Proteus syndrome (PS) is a complex disorder characterized by variable clinical findings of overgrowth and tumor susceptibility. This report presents the first known association between PS and an ovarian germ cell tumor in an adolescent with immature teratoma. A review of the diagnosis of PS and associated tumors is included.

Background and purpose: Obesity is associated with an elevated risk of severe respiratory infections and inflammatory lung diseases. The objectives were to investigate (i) the production of adiponectin by human lung explants, (ii) the expression of the adiponectin receptors AdipoR1 and AdipoR2 by human lung macrophages (LMs), and (iii) the impact of recombinant human adiponectin and a small-molecule APN receptor agonist (AdipoRon) on LMs activation. Experimental approach: Human parenchyma explants and LMs were isolated from patients operated for carcinoma. The LMs were cultured with recombinant adiponectin or AdipoRon and stimulated with LPS (10 ng.mL-1), poly(I:C) (10 µg.mL-1) or interleukin(IL)-4 (10 ng.mL-1) for 24 h. Cytokines or adiponectin, released by explants or LMs, were measured using ELISAs. The mRNA levels of AdipoR1 and AdipoR2 were determined using real-time quantitative PCR. AdipoRs expression was also assessed with confocal microscopy. Key results: Adiponectin was released by lung explants at a level negatively correlated with the donor’s body mass index. AdipoR1 and AdipoR2 were both expressed in LMs. Adiponectin (3-30 µg.mL-1) and AdipoRon (25-50 μM) markedly inhibited the LPS- and poly(I:C)-induced release of Tumor Necrosis Factor-alpha, IL-6 and chemokines (CCL3, CCL4, CCL5, CXCL1, CXCL8, CXCL10) and the IL-4-induced release of chemokines (CCL13, CCL17, CCL22) in a concentration-dependent manner. Recombinant adiponectin produced in mammalian cells (lacking low molecular weight isoforms) had no effects on LMs. Conclusions and implications: The low-molecular-weight isoforms of adiponectin and AdipoRon have an anti-inflammatory activity in the lung environment. Targeting adiponectin receptors may constitute a new means of controlling airways inflammation.

Aim: Alemtuzumab is a lymphodepleting monoclonal antibody utilized in conditioning regimens for allogeneic hematopoietic cell transplantation (HCT). A therapeutic range of 0.15-0.6 µg/mL on the day of transplantation is associated with better HCT outcomes. The purpose of this study was to characterize alemtuzumab population pharmacokinetic/pharmacodynamic (PK/PD) and to propose individualized subcutaneous dosing schemes to achieve this optimal level for pediatric patients. Methods: Alemtuzumab concentration and absolute lymphocyte count (ALC) profiles were obtained from 29 patients with non-malignant disorders undergoing HCT. PK/ PD analyses were performed using non-linear mixed effects modeling. Monte Carlo simulation was conducted to evaluate different improved dosing approaches. Results: A one-compartment model with sequential zero- and first-order absorption adequately described subcutaneously administered alemtuzumab PK. Model fit was significantly improved by including allometrically scaled body weight on clearance (0.080 L/h/70kg) and volume of distribution (17.4 L/70kg). ALC reduction following subcutaneous alemtuzumab was swift. An inhibitory Emax model best characterized the relationship between alemtuzumab concentration and ALC. Emax and EC50 were estimated as 1.18*103/µL and 0.045µg/mL, respectively. The currently used per kg dosing was found to cause uneven alemtuzumab exposure across different age and weight cohorts. Simulations indicated target achieving dose as allometry-based of 18 mg*(weight/70)0.75 or body surface area (BSA)-based of 10 mg/m2, divided over 3 days, with a potential individualized top-up dose; both of which yielded similar results. Conclusion: An allometry- or BSA-based starting dosing regimen in combination with individualized Bayesian PK estimation using concentration feedback is proposed for alemtuzumab precision dosing in children undergoing allogeneic HCT.

