Background: As in LMICs, the prognosis of childhood ALL in Indonesia was lower than in HICs. Indonesian-ALL2013 protocol resulted in more toxicities and abandonments than expected. Therefore, it was modified into a pilot ALL2016 protocol. Changes to the ALL2013 protocol: no anthracyclines in SR, dexamethasone replaced prednisone in reinduction for HR and some drugs were rescheduled. Procedure: We compare the outcome of ALL2013 and ALL2016. Results: A total of 383 children with ALL were diagnosed, 21 were excluded. ALL2013 included 174 patients (106 SR and 68 HR) and ALL2016 188 (91 SR and 97 HR). The outcome of the ALL2016 was better than the ALL2013 (pOS 67.0% vs 60.3%; p=0.087 and pEFS 50.0% vs 37.9%; p=0.012) even when the number of HR patients was significantly higher in ALL2016 (51.6% vs 39.1%). The ALL2016 showed an early advantage for SR patients (pEFS 56.7% vs 47.2%; p=0.114 and pOS 74.4% vs 69.8%; p=0.298) due to the decrease of toxic deaths (10.4% vs 5.5%; p=0.211) however the number of late relapses were still high (19.5% vs 13.2%; p=0.282). In the HR group, both pEFS and pOS were significantly better in ALL2016 (pEFS 43.3% vs 23.5%; p=0.010 and pOS 59.8% vs 45.6%; p=0.036) due to less relapses (14.4% vs 29.4%; p=0.019). Both SR and HR showed a smaller number of abandonments in ALL2016. Conclusions: After small changes in protocol, initial toxicity and abandonments were reduced and the pOS and pEFS were improved. However, relapses still need to be lessened in the next protocol.

Background The aim of this study was to analyse the perioperative results and long term survival of re-sternotomy for surgical aortic valve replacement (SAVR) in octogenarians. Methods This is a retrospective, single centre study (Apr 2000 – Dec 2019). Perioperative data were compared for re-sternotomy with isolated SAVR (Isolated redoSAVR) and re-sternotomy with SAVR and concomitant cardiac procedure (Associated redoSAVR). Regression analyses were performed to identify predictors of in patient mortality. Hazard ratios were calculated, and Kaplan Meier survival curves were compared for groups. Results There were 163 patients (Isolated redoSAVR; 69, Associated redoSAVR; 94). Mean age was 83±3 years and mean logEuroSCORE was 21±12. Follow up was 4.2±3.5 years. Inpatient mortality was 4.9% (1.4% versus 7.4% for Isolated redoSAVR and Associated redoSAVR respectively, p=0.08). TIA/stroke rate was 8% (9% versus 7% for Isolated redoSAVR and Associated redoSAVR respectively, p=0.78). COPD was a predictor of inpatient mortality (OR; 8.86, 95%CI; 1.19, 66.11, p=0.03). Survival was 88.7% at 1 year, 86.4% at 2 years, 70.1% at 5 years, 49.5% at 7 years and 26.3% at 10 years. There was no survival difference between Isolated redoSAVR and Associated redoSAVR (logrank p=0.36, Wilcoxon p=0.84). Significant predictors of adverse long term survival were COPD, postoperative TIA/stroke and length of stay. Survival is lower than age and gender matched first time SAVR and general population of UK. Conclusions RedoSAVR in octogenarians is associated with acceptable but significant morbidity and mortality. Shared decision making should consider emerging transcatheter therapies as viable options in selected patients.

We first consider the nonlinear time fractional diffusion equation D^{1+α}u+D^β u−∆_{H} u=|u|^p posed on the Heisenberg group H, where 1 < p is a positive real nimber to be specified later; D^δ_{0|t} is the Liouville-Caputo derivative of order δ. For 0 < α < 1,0 < β ≤ 1. This equation interpolates the heat equation and the wave equation with the linear damping D^β_{0|t}u. We present the Fujita exponent for blow-up. Then establish sufficient conditions ensuring non-existence of local solutions. We extend the analysis to the case of the system D^{1+α}u+D^β u−∆_{H} u=|v|^q D^{1+δ}v+D^γ v−∆_{H} v=|u|^p. Our method of proof is based on the nonlinear capacity method.

