is a major threat to rice production worldwide. The mechanisms underlying rice resistance to M. oryzae, such as transcriptional reprogramming and signaling networks, remain elusive. In this study, we carried out an in-depth comparative transcriptome study on the susceptible and resistant rice cultivar in response to M. oryzae. Our analysis highlighted that a rapid, high-amplitude transcriptional reprogramming was important for rice defense against blast fungus. The ribosome- and protein translation-related genes were significantly enriched in differentially expressed genes (DEGs) at 12 hpi in both cultivars, indicating that the protein translation machinery is regulated in the activation of immunity in rice. Furthermore, we identified a core set of genes that are involved in the rice response to biotic as well as to abiotic stress. More importantly, among the core genes, we demonstrated that the metallothionein OsMT1a and OsMT1b genes positively while a peroxidase gene Perox4 negatively regulated rice resistance to M. oryzae. Our study provides novel insight into transcriptional reprogramming and a valuable resource for functional studies on rice immune signaling components in resistance to blast disease.

Lesion mimic mutants are used to elucidate mechanisms controlling plant responses to pathogen attacks and environmental stresses. Here, a new rice (Oryza sativa) lesion mimic mutant, natural blight leaf 3 (nbl3), was identified from T-DNA insertion lines. The causative gene, OsNBL3, encodes a mitochondria-localized pentatricopeptide repeat (PPR) protein. The nbl3 mutant exhibited spontaneous cell death and H2O2 accumulation as evidenced by Trypan blue, 3,3’-diaminobenzidine and tetranitroblue tetrazolium chloride analyses. Additionally, nbl3 displayed enhanced resistance to the fungal and bacterial pathogens Magnaporthe oryzae and Xanthomonas oryzae pv. oryzae. This resistance was consistent with the upregulation of several defence-related genes; thus defence responses were induced in nbl3. RNA interference lines of OsNBL3 exhibited enhanced disease resistance similar to that of nbl3, while the disease resistance of overexpression lines did not differ from that of the wild type. In addition, nbl3 displayed improved tolerance to salt treatment, accompanied by upregulation of several salt-associated marker genes. Disruption of OsNBL3 leads to destruction of mitochondria and elevated use of alternative respiratory pathways. OsNBL3 was found to mainly participate in the splicing of mitochondrial gene nad5 intron 4. Overall, the results demonstrated that a PPR protein was involved in disease resistance and salt tolerance in rice.

Introduction and objectives The advantages of sedation in patients undergoing transesophageal echocardiography (TEE) are well established, but the increasing number of TEE studies may limit the capacity of Anesthesiology services. In this study we analyze the effectiveness and safety of a moderate sedation program carried out by non-anesthesiologist professionals (NAP). Methods Descriptive and prospective study that included all consecutive patients undergoing a TEE procedure under moderate sedation by NAP and by anesthesiologists (AP) from September 2018 to September 2019. Patients were selected according to a specific algorithm agreed upon with the Anesthesiology department. We analyze current indications for TEE, complication rates, and recovery times associated with sedation. Results We performed 267 procedures in 252 patients (54% male, 69yo). Main indications were screening or monitoring of surgical and percutaneous cardiac interventions (47.9%), endocarditis (28.5%) and stroke (20.6%). Patients in the NAP group were younger (59 vs 71 yo), less hypertensive (43% vs 61%), with less lung disease (4% vs 24%), lower risk of difficult airway (1% vs 22%) and lower comorbidity (ASA scale ≥III 13% vs 77%). Complications were more frequent in the AP group (26% vs 9%), mainly mild respiratory (19% vs 9%). Multivariate adjustment showed events were associated with the presence of lung disease and higher ASA degree. Recovery time was longer in the AP sedation group (20min vs 15min). Conclusions TEE indications are changing and involve larger and more complex studies. Moderate sedation with propofol performed by NAP is safe in selected patients, with adequate recovery times.