The intra-aortic balloon pump (IABP) is used to prevent complications after coronary artery bypass grafting (CABG) surgery; although some results are controversial nowadays even contradictory. A new article on this field is published in this edition and shows that the risk factors for in-hospital mortality are the preoperative plasma creatinine level and cardiopulmonary bypass time in 177 patients. About the prophylactic use of the IABP regarding mortality the results reflected so far in meta-analyses have been highly contradictory between them, and the risk factors associated with it have been several and different. This lack of evidence has resulted in the continued variation of IABP use in these procedures. A large, multicenter RCT is certainly required to take the next step towards more definitive evidence, either for or against, the use of IABP in high-risk CABG. Until then, the unanswered questions regarding this topic will remain.

Background: Sudden cardiac death (SCD) is a major driver of mortality in patients with end-stage renal disease (ESRD) on hemodialysis (HD). The degree to which ventricular arrhythmias (VA) play a role in SCD in ESRD patients is unclear. Objective: Use cardiac implantable electronic devices (CIEDs) to clarify VA burden in ESRD patients overall and in relation to interdialytic cycle. Methods: We identified 44 patients at a single academic center with CIEDs, 22 on HD, along with 22 age- and sex-matched controls. Device interrogations from 11/13/14 – 4/8/19 were reviewed. Results: Overall, there were no differences in HD patients and controls in adjusted overall event rate (HD 9.81 x 10-5 ± 1.5 x 10-3 events/patient-hours vs control 3.71 x 10-5 ± 9.1 x 10-4 events/patient-hours, p = 0.902), or proportion of patients experiencing VA event (HD 45.4% vs control 63.6%, p = 0.226). There was no difference in ventricular pacing burden. Controls were more likely to require device therapy for VT/VF episodes (total ATP episodes 2/38 in HD vs 10/22 in controls, p < 0.01, total ICD shocks 10/38 in HD vs 17/22 in controls, p < 0.01). HD patients were most likely to experience VA within 12-hours of HD completion (p < 0.01), and the vast majority of events were NSVT. Conclusion: VA and ventricular pacing burden was similar by CIED analysis between groups. In HD patients, VA were likely to occur within the first 12 hours post-dialysis, were primarily NSVT, and were unlikely to require device therapy.

Infective endocarditis (IE) still has a high risk of mortality and morbidity, despite of developments in medical treatment. Intracranial hemorrhage is one of serious complication, which has poor outcome. We present a 30-year-old male with diagnosis of IE. He had severe aortic regurgitation and oscillating vegetations on both side of the aortic valve. Although there was no neurological symptom in preoperative period, cranial magnetic resonance imaging (MRI) revealed millimetric size ischemic lesions at the right cerebral hemisphere. We performed Ozaki procedure. However, cerebral hemorrhage occurred on the first postoperative day. Computerized tomography (CT) revealed hematoma in parietal and occipital lobes. He was treated with conservative anti-edema therapy and discharged from the hospital on the 25th day with minor visual defect of his eye. Echocardiography control revealed mild aortic regurgitation without any other pathologic finding after 18 months. Aortic neocuspidization by using using of glutaraldehyde treated autologous pericardium decreases the risk of fibrosis and calcification, and thrombosis events. Possibility of suspending the anticoagulant and antiplatelet regimen is a significant advantage in this type of repair. Ozaki procedure might be the first-choice surgical reconstruction technique in anatomically suitable IE cases.

An early-morning flowering (EMF) trait is supposed to be effective in enhancing grain yield due to mitigation of heat-induced spikelet sterility at flowering in rice. This study evaluated (i) phenotypic differences between a near-isogenic line carrying a QTL for EMF trait, designated as IR64+qEMF3, and a recurrent parent, IR64, under wide variation in climates and (ii) whether an EMF trait can enhance grain yield under heat stress at flowering. IR64+qEMF3 had significant earlier flower opening time (FOT) in diverse environmental conditions including temperate, subtropical, and tropical regions. Under normal temperatures at flowering, IR64+qEMF3 had similar grain yield to IR64 with some significant changes in agronomic traits and yield components. Field trials in heat-vulnerable regions of central Myanmar for seven crop seasons showed that higher percentage of filled grains contributed to the significantly higher grain yield in IR64+qEMF3 among yield components when plants were exposed to daily maximum air temperatures around 36.5 oC or higher. Lower spikelet sterility in IR64+qEMF3 was attributed to the earlier FOT during cooler early morning hours. This is the first field study that clearly demonstrates the enhancement of heat-resilience due to EMF trait at flowering.