The information detection of complex systems from data is currently undergoing a revolution,driven by the emergence of big data and machine learning methodology. Discovering governingequations and quantifying dynamical properties of complex systems are among central challenges. Inthis work, we devise a nonparametric approach to learn the relative entropy rate from observationsof stochastic differential equations with different drift functions. The estimator corresponding tothe relative entropy rate then is presented via the Gaussian process kernel theory. Meanwhile, thisapproach enables to extract the governing equations. We illustrate our approach in several examples.Numerical experiments show the proposed approach performs well for rational drift functions, notonly polynomial drift functions.

The cytochrome oxidase subunit I (COI) gene was amplified and analyzed for 70 Mediterranean Chondrosia reniformis, collected from eight localities in Tunisia. Polymorphism results revealed high values of haplotype diversity (Hd) and very low nucleotide diversity (π). Thus, these results suggest that our sponge populations of C. reniformis may have undergone a bottleneck followed by rapid demographic expansion. This suggestion is strongly confirmed by the results of neutrality tests and “mismatch distribution”. The important number of haplotypes between localities and the high genetic differentiation (Fst ranged from 0.590 to 0.788) of the current C. reniformis populations could be maintained by the limited gene flow Nm (0.10 - 0.18). Both haplotype Network and the biogeographic analysis showed a structured distribution according to the geographic origin. C. reniformis populations are subdivided into two major clades: Western and Eastern Mediterranean. This pattern seems to be associated with the well-known discontinuous biogeographic area: the Siculo-Tunisian Strait, which separates two water bodies circulating with different hydrological, physical, and chemical characteristics. The short dispersal of pelagic larvae of C. reniformis and the marine bio-geographic barrier created high differentiation among populations. Additionally, it is noteworthy to mention that the “Mahres / Kerkennah” group diverged from Eastern groups in a single sub-clade. This result was expected, the region Mahres / Kerkennah, presented a particular marine environment.

Increased prevalence of Autoimmune Diseases in Children with Chronic Spontaneous UrticariaMichelle Le, MD1, Lydia Zhang MD2, Sofianne Gabrielli MSc2, Connor Prosty BSc, MD(c)1, Laura May Miles LLM, MD(c)2, Elena Netchiporouk, MD, MSc1, Sharon Baum, MD3, Shoshana Greenberger, MD3, Luis F. Ensina, MD, MSc, PhD4, Fatemeh Jafarian, MD1, Xun Zhang, PhD5, Moshe Ben-Shoshan, MD, MSc21Division of Dermatology, McGill University, Montreal, QC, Canada2Division of Pediatric Allergy and Clinical Immunology, Department of Pediatrics, McGill University Health Centre, Montreal, QC, Canada3Department of Dermatology, Chaim Sheba Medical Center, Tel-Aviv University, Sackler School of Medicine, Tel Hashomer, Israel4Department of Pediatrics, Federal University of São Paolo, Brazil5Centre for Outcome Research and Evaluation, Research Institute of McGill University Health Centre, Montreal, QC, CanadaCorrespondence: Michelle Le, M.D., 1001 Decarie Blvd, Montréal, Québec, H4A 3J1 email: [email protected] type: LetterManuscript word count: 981References : 10Tables : 1Figures: NoneFunding sources : NoneConflicts of interest: None declaredIRB Approval Status : Reviewed and approved by McGill University Health Centre; approval 12-255GEN

In order to address the challenge of pressure swing adsorption system optimization, an optimization framework based on pseudo transient continuation method was used and vacuum rapid pressure swing adsorption process for oxygen production as a typical example. A pseudo transient model library was established and a robust two-stage dynamic tearing model was proposed to deal with the cyclic steady state conditions. Furthermore, the time constants were discussed and a practical time constant strategy and expressions were proposed for the stability and efficiency of calculation. Finally, reduced successive quadratic programming and time relaxation algorithm were used for the optimization of the two systems respectively, and the optimization results showed that although the simulation time of pseudo transient system is slightly higher than that of single discretization system, the optimization expense of single discretization system in two cases were 5.7 times and 11.6 times of that of pseudo transient system respectively.