Letter to the Editor, BJOG Exchange

In general, it is accepted that gap formation significantly affects the placement of scatter-hoarded seeds by small rodents, but the effects of different forest gap sizes on the seed-eating and scatter-hoarding behaviors of small rodents remain unclear. Thus, we examined the effects of a closed canopy forest, forest edge, and gaps with different sizes on the spatial dispersal of Quercus variabilis acorns and cache placement by small rodents using coded plastic tags in the Taihang Mountains, China. The seeds were removed rapidly and there were significant differences in the seed-eating and caching strategies between the stand types. We found that Q. variabilis acorns were usually eaten after being removed from the closed canopy forest and forest edges. By contrast, the Q. variabilis acorns in the forest gap stands were more likely to be scatter hoarded. The dispersal distances of Q. variabilis acorns were significantly longer in the forest gap plots compared with the closed canopy and forest edge plots. However, the proportions of scatter-hoarded seeds did not increase significantly as the gap size increased. In small-scale oak reforestation projects or research, creating small gaps to promote rodent-mediated seed dispersal may effectively accelerate forest recovery and successional processes.

The ascending aorta and arch have until recently been one of the last bastions of cardiovascular surgery, where life-threatening diseases impose the need for prompt correction and reversal of the impending adverse prognosis. Though a disease where dogmatic recommendations prevail, with upfront surgical intervention in the mind of every physician, type A acute aortic dissection (AAD) is a subject still blurred by many uncertainties. Endovascular intervention for the treatment of type A AAD are rapidly progressing and utilization of transcatheter therapies in the ascending aorta for treating type A AAD has demonstrated technical success in small studies, low early mortality rates, and relatively acceptable aorta-related mortality rates in the long-term. These findings strengthen the preponderant role of the endovascular heart surgeon on the management of these procedures, where a combination of wire skill training and surgical proficiency encompassing all technical options available makes it distinctive and resourceful, able to provide complete resolution to each multicomponent of this disease in one setting, besides the promptness to repair the inherent complications that are to accompany these interventions. Transcatheter procedures and open surgery are to coexist side by side and to be regarded as complementary rather than competing. Substantial more refinement and technological innovation will be necessary before endovascular repair of type A AAD comes to widespread use, the ideal timespan for cardiovascular surgeons to be involved, and prepared to take on the challenges of leading this new enterprise.

fifty years old woman with dyspnea of exertion, rupture of sinus Valsalva to right atrium and patent foramen oval in echocardiography referred to our hospital. After device closure of the rupture, she developed orthostatic hypoxemia. Invasive intra-cardiac evaluation confirmed the diagnosis of Platypnea-Orthodeoxia Syndrome which was closed with device

Compliment activation has been implicated in Delayed Hemolytic Transfusion Reaction (DHTR) in patients with sickle cell disease, and eculizumab has been reported as an effective treatment for patients with DHTR. Previously reported patients with SCD and DHTR responded well after few doses of eculizumab. We report on the long-term use of eculizumab in a pediatric sickle cell patient with DHTR who had a slow and less sustained response. Long-term use of eculizumab in this SCD patient was effective and well tolerated.

Poor adherence to 6-mercaptopurine during acute lymphoblastic leukemia (ALL) therapy increases relapse risk. Clinically-significant non-adherence has been documented in up to 30% of children treated for ALL on Children’s Oncology Group trials. Whether non-adherence rates vary across regimens with different chemotherapy schedules and modes of administration is not known. In a cross-sectional survey study of N= 61 children treated on, or as per Dana-Farber Cancer Institute (DFCI) ALL Consortium Protocol 11-001, 25% (95% CI 14 – 37%) of respondents self-reported non-adherence to 6MP, suggesting that the frequency of non-adherence may be similar across different Consortia regimens.