Referring to a literature review published recently in this Journal, we report a single-center case series of 45 children and adolescents (age 2-17 years) with suspected tuberculosis (TB) and negative microscopy on repeated sputum or gastric aspirate samples. All subjects underwent flexible airway endoscopy including bronchoalveolar lavage (BAL) and endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) without adverse events. Among 41 subjects with a final TB diagnosis, Mycobacterium tuberculosis was detected by PCR and/or culture in 20 (49% bacteriological confirmation) with 11 cases relying exclusively on results from TBNA samples. Only 7 of 17 positive culture results related to sputum (17% confirmation rate), and 9 of 17 on the combination of sputum and BAL (22%) respectively. The sampling site of a person’s first positive culture was TBNA in 13 of 17 cases (76%). Bacteriological confirmation was essential for diagnostic accuracy and tailored treatment based on individual drug susceptibility testing. We therefore recommend the inclusion of bronchoscopy and EBUS-TBNA in a comprehensive diagnostic protocol for smear-negative pediatric TB suspects.

A 52-year-old female was admitted to rule out an acute coronary syndrome.Her Troponin, ECG, MPS were negative. Further testing she was found to have extremely high high-density lipoprotein level of 218 mg/dl.Due to the persistent nature of the chest pain, LHC was done with 50% stenosis of RCA.

Sympathectomy - A “one hit wonder” for life?Fabrizio R. Assis, M.D. Harikrishna Tandri, M.D.From Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

Introduction Although left atrial appendage (LAA) obliteration is the cornerstone of stroke prevention in surgical treatment of atrial fibrillation (AF), little is known about its direct impact on hemodynamics. In the current pilot study, we evaluated the hemodynamic effect of LAA closure by clipping in patients undergoing hybrid AF ablation. Methods Seven patients with paroxysmal or persistent AF were included. Hemodynamic and intracardiac pressure measurements such as systemic, pulmonary artery (PA), central venous and LA pressure, cardiac output and indexed left ventricular stroke volume (LVSVi) were measured directly before (T0) and after (T1), and 10 minutes after (T2) LAA closure. Results Of the 7 patients (median 66 yrs), 5 were in AF at the time of incision. There were no differences between T0 and T1, T1 and T2 and T0 and T2 for LA pressure, mean PA pressure, LVSVi and other hemodynamic parameters such as central venous oxygenation and pressure, or systemic arterial pressure. Conclusion In this pilot study, the direct hemodynamic effect of LAA closure is evaluated for the first time. Clipping of the LAA is safe and does not directly affect hemodynamic and intracardiac pressures.

AllergyEditorial (invited)

Prosthetic valve thrombosis ( PVT) is a serious complication after prosthetic heart valve replacement.When thrombosis causes the prosthetic valve to disfunction, it may cause the patient to die.We successfully treated a patient with acute left heart failure due to prosthetic valve thrombosis. The report is as follows.

Surgical treatment of complex coarctation is still a challenge. We performed extra-anatomic aortic bypass and Bentall procedure for a 10-year old boy diagnosed with critical aortic coarctation, aortic aneurysm, and severe aortic valve insufficiency who previously received Switch procedure. The patient is alive and well 52 months postoperatively with a satisfactory result. Extra-anatomic aortic bypass is a safe and effective procedure for patients with complex coarctation.