Nitric oxide has been used to treat respiratory failure in post-pediatric cardiac surgical patients. High frequency oscillator ventilation is used to rescue infants who have failed conventional ventilation. In this issue a study is presented showing the benefit of combining these two therapies for improved outcomes in infants with hypoxic respiratory failure after congenital heart surgery

While treatment protocols for Hodgkin Lymphoma (HL) are well established, there is no literature available to guide therapy or estimate prognosis for patients with Fontan physiology who develop HL. The physiology of a Fontan procedure can result in the inability to tolerate chemotherapy toxicities, supportive care and infection. We present a series of 3 patients with Fontan physiology who were treated for HL and discuss their clinical course and treatment.

Aim We aimed to explore the effect of pregnancy on bedaquiline pharmacokinetics and describe bedaquiline exposure in the human milk of mothers treated for rifampicin-resistant TB, where there is no human data available. Methods We performed a longitudinal pharmacokinetic study in pregnant women treated for rifampicin-resistant TB to explore the effect of pregnancy on bedaquiline exposure. Pharmacokinetic sampling was performed at four time-points over six hours in the third trimester, and again at approximately six weeks postpartum. We obtained serial human milk samples from breastfeeding mothers, and a single plasma sample taken from breastfed and non-breastfed infants to assess bedaquiline exposure. We used liquid chromatography-tandem mass spectrometry to perform the human milk and plasma bedaquiline assays, and population pharmacokinetic modelling to interpret the bedaquiline concentrations. Results We recruited 13 women, six of whom completed the ante- and post-partum PK sampling. All participants were HIV-positive on antiretroviral therapy. We observed lower ante- and post-partum bedaquiline exposures than reported in non-pregnant controls. Bedaquiline concentrations in human milk were higher than maternal plasma (milk to maternal plasma ratio: 24:1). A single random plasma bedaquiline and M2 concentration was available in four infants (median age: 6.5 weeks): concentrations in the one breastfed infant were similar to maternal plasma concentrations; concentrations in the three non-breastfed infants were detectable but lower than maternal plasma concentrations. Conclusion We report low exposure of bedaquiline in pregnant women treated for rifampicin-resistant TB. Bedaquiline significantly accumulates in human milk; breastfed infants receive mg/kg doses of bedaquiline equivalent to maternal doses.

High Defibrillation Threshold: Brace For Impact Karam Ayoub, MD 1; Travis Richardson , MD11. Division of Cardiac Electrophysiology, Vanderbilt University Medical Center, Nashville, TN, USA.Disclosures : Dr. Richardson has received research funding from Medtronic Inc. and served as a consultant for Philips Inc. and Biosense-Webster Inc.Conflict of interest : noneFunding : noneKey words : Defibrillator , Mortality, Defibrillation Threshold, Sudden Cardiac DeathTotal word count: 1168

The snowpack regime influences the timing of soil water available for transpiration and synchrony with the evapotranspiration (ET) energy demand (air temperature, VPD, and shortwave radiation). Variability of snowmelt timing, soil water availability, and the energy demand results in heterogeneous ET rates throughout a watershed. In this study, we assess how ET and growing season length vary across five sites on an elevational gradient in the Dry Creek Watershed, ID, USA. We compared trends of daily and annual ET between 2012 and 2017 to environmental parameters of soil moisture, air temperature, vapor pressure deficit, snow cover, and precipitation and evaluate how ET varies between sites and what influences annual ET at each site. We observed three trends in ET across the watershed. The first trend is at the low elevation site where the snow cover is not continuous throughout the winter and rain is the dominant precipitation form. The first day of the growing season and ET occurs early in the season when the energy demand is low and soil water is available. Annual ET at the low elevation site is a balance between spring precipitation providing soil water into the summer season and limiting the ET energy demand. The second trend occurs at the middle elevation site located in the rain-snow transition. At this site, ET increases with snow depth and spring precipitation extending the soil water availability into the summer season. At the higher elevation sites, ET is aligned with the energy demand and limited by growing season length. At the high elevation sites, decreasing snow depth and spring precipitation and increasing spring air temperatures result in greater annual ET rates. The observations from this study highlight the influence of environmental parameters and the potential sensitivity of ET to climate change.