DNA-based techniques are increasingly used to assess biodiversity both above- and belowground. Most effort has focussed on bioinformatics and sample collection, whereas less is known about the consequences of mixing collected environmental DNA (eDNA), post-extraction and pre-PCR. We applied varying degrees of pooling to stand-alone eDNA samples collected across a non-native plant invasion density gradient, and compared the fungal communities of pooled and unpooled samples. Pooling soil eDNA decreased observable fungal rarefied richness in our samples, led to phylum-specific shifts in proportional abundance, and increased the sensitivity of detection for the invasive plant’s overall impact on fungal diversity. We demonstrate that pooling fungal eDNA could change the outcome of similar eDNA studies where the aim is to: 1) identify the rare biosphere within a soil community, 2) estimate species richness and proportional abundance, or 3) assess the impact of an invasive plant on soil fungi. Sample pooling might be appropriate when determining larger-scale overarching responses of soil communities, as pooling increased the sensitivity of measurable effects of an invasive plant on soil fungal diversity.

Background: We have previously reported that more than half of the patients who achieved desensitization after wheat rush oral immunotherapy (OIT) developed exercise-induced allergic reaction on desensitization (EIARD). However, data on EIARDs after slow OIT are lacking. Therefore, this study aimed to investigate the results of exercise provocation tests (EPTs) in patients after slow OIT for cow’s milk and wheat allergies. Methods: This was a retrospective chart review of 87 EPTs in 74 patients. The EPTs were performed in patients who were desensitized to at least 6,600 mg cow’s milk protein or 5,200 mg wheat protein with slow OIT and were identified to be at a high risk of EIARDs. EPTs were performed after ingestion of the maximum desensitization dose. The patients’ clinical characteristics and symptoms were analyzed. Results: The EPT results were positive for cow’s milk in 49% (21/43) of the patients and for wheat in 48% (15/31) of the patients. There was no significant difference in the clinical characteristics between the EIARD-positive and EIARD-negative groups. The specific IgE (sIgE) levels before OIT and the reduction rates of sIgE before and after OIT did not correlate with the outcomes of the EPTs. Among the EIARD-positive patients, 13 patients (cow’s milk, n=7; wheat, n=6) underwent a second EPT, and the EIARD disappeared in 8 patients (cow’s milk, n=4; wheat, n=4). Conclusion: EIARDs were observed after slow OIT for cow’s milk and wheat. Further research into the predictive factors of EIARDs in these patients is needed to understand its clinical manifestations.

Previous history of immediate reactions changes predictive accuracy for pediatric peanut allergyNaoko Fusayasua, MD, Tomoyuki Asaumia, MD, Kyohei Takahashia,b, MD, Ken-ichi Nagakuraa,c , MD, PhD, Makoto Nishinoa,b, MD, Sakura Satob,d, MD, Noriyuki Yanagidaa,d, MD, Motohiro Ebisawad, MD, PhD,aDepartment of Pediatrics, National Hospital Organization Sagamihara National Hospital, Kanagawa, JapanbCourse of Allergy and Clinical Immunology, Juntendo University Graduate School of Medicine, Tokyo, JapancDepartment of Pediatrics, Jikei University School of Medicine, Tokyo, JapandDepartment of Allergy, Clinical Research Center for Allergy and Rheumatology, National Hospital Organization Sagamihara National Hospital, Kanagawa, Japan

Background: The role of Cardiopulmonary Exercise Testing (CPET) in the assessment of prognosis in CF is crucial. However, as the overall survival of the disease becomes better, the need for examinations that can predict pulmonary exacerbations (PEx) and subsequent deterioration becomes evident. Aim: To evaluate whether CPET derived parameters can be used as prognostic indexes for pulmonary exacerbations in patients with CF. Methods: Data from a 10-year follow up with CPET and spirometry of CF patients were used to perform our analyses. Pulmonary exacerbations were recorded. We used a survival analysis through Cox Regression to assess the prognostic role of CPET parameters for PeX. CPET parameters and other variables such as sputum culture, age, and spirometry measurements were tested via multivariate cox models. Results: During a 10-year period (2009-2019) 78 CF patients underwent CPET. Cox regression analysis revealed that VO2peak% predicted (Hazard ratio (HR), 0.988 (0.975, 1.000) p=0.042), PetCO2 ( End-tidal CO2 at peak exercise) (HR 0.948 (0.913, 0.984) p=0.005), VE/VO2, (respiratory equivalent for oxygen at peak exercise) (HR 1.032 (1.003, 1.062) p=0.033 were significant predictors of pulmonary exacerbations in the short term after the CPET. Additionally, patients with VO2peak% predicted <60% had 4,5 times higher relative risk of having a PEx than those with higher exercise capacity. Conclusions: CPET can provide valuable information regarding upcoming pulmonary exacerbation in CF. Patients with VO2peak <60% are at great risk of subsequent deterioration. Regular follow up of CF patients with Exercise Testing can highlight their clinical image and direct therapeutic interventions.

