Children less than 18 years of age account for an estimated 500,000 to 1.5 million global SARS-CoV-2 cases. Lower prevalence of COVID-19 among children, in addition to higher numbers of mild and asymptomatic cases, continues to provide challenges in determining appropriate prevention and treatment courses. Here, we summarize the current evidence on the transmission, clinical presentation, complications and risk factors in regards to SARS-CoV-2 in children and highlight crucial gaps in knowledge going forward. Based on current evidence, children are rarely the primary source of secondary transmission in the household or in child care and school settings and are more likely to contract the virus from an adult household member. Higher transmission rates are observed in older children (10-19 years old) compared to younger children (<10 years old). While increasing incidence of COVID-19 in neonates raises the suspicion of vertical transmission, it is unlikely that breast milk is a vehicle for transmission from mother to infant. The vast majority of clinical cases of COVID-19 in children are mild, but there are rare cases that have developed complications such as multisystem inflammatory syndrome in children (MIS-C), which often presents with severe cardiac symptoms requiring intensive care. Childhood obesity is associated with a higher risk of infection and a more severe clinical presentation. Although immediate mortality rates among children are low, long-term respiratory and developmental implications of the disease remain unknown in this young and vulnerable population.

Clay aquitards are semipermeable membranes that allow groundwater flow while retarding solute migration have been researched extensively but also subjected to much debate. In this study, we collected clay samples from drilling cores (30–90m) in the Hengshui area located in the Hebei Plain, then extracted pore water using a high-pressure squeezing device. Vertical hydrochemical and isotopic profile variation trends for the pore water were revealed using hydrochemical (Cl－, Na+, Ca2+, K+, Mg2+, and SO42-) and stable isotopic measurements of H, O, and Cl. The results showed that the hydrochemical clay interlayer pore water of the saline aquifer is Cl•SO4-Na•Mg type and the average total dissolved solids（TDS）is 10.17g/L. The hydrochemical clay aquitard pore water is of the Cl•SO4-Na•Ca type with an average TDS of 1.9g/L. The hydrochemical clay interlayer pore water of aquifer II is of Cl-Na•Ca type with an average TDS of 1.1g/L. Our results showed that the water quality of the aquifer II is not affected by the upper part of saline aquifer, thus the clay aquitard acts as a significant barrier to salt movement. A polarization layer concentrated in ions was formed between the upper part of saline aquifer and the clay aquitard. The concentration polarization layer increases the salt-inhibition effect. Isotpic H, O, and Cl results showed significant fractionation. The pore water of aquifer II lacked heavy isotopes(D、18O、37Cl), but had significant heavy isotope enrichment in the concentrated polarized layer (the δD value was -76‰, the δ18O value was -8.4‰, and the δ37Cl value was 1.59‰). Hyperfiltration thus played a significant role in isotope fractionation.

Objectives: Assess first trimester serum placental growth factor (PLGF), soluble fms-like tyrosine kinase-1 (sFLT-1), interleukin-6 (IL-6), tumour necrosis factor-α (TNF-α), endothelin and vascular cell adhesion molecule (VCAM) in women with chronic hypertension (CH) stratified according to blood pressure (BP) control. Design: Case-control. Setting: Tertiary referral centre. Population: 650 women with CH, 142 normotensive controls. Methods: In the first trimester, patients with CH were subdivided into 4 groups. Group 1 included women without pre-pregnancy CH presenting with BP ≥140/90mmHg. Groups 2-4 had pre-pregnancy CH; in group 2 the BP was <140/90mmHg without antihypertensive medication, in group 3 the BP was <140/90mmHg with antihypertensive medication and in group 4 the BP was ≥ 140/90 mmHg despite antihypertensive medication. PLGF, sFLT-1, IL-6, TNF-α, endothelin and VCAM were measured at 11+0-13+6 weeks’ and converted into multiples of the expected median (MoM) using multivariate regression analysis in the controls. Main outcome measure: Comparisons of MoM values of PLGF, sFLT-1, IL-6, TNF-α, endothelin and VCAM between the 4 CH groups and the controls were made using analysis of variance or Kruskal-Wallis tests. Results: In the CH groups, compared to controls, PLGF was reduced in groups 2-4, sFLT-1 was reduced in groups 2 and 3, endothelin was increased in groups 1 and 4 but IL-6 was reduced in group 4. Conclusion: In women with CH, differences exist in first trimester angiogenic and inflammatory profiles according to BP control. Further evaluation is needed to determine if these differences are useful in the stratification of care.

Soil moisture plays a significant role in land-atmosphere interactions. Changing fractions of latent and sensible heat fluxes caused by soil moisture variations can affect near-surface air temperature, thus influencing the cooling effect of the oasis in arid regions. In this study, the framework for the evaporative fraction (EF) dependence on soil moisture is used to analyze the impacts of soil moisture variation on near-surface air temperature and the oasis effect. The results showed that the contribution rate of soil moisture to EF was significantly higher than that of EF to temperature. Under the interaction of temperature sensitivity to EF and EF to soil moisture, the ∂T/∂ϴ presented a similar tempo-spatial variation with both of the above. It was most significant in oasis areas during summer (−1.676), while it was weaker in plain desert areas during the autumn (−0.071). In the study region, the effect of soil moisture variation on air temperature can reach 0.018–0.242 K for different land-cover types in summer. The maximum variation of soil moisture in summer can alter air temperature by up to 0.386 K. The difference in temperature variability between the oasis and desert areas promoted the formation of the oasis effect. For different oasis, the multi-year average oasis cold effect index (OCI) ranged from −1.36 K to −0.26 K, while average summer OCI ranged from −1.38 K to −0.29 K. The lower bound of the cooling effect of oasis ranged from −4.97 to −1.69 K. The analysis framework and results of this study will provide a new perspective for further research on the evolution process of the oasis effect and water-heat balance in arid areas.