Paclitaxel-coated balloons have demonstrated improved efficacy compared with uncoated percutaneous transluminal angioplasty for femoropopliteal artery disease. While applying a long balloon, twisting of the balloon can be occurred. We reported two cases with twisting of the Ranger drug-coated balloon for treating superficial femoral artery.

Fluvoxamine for COVID-19 ICU patients?Vladimir TrkuljaDepartment of PharmacologyZagreb University School of MedicineŠalata 11, Zagreb, [email protected] of words: 800Number of figures/tables: 1To the Editor,I read with interest a recently BJCP-accepted manuscript on the use of fluvoxamine in COVID-19 patients who needed admission to an intensive care unit (ICU) 1. It was instructive to read about the pre-existing clinical experience and about possible mechanisms of presumed benefits of fluvoxamine in COVID-19. However, attention needs to be drawn to the suggested effect of fluvoxamine quantified as a 40% reduction in instantaneous risk of death. The authors report1 on a cohort (n=51) of patients who, upon ICU admission, were treated with oral fluvoxamine added to the standard of care (SoC) (3x100 mg/day over 15 days, then 2x50 mg/day over 7 days), and who were compared to a cohort (n=51) of SoC-only patients. The two cohorts were said to be matched 1. Based on reported data 1, it appears that the patients were matched exactly in respect to gender and COVID-19 vaccination status, and, seemingly, on a rather narrow age-caliper, but the matching method was not reported 1; not reported was also a measure of matching adequacy – standardized difference (d ), a preferred method of balance assessment (adequate if d <0.1) since independent of the sample size 2. Based on the reported data1, for example, the fluvoxamine – SoC d regarding body mass index was -0.30 (-0.31 in women and -0.29 in men); also, d=-0.122 regarding history of diabetes,d= -0.350 regarding history of treated hypertension,d=-0.11 regarding on-admission APACHE score – all suggesting a considerable imbalance between the two cohorts (lower values in the fluvoxamine cohort). The authors provide Kaplan-Meier curves of time-to-death (or ICU discharge) but without the numbers at risk1. Still, data could be read from the graphs and curves reconstructed (Figure 1A):(i) the first marked difference between the treated and controls occurs during the first 7 days of observation – 3 patients died and 3 were censored in the former, and 11 died and 4 were censored the latter cohort (Figure 1A). This difference in deaths (3 vs. 11) did not change over the entire later period since the overall difference in the number of deaths was 9 (30/51 in treated vs. 39/51 in controls). This would indicate a very rapid-onset (and subsequently “lost”) effect of fluvoxamine, which does not seem pharmacologically plausible. The assumed fluvoxamine mechanisms1 are not of the immediate-onset type; with a 3x100 mg/day dosing, elimination half-life is likely to extend well beyond 30 hours, hence steady-state would be achieved only after 7-10 days 3. Combined with the baseline imbalance between groups, this indicates that the initial separation of the two curves – more or less preserved throughout the entire subsequent period - was likely not attributable to fluvoxamine; (ii) after day 21, and particularly after day 28, the numbers at risk were very low, and after day 35 there were no further events (Figure 1A), hence accounting for the entire curve is likely misleading 4; (iii) although the curves do not cross (Figure 1A), they indicate a possibility that hazard ratio varied over time. Hazard ratio as generated in a Cox proportional hazard model (as done by the authors) is an average