BACKGROUND/AIM: Propranolol is a beta-adrenergic receptor blocker which is used for the treatment of portal hypertension in patients with liver cirrhosis. The systemic exposure of propranolol may vary according to the extent of portal hypertension and liver function. The objective of this study was to propose a model for predicting the exposure of propranolol. METHODS: Thirty normal subjects, 18 patients with chronic active hepatitis (CAH), and 54 patients with cirrhosis were included in this study. Blood samples for pharmacokinetic analysis were taken up to 8 hours post-dose. Pharmacokinetic analysis was performed using a non-compartmental model. The extent of portal hypertension was evaluated by heart-to-liver radioactivity uptake ratio (H/L ratio) using 201TI per rectal scintigraphy. A multivariate regression analysis was performed to determine the best model for estimating the Cmax or AUC of propranolol. RESULTS: Twenty-four normal subjects, 18 CAH patients, and 36 cirrhosis patients completed the study. A multivariate stepwise linear regression analysis revealed that sex, weight, total bilirubin concentrations, platelet counts, and H/L ratio affected the exposure of propranolol: Cmax (ng/mL) = 50.976-18.743×sex[M:1;F:0]-0.408×weight+6.155×total bilirubin+35.328×H/L ratio (adjusted r2=0.440); AUClast (ng·h/mL) = 298.86–71.080×sex[M:1;F:0]–2.158×weight–0.312×platelet count+26.372×total bilirubin+176.745×H/L ratio (adjusted r2=0.500). CONCLUSION: A multivariate model based on laboratory tests, H/L ratio, body weight, and sex can predict the systemic exposure of propranolol and thereby inform the prescription of propranolol in patients with liver disease.

Background: The success of subcutaneous immunotherapy (SCIT) mostly depends on regular injections. Our aim was to investigate adherence to SCIT with aeroallergens during the COVID-19 pandemic and demonstrate clinical consequences of treatment disruptions in real-life. Methods: Visual analogue scale for quality of life (VAS-QoL), VAS for symptom scores (VAS-symptom), medication scores (MSs) and total symptom scores (TSS-6) were recorded during the pandemic in 327 adult allergic rhinitis and/or asthmatic patients receiving maintenance SCIT and these scores were compared with the pre-pandemic data. Patients were grouped according to SCIT administration intervals; no delay (Group 1), <2 months (Group 2), and ≥2 month intervals (Group 3). Results: 104 (31.8%) patients (Group 3) were considered as non-adherent which was mostly related to receiving SCIT with HDMs and using public transportation for reaching the hospital. Median MS, VAS-symptom and TSS-6 scores of Group 3 patients during the pandemic were higher than the pre-pandemic scores (p=0.005, p<0.001, p<0.001, respectively) whereas median VAS-QoL scores of Group 3 during the pandemic were lower than the pre-pandemic scores (p<0.001). Median TSS-6 and VAS-symptom scores were the highest in Group 3 compared to other groups (p<0.001 for each comparison). Median VAS-QoL scores were the lowest in Group 3 compared to Group 1 and Group 2 (p<0.001, p=0.043, respectively). Conclusion: When precautions in allergy clinics are carefully applied, adherence to SCIT can be high during a pandemic. Patients must be warned about adhering to SCIT injections since delays in SCIT administration can deteriorate clinical symptoms.

Ecological theory recognizes the importance of the variety of species for maintaining the functioning of ecosystems and their derived services. We assert that when studying the effects of shifts in biodiversity levels using mathematical models, their dynamics must be sensitive to the variety of species traits but not to raw species numbers, a property that we call scale--invariance. We present a testing procedure for verifying scale--invariance of ecological network models ---with or without trait adaptation--- expressed as ODEs. Furthermore, we applied our test to several influential models used for evaluating biodiversity effects on ecosystem functioning. In most of the surveyed studies the equations failed our test. This raises doubts about the validity of previous results and calls for revisiting the theory derived from these studies. Our results foster the creation of artifact--free models, a necessary step towards building a more robust theory of biodiversity--driven ecosystem functioning.