A recent review on optimal strategies for preserving biodiversity within human-modified landscapes suggests that that forest cover needs to be restored or maintained to at least 40%. While we agree that it is paramount to protect and increase cover in forested biomes, no evidence is presented to support this 40% threshold. Furthermore, there are several issues regarding implementation of such policy or social-economic constraints that makes this suggestion unhelpful and potentially dangerous.

Background: The levonorgestrel intrauterine systems (LNG-IUS) is widely used, but few studies report incidence rates of side-effects of LNG-IUS. Objectives: The purpose of this study was to investigate short term side effects of LNG-IUS and to compare the side effects at different dosages of LNG-IUS’s. Search strategy: We searched electronic databases (MEDLINE, Embase, Cochrane) for RCT’s and observational studies between January 1970 and April 2019 published in English. Selection criteria: Studies including women seeking contraception and receiving a LNG-IUS, compared to either women without hormonal contraception or a different dosage of a LNG-IUS. Data Collection and analysis: We evaluated randomized controlled trials with the Cochrane Risk of Bias tool and observational studies with ROBINS-I. For outcomes with data from at least two studies, meta-analysis was conducted using RevMan (version 5.3). The quality of evidence was assessed using the GRADE. Main results: We found an increase in risk of nervousness, depression, ovarian cysts and of amenorrhea. One study compared two different LNG-IUSs and found a decreased risk of developing ovarian cysts and an uncertain risk of ectopic pregnancies and mood swings in low dose LNG-IUS. Conclusions: We found that LNG-IUS increases risk of nervousness, depression, ovarian cysts and amenorrhea but the quality of evidence was low and the absolute risk small. Low-dosage LNG-IUS decreases the risk of ovarian cysts compared to high dose. To achieve higher quality of evidence, further studies are needed. Funding: No funding was received for this study. Keywords: LNG-IUS, LNG-IUD, side-effects, ovarian cysts, amenorrhea, depression, ectopic pregnancies

Purpose: Diffuse mega-aorta is challenging. Prior studies have raised concerns regarding the safety of the open two-stage elephant trunk (ET) approach for extensive thoracic aortic aneurysm (TAA), specifically in regard to inter-stage mortality. This study evaluates the safety of the two-stage ET approach for management of extensive TAA. Methods: Between 2003–2018, 152 patients underwent a Stage I ET procedure by a single surgeon (mean age 64.5±14.8). Second stage ET procedure was planned in 60 patients (39.4%) and to-date has been performed in 54 patients (90%). (In the remaining patients, the elephant trunk was prophylactic for the long-term, with no plan for near-term utilization). Results: In-hospital mortality after the Stage I procedure was 3.3% (5/152). In patients planned for Stage II, the median inter-stage interval was 5 weeks (range: 0-14). Of the remaining six patients with planned, but uncompleted Stage II procedures, five patients expired from various causes in the interval period (inter-stage mortality of 8.3%). There were no cases of aortic rupture in the inter-stage interval. Stage II was completed in 58 patients (including 4 unplanned) with 30-day morality of 10.3% (6/58). Seven patients developed strokes after Stage II (12%), and three patients (5.1%) developed paraplegia. Conclusions: The overall mortality, including Stage I, inter-stage interval, and Stage II was 18.6%. This cumulative mortality for the open two-staged ET approach for treatment of extensive TAA is acceptable for aortic disease of this severity. Fear of inter-stage rupture should not preclude the aggressive Two-Stage approach to management of extensive TAA.