of values that can change over time5; it is also inherently prone to selection bias and, even in absence of confounding its interpretation is not straightforward5. This holds for randomized and particularly for non-randomized settings 5. Reconstructed data depicted in Figure 1A were used to fit a complementary log-log model for continuous time process taking into account the first 35 days (no events after that point): the method treats time as a continuous but more “coarsely” measured variable, in intervals of identical length (in this case 7-day intervals, i.e., weeks); based on assumption of constant hazard within the interval, the method provides period-specific (for weeks 1-5) hazard ratios 6, which is likely a preferable option 5. Figure 1B depicts estimated probabilities of death and HRs: it is only during week 1 that the hazard appeared lower in treated – a period during which, as elaborated, fluvoxamine most likely had no effect. Finally, authors fitted a multivariable Cox model 1to substantiate the fluvoxamine effect. With a total of 15 independents in a study with 102 subjects, the model was likely overfitted and susceptible to bias arising from over(unnecessary)-adjustments 7. But more importantly, it included adjustment for renal replacement therapy (RRT), which was actually one of the outcomes. Inadequacy of adjustments for post-exposure outcomes as if they were baseline covariates has been extensively elaborated 8 and almost inevitably results in a considerable bias, regardless of whether the respective variable was actually a mediator or a collider 8. Such adjustments require implementation of marginal structural models or some of the g-estimation methods 9.Overall, the reported difference between the two cohorts of patients is more likely bias arising from design and analysis than evidence supporting a causal effect of fluvoxamine.ReferencesČalušić M, Marčec R, Lukša L et al. Safety and efficacy of fluvoxamine in COVID-19 ICU patients: an open label, prospective cohort trial with matched controls. Br J Clin Pharmacol . 2021; doi: 10.1111/bcp.15126.Stuart EA. Matching methods for causal inference: a review and a look forward. Stat Sci . 2010; 25(1):1-21.Hiemke C, Hartter S. Pharmacokinetics of selective serotonin reuptake inhibitors. Pharmacol Ther . 2000; 85 (1):11-28.Machin D, Cheung YB, Parmar MKB, eds. Survival analysis: a practical approach . 2nd ed. Chichester, West Sussex: John Wiley & Sons Ltd; 2006. p.38.Hernan MA. The hazards of hazard ratios. Epidemiology 2010; 21(1):13-15.Prentice RL, Gloecker LA. Regression analysis of grouped survival data with application to breast cancer data. Biometrics 1978; 34(1):57-67.Schisterman EF, Core SF, Platt RW. Overadjustment bias and unnecessary adjustment in epidemiological studies. Epidemiology 2009; 20(4):488-495.Greenland S. Quantifying biases in causal models: classical confounding vs collider-stratification bias. Epidemiology 2003; 14(4):300-306.Hernan MA, Robins JM, eds. Causal inference: What if . 1st ed. CRC Press LLC; 2019.Figure 1 . Summary of re-analysis of survival data published in ref. 1. A . Reconstructed curves of Kaplan-Meier product-limit estimates. Data1 were read using a digitizing software, and were re-analyzed and curves were drawn using JMP 13 software (SAS Institute Inc., Cary, NC). Upward oriented ticks indicate censorings, downward oriented ticks indicate failures. ICU – intensive care unit. B . Estimated probabilities of death during weeks 1 to 5 by treatment (Fluvox – fluvoxamine) and period-specific hazard ratios (HR) with confidence intervals. A complementary log-log model was fitted to reconstituted data using SAS 9.4 for Windows (SAS Inc., Cary, NC).