Objectives To investigate the outcomes of internal ureteral stent versus ureteroscopy for pregnant women with urolithiasis. Data Sources Relevant studies published from January 1980 to April 2020 were identified through a systematic literature search in MEDLINE, EMBASE, Web of Science and Cochrane Library. Study Eligibility Criteria Total of 453 studies were initially identified. Pregnant women in any pregnancy stages who underwent D-J stent insertion only or ureteroscopy operation were included. The number of related participants in each group of study should be more than 10. This systematic review has been registered on PROSPERO (CRD42020195607). Results A total of 25 studies were identified with 131 cases serial stenting and 789 cases URS. The pooled operation success rate was 97% for D-J stent insertion, and 99% for URS. For internal ureteral stent therapy, normal fertility outcome rate was 99%, but the pooled incidence of complications was about 45%. For the URS group, normal fertility outcome rate was 99%, and the pooled incidence of complications was about 1%. However, the pooled premature and abortion incidence rate of two groups were the same as less than 1%, and same in serious complication incidence rate. Conclusions Although internal ureteral stent may cause more slight complications, ureteroscopy operation and internal ureteral stent showed less side effective on fertility results. Evidence suggests that URS therapy have greater advantage for pregnancy with urinary stones when the condition permits. As it is proved safe and effective, internal ureteral stent could be considered at emergency or other special situations.

Steam sediment transport is a convolution of climate, weather, geology, topography, biology, and human influence. In addition to providing water and food security for dryland rural communities, sand dams—small weirs designed to trap only the coarse fractions of transported sediments in seasonal and ephemeral streams—illuminate many complexities of geomorphological dynamics. Sand dams store water in interstitial riverbed pores and the size of deposited sediment particles largely determines the recoverability of stored water: fine materials limit transmission and provide lower volumetric yield. Can a sand dam be designed for a particular reach-scale, hydro-sedimentary context to limit capture of fine particles? We argue that the Rouse number provides a useful criterion for identifying regimes where the target material grades are trapped. These ideas were tested using sediment data collected in Kenya and HEC-RAS numerical simulations to evaluate the sensitivity of sedimentation processes to spillway height. We show that constructing sand dams in stages results in more targeted trapping of coarse material. Surprisingly, sedimentation is shown to be more sensitive to variation in spillway height than the flood hydrograph, especially when a dam is short. A method for evaluating the need for spillway staging (essentially controlling the bedform) based on the modeled Rouse number allows evaluation of costs and expected benefits. Beyond sand dams, this supports the observation that for dryland streams with peaky flows and high sediment loading, local hydraulic controls are typically more diagnostic of streambed sediment composition than is the sediment source.

Stable isotopes in precipitation and vapor are a powerful tool for tracing the origin of moisture and mixing processes. This paper discusses time and space variation of δ18O in precipitation and controlling features over upper Blue Nile Basin using data from GNIP, observed data in 2014 and simulated data by AGCM. IsoGSM simulation in precipitation was verified with observation. The δ18O variation shows clear seasonality with the lowest 18O values in August and dry season, and enriched 18O in spring, June and September. Spring sample is enriched compared to summer, and assumed to be related with moisture sources. More enriched isotopes in spring and lower d-excess could be related to the source of air masses in short travel path from North Indian Ocean, Mediterranean and Red sea while summer rain is depleted with larger d-excess could be related to longer travel path of moisture from south Indian Ocean with mixing of potential evaporated moisture from open surface and transpired moisture from Congo vegetation and also from Gulf of Guinea. The isotopic statistics of three stations shows maximum, minimum and average value of (8.23‰, -11.73‰, 0.04‰) in Addis Ababa, (5.26‰, -12.74‰, and -2.52‰) in Entoto Hill and (4.08‰, -9.65‰, 2.41‰) in Debremarkos respectively. The δ2H- δ18O relationships, monthly weighted d-excess variation in the Basin revealed the temporal variation of δ18O in precipitation is essentially shaped by the source of the moisture and spatial differences is due to Rayleigh rainout effect along the moisture trajectory. The source of moisture is primarily controlled by the north south movement of ITCZ within the Basin. The study recommends the use of model simulated δ18O as good alternative for hydrological and hydrologeological investigations when needed.