Rationale, aims and objective The prevalence of colorectal cancer in the elderly is increasing with older patients undergoing surgery. The aim of the study was two-fold: to evaluate the post-operative outcomes for patients ≥ 85 years old following colorectal cancer resection as well as evaluating the outcomes of laparoscopic resection of colorectal cancer in patients over 85. Methods The study was divided into two parts. For part one, patients were divided into two groups based on age: those age ≥ 85 years old and those aged 75-84 years old. Short term surgical outcomes and clinicopathological features were compared using appropriate parametric and non-parametric testing. For part two, patient’s over 85 years old were divided into two groups based upon operative technique: laparoscopic vs open colorectal resection. Short-term post-operative outcomes of each approach were assessed. Results The median length of stay (LOS) between patients over 85 and those aged 75-85 was eight days, with no statistically significant difference in LOS between the groups (p=0.29). No significant difference was identified between the older and younger groups with regards to severity of complications (p=0.93), ASA grading (p=0.43) or 30-day mortality (2 vs 2%, p= p=0.96). Patients over 85 who underwent laparoscopic colorectal resection were compared to those who underwent an open resection. The median length of stay between the group was similar (8 vs 9 days respectively) with no significant difference in length of stay (p=0.18). There was no significant difference in 30-day mortality rates (0% vs 9%, p=0.063) or severity of complication grades (p=0.46) between the laparoscopic and open surgical groups. Conclusion No significant short term surgical differences were identified in patients ≥ 85 years old when compared to those 75-85 years old. There is no difference in short term surgical outcomes between laparoscopic or open colorectal resections in patients over 85.

Rationale, Aims, and Objectives: The risk of mental health problems during the coronavirus pandemic is greater for critical care patients, and has led to demand for services to provide effective training in psychological skills to healthcare professionals (HCPs) to enable a timely, service-wide response. A one-day psychological skills training workshop was developed to build critical care HCPs confidence in screening for psychological distress and delivering Cognitive-Behavioural Therapy (CBT) low-intensity psychological interventions. This study aimed to (1) examine whether the training package improved HCPs confidence in assessing and managing symptoms of depression, anxiety, post-traumatic stress disorder and delirium among critical care patients, and (2) explore how HCPs implemented learned skills in practice. Method: A mixed methods design was used. Self-reported pre and post training questionnaires examined participant confidence in delivering psychological assessments and interventions to patients. A paired-sample t-test and Wilcoxon tests examined differences between pre and post scores. Participants were invited to a semi-structured interview one year after attending the training day. Qualitative data were thematically analysed to explore how practitioners implemented learning into clinical practice. Results: Most participants (55 of 58) completed pre and post questionnaires. There was a significant improvement in participants’ confidence to assess and manage symptoms of psychological distress using brief CBT skills. Four participants were interviewed at follow-up and four themes emerged from analysis: ‘facilitating psychologically-informed conversations with patients’; ‘recognising the benefits of using standardised questionnaires’; ‘facilitating implementation with pre-existing skills and experience’; and ‘barriers to implementation’. Conclusion: The training workshop significantly improved confidence in delivering psychological support with a large effect size. This validates and generalises results from previous studies using similar training in cancer care. Integrating pre-existing skills and knowledge whilst acknowledging and managing HCPs anxieties may help to further boost their confidence in using psychological skills while maintaining rapport with patients.