Only a few studies on the nocturnal behavior of African ungulates exist so far, with mostly small sample sizes. For a comprehensive understanding of nocturnal behavior, this database needs to be expanded. Zoo animals offer a good opportunity to lay the corresponding foundations. The results can provide clues for the study of wild animals and furthermore contribute to a better understanding of animal welfare and better husbandry conditions in zoos. To tackle this open question, we developed a stand-alone open-source software based on deep learning techniques, named BOVIDS (Behavioral Observations by Videos and Images using a Deep-Learning Software). This software is used to identify ungulates in their enclosure and to determine crucial behavioral poses on video material with an accuracy of 99.4%. A case study on 25 Common Elands (Tragelaphus oryx) out of 5 EAZA zoos with a total of 11,411 hours video material out of 822 nights is conducted, yielding the first detailed description of the nightly behavior of Common Elands. Our results indicate that age and sex are influencing factors on the nocturnal activity budget, the length of behavioral phases as well as the number of phases per behavioral state during the night. Finally, the results suggest the existence of species-specific rhythms that open future research directions.

In U.S. academic institutions, efforts often concentrate on enhancing the recruitment of students from underrepresented groups, focusing on gender and/or race. Yet, non-demographic forms of diversity have received little attention, such as environmental worldviews, i.e., differences in the metaphysical, epistemological, and ethical beliefs that define how humans view, value, and interact with the natural world. Here, we develop an exploratory measure of environmental worldview diversity among undergraduate students enrolled in natural resource related programs. We tested our procedure at Oregon State University, a large public land-grant university in the US. Many students reported metaphysical, epistemological, and/or ethical beliefs that deviate from what has been philosophically characterized as the dominant western worldview of natural resources (anthropocentric, dualistic, hierarchical, utilitarian, mechanistic). Our results suggest that, although forestry students’ environmental worldviews are in some ways more closely aligned with the dominant western worldview than other students in natural resources, generally their worldviews reflect long-term generational shifts away from a strict resource-commodity value orientation, as documented in past research. Our findings highlight the importance of considering environmental worldviews as a dimension of diversity within the new generation natural resource students. Future efforts toward understanding these levels of difference can be important assets in designing programs which appeal to wide variety of students; ultimately helping efforts to recruit and retain a diverse of aspiring natural resource professionals.

Niche partitioning is often vital for the coexistence of ecologically similar species under limited resources. Here I will report the nesting strategy of the two sympatric songbirds and the species differences, which have been overlooked in the past. Blue-capped and red-cheeked cordon-bleus are socially monogamous, biparental songbirds (family Estrildidae) that sympatrically inhabit East Africa. My field observation during their breeding season revealed that red-cheeked cordon-bleus build their nests near wasp nests more frequently than blue-capped cordon-bleus. Blue-capped cordon-bleus instead tended to take over weaver’s old nest more often or use a broader range of nesting materials compared to red-cheeked cordon-bleus. These nesting strategies are already described in the literature as common behaviors in both species. However, the species differences of the adopting strategies have never been reported. While Estrildid finches are one of the best well-studied bird families of their behavior under the captive condition, my finding suggests that we still have limited knowledge of their wild behaviors and ecological plausibility, which is required to understand the functions and evolution.

Background: Thromboembolism-associated stroke is the most feared complication of Atrial fibrillation (AF). Percutaneous left atrial appendage closure (pLAAC) is indicated for stroke prevention in patients with AF who can’t tolerate long-term anticoagulation. We aim to study gender differences in peri-procedural and readmissions outcomes in pLAAC patients. Methods: Using the national readmission database from January 2016 to December 2018, AF patients undergoing the pLAAC procedure were identified. We used multivariate logistic regression analyses and time-to-event Cox regression analyses to conduct the study. Propensity matching with the Greedy method was done for the accuracy of results. Result: 28,819 patients were included in our study. Among them 11,946 (41.5%) were women and 16,873 (58.6%) were men. The mean age of overall population was 76.1 ± 8.5 years, with women ~ 1 year older than men. The overall rate of complications was higher in women (8.6% vs 6.6%, P<0.001), primarily driven by bleeding-related complications i.e., Major bleed (OR: 1.32 95% CI: 1.03-1.69, p=0.029), blood transfusion (OR: 1.45, 95% CI: 1.06-1.97, p=0.019) and cardiac tamponade (OR: 1.80, 95% CI: 1.13-2.89, p=0.014). Women had two times higher peri-procedural ischemic stroke. There was no difference in peri-procedural mortality. Women remained at 20% and 13% higher risk for readmission at 30 days and 6 months of discharge. Conclusion: Women had higher peri-procedural complications and were at higher risk of readmissions at 30 days and six months. However, there was no difference in mortality during the index hospitalization. Further studies are necessary to determine causality.