The subsurface barrier is one of various engineering measures used to prevent seawater intrusion in coastal regions which has been widely applied. However, its two common types, the cut-off wall and the subsurface dam, are both found to cause nitrate (NO3-) accumulation in landward aquifers. In this study, numerical simulations were conducted to investigate the mechanism of NO3- accumulation caused by the two types of subsurface barriers, as well as the influence of several key parameters, i.e. the infiltration NO3- concentration, the inflow DOC concentration, the barrier height and the barrier location on the performance of the subsurface barriers. The results showed that the cut-off wall generally requires a large height to ensure a satisfactory seawater prevention effectiveness, and it is more likely to cause NO3- accumulation compared to a subsurface dam. On the other hand, despite the subsurface dam may not result in the significant increase of NO3- concentration in groundwater upstream, it cannot be applied to the areas where SI has occurred due to the residual seawater problem. Moreover, the construction of a cut-off wall results in a stagnation zone appeared at the upper corner of the barrier, where accumulated NO3- significantly. With the increase of the barrier height, the stagnation zone expanded, leading to further increase of mean NO3- concentration in the landward aquifer. Since the construction of a subsurface dam will not generate such a zone, the subsurface dam generally has little impact on NO3- accumulation.

A regional coupled approach to water cycle prediction is demonstrated for the 4-month period from November 2013 to February 2014 through analysis of precipitation, soil moisture, river flow and coastal ocean simulations produced by a km-scale atmosphere-land-ocean coupled system focussed on the United Kingdom (UK), running with horizontal grid spacing of around 1.5 km across all components. The Unified Model atmosphere component, in which convection is explicitly simulated, reproduces the observed UK rainfall accumulation (r2 of 0.62 for daily accumulation), but there is a notable bias in its distribution – too dry over western upland areas and too wet further east. The JULES land surface model soil moisture state is shown to be in broad agreement with a limited number of cosmic-ray neutron probe observations. A comparison of observed and simulated river flow shows the coupled system is useful for predicting broad scale features, such as distinguishing high and low flow regions and times during the period of interest but are shown to be less accurate than optimised hydrological models. The impact of simulated river discharge on NEMO model simulations of coastal ocean state is explored in the coupled system, with comparisons provided relative to experiments using climatological river input and no river input around the UK coasts. Results show that the freshwater flux around the UK contributes of order 0.2 psu to the mean surface salinity, and comparisons to profile observations give evidence of an improved vertical structure when applying simulated flows. This study represents a baseline assessment of the coupled system performance, with priorities for future model developments discussed.

Despite the growing number of recent studies on genome-wide divergence during speciation, the genetic basis and mechanisms of genomic divergence are still incompletely understood. In most species, natural selection plays a key role in heterogeneous genomic divergence. Additionally, intrinsic barriers, such as chromosomal rearrangements or gene incompatibilities, can also cause genomic heterogeneity. Based on whole genome re-sequencing data from 27 Populus alba and 28 P. adenopoda individuals, we explored the reasons for heterogeneous genomic divergence of these two closely related species. The results showed that the two species diverged ~5-10 million years ago (Mya), when the Qinghai-Tibet Plateau reached a certain height and the inland climate of the Asian continent became arid, which is associated with the fact that the two species begin to diverge and eventually led to speciation. In highly differentiated regions, the absolute divergence (dxy) was significantly higher than genomic background, and relative and absolute divergence were highly correlated, which indicates that intrinsic barriers played an important role in maintaining genomic heterogeneous divergence. Additionally, θπ and shared polymorphisms decreased while fixed differences increased in highly differentiated regions, which are characteristics of natural selection. The above description indicates that the combination of intrinsic barriers and natural selection result in heterogeneous genomic divergence and reproductive isolation. We further found some genes that are related to reproduction may be involved in explaining the reproductive isolation of the two species.

A document by Jianghui Cai. Click on the document to view its contents.