Rationale, aims and objectives: Polypharmacy is a risk factor for the health and safety of elderly patients. To determine whether pharmacists could reduce the number of medications administered to patients with polypharmacy in a clinical setting via counselling and medical review. Method: The assigned clinical pharmacists conducted a medication review of outpatients at the Showa University Hospital. When a medication-related risk was identified, the pharmacists counseled the patients. We retrospectively surveyed the medical records of 13 outpatients who received interventions (medication review and counseling) by clinical pharmacists between January 2017 and June 2017. Adverse events or changes in the physical conditions of patients were assessed for 6 months. The suitability of medications was assessed using the medication appropriateness index (MAI) by two pharmacists before the review and 6 months post-review. Results: The number of coadministered medications was 17 (9–30) [median (range)] before the intervention; it significantly reduced to 8 (8–29) just after the intervention and to 13 (8–27) 6 months post-intervention. The MAI score was sustained for up to 6 months after the intervention (before vs. just after and 6 months after the intervention: 9 [3–23] vs. 4 [0–22] and 2 [0–23], p < 0.005). No adverse events were observed for 6 months. Conclusions: Pharmaceutical counseling and medication review by clinical pharmacists reduced polypharmacy without any adverse events for at least 6 months despite limited number of assessments. Thus, interventions (medication review and counseling) by clinical pharmacists are a useful method to resolve polypharmacy in outpatients.

Breast cancer is the commonest cancer among women in the western world, accounting for up to 30% of all cancers in women. There is a long-standing controversy about the potential link to hormone replacement therapy (HRT), with large observational studies suggesting that HRT increases the risk, while the Women’s Health Initiative (WHI), a prospective, randomised placebo-controlled trial has reported several times over a period of 20 years that combined (oestrogen and progestogen) HRT increases the risk, while oestrogen-only HRT given to women who have had a prior hysterectomy, is associated with a significantly reduced risk of developing breast cancer.

Amplification-independent c-MYC overexpression is suggested in multiple cancers. Targeting c-MYC activity has therapeutic potential, but efforts thus far have been mostly unsuccessful. To find a druggable target to modulate c-MYC activity in cancer, we identified two kinases, MAPKAPK2 and the DNA-dependent protein kinase catalytic subunit (DNA-PKcs), which phosphorylate the S111 and the S93 residues of OCT4, respectively, to transcriptionally activate c-MYC. Using these observations, we present here a novel cell-based luminescence assay to identify compounds that inhibit the interaction between DNA-PKcs and OCT4. After screening approximately 80,000 compounds, we identified 56 compounds (“hits”) that inhibited the luminescence reaction. Using a custom antibody specific for pOCT4S93, the “hits” were validated for their effect on OCT4 phosphorylation and activation. Seven compounds were selected for the second step of validation, which focused on the interaction between kinase and substrate. After further characterization, we identified two compounds that significantly impaired the ability of DNA-PKcs to bind to and phosphorylate OCT4. The compounds demonstrate a significant ability to kill cancer cells in the nanomolar range. In conclusion, we developed a cell-based luminescence assay to identify novel inhibitors targeting c-MYC transcriptional activation, and have found two compounds that may function as lead compounds for further development.

The largest populations of the human virome belong to bacteriophages. M13 filamentous bacteriophages can survive, circulate and being cleared within the body. The M13 phage has been developed as a new therapeutic application due to its ability. Being detected by innate immune cells, M13 phage triggers an immune response. Hereupon, macrophages are counted as the first immune cells stimulated by phage particles. The possible interference between immune responses with the phage-induced treatment process, necessitates determining M13 phage effect on immune responses. For this purpose, M13 phage with RGD were used as substrates for macrophage culture. Gelatin and uncoated wells were used as controls. 2 and 7 days post culture on the coated surfaces, peritoneal macrophages were analyzed in terms of morphological characteristics and metabolic profile and measurement of cytokines production. Macrophages on M13 phage containing surfaces secreted anti-inflammatory cytokines, increased efferocytosis activity and show metabolic profile of an M2 macrophage. The results demonstrate that M13 phage can modulate immune responses by polarization of macrophages toward anti-inflammatory phenotype over time. Moreover, the combination of RGD peptide motif with M13 phage was able to stimulate macrophage polarization more effectively which may introduce an Immune-modulating technology for therapy and biocontrol.