Aims: The differential diagnosis of Fever of Unknown Origin (FUO) is still a major clinical challenge despite the advances in diagnostic procedures. In this multicenter study, we aimed to reveal FUO etiology and factors influencing the final diagnosis of FUO in Turkey. Methods: A total of 214 patients with FUO between the years 2015-2019 from 13 tertiary training and research hospitals were retrospectively evaluated. Results: The etiologic distribution of FUO was infections (44.9%), malignancies (15.42%), autoimmune/inflammatory (11.68%) diseases, miscellaneous diseases (8.41%) and undiagnosed cases (19.62%). Brucellosis (10.25%), extrapulmonary tuberculosis (6.54%) and infective endocarditis (6.54%) were the most frequent three infective causes. Solid malignancies (7.1%) and lymphoma (5.6%), adult-onset still’s disease (6.07%) and thyroiditis (5.14%) were other frequent diseases. The etiologic spectrum did not differ in elderly (p<0.05). Infections were less frequent in Western (34.62%) compared to Eastern regions of Turkey (60.71%) (p< 0.001, OR: 0.31, 95% Cl: 0.19 to 0.60). The ratio of undiagnosed etiology was significantly higher in elderly (p: 0.046, OR: 2.34, 95% Cl: 1.00 to 5.48) and significantly lower in Western Turkey (p: 0.004, OR: 3.07, 95% Cl: 1.39 to 6.71). Conclusion: Brucellosis, extrapulmonary tuberculosis and infective endocarditis remain to be the most frequent infective causes of FUO in Turkey. Solid tumors and lymphomas, AOSD and thyroiditis are the other common diseases. The etiologic spectrum did not differ in elderly, on the other hand, infections were more common in Eastern Turkey. A considerable amount of etiology remained undiagnosed despite the state-of-the-art technology in healthcare services.

Nicotinamide-adenine dinucleotide (NAD) is involved in redox homeostasis and acts as a substrate for NADases, including poly (ADP-ribose) polymerases (PARPs) that add poly (ADP-ribose) polymers to proteins and DNA, and sirtuins that deacetylate proteins. Nicotinamide, a biproduct of NADases increases circadian period in both plants and animals. In mammals, the effect of nicotinamide on circadian period might be mediated by the PARPs and sirtuins because thy directly bind to core circadian oscillator genes. We have investigated whether PARPs and sirtuins contribute to the regulation of the circadian oscillator in Arabidopsis. We found no evidence that PARPs and sirtuins regulate the circadian oscillator of Arabidopsis or are involved in the response to nicotinamide. RNA-seq analysis indicated that PARPs regulate the expression of only a few genes, including FLOWERING LOCUS C. However, we found profound effects of reduced sirtuin 1 expression on gene expression during the day but not at night, and an embryo lethal phenotype in knockouts. Our results demonstrate that PARPS and sirtuins are not associated with NAD regulation of the circadian oscillator and that sirtuin 1 is associated with daytime regulation of gene expression.

For procellariiform seabirds, wind and body morphology are crucial determinants of flight costs and flight speeds. During chick-rearing, parental seabirds commute frequently to provision their chicks, and their body mass changes between outbound and return legs. In Antarctica, the typical diurnal katabatic winds which blow stronger in the mornings, form al natural experiment to investigate flight behaviours in response to wind conditions. We GPS-tracked three closely related species of sympatrically breeding Antarctic fulmarine petrels which differ in wing loading and aspect ratio and investigated their flight behaviour in response to wind and changes in body mass. All three species reached higher flight speeds under stronger tailwinds, especially on return legs from foraging, when wing loading was increased since birds carried food for their chicks. Flight speeds decreased under stronger headwinds. Antarctic petrels (Thalassoica antarctica; intermediate body mass, highest wind loading and aspect ratio) responded stronger to changes in wind speed and direction than cape petrels (Daption capense; lowest body mass, wing loading and aspect ratio) or southern fulmars (Fulmarus glacialoides; highest body mass, intermediate wing loading and aspect ratio). Birds did not adjust their flight direction in relation to wind direction nor maximum distance to nest when they encountered strong headwinds on their outbound commutes. However, birds appeared to adjust the timing of commutes to those hours of the day when headwinds were weakest and they were more likely to encounter favourable tail- and crosswinds. Despite these adaptations to the predictable diurnal wind conditions, birds frequently encountered unfavourably strong headwinds, possibly as a result of weather systems disrupting the katabatics coupled with the need to feed. How the predicted decrease in Antarctic near-coastal wind speeds over the remainder of the century will affect flight costs and breeding success which ultimately drives population trajectories remains to be seen.

Competition between the sympatric harbour (Phoca vitulina) and grey seals (Halichoerus grypus) is thought to underlie some recent local declines of the former while the population of the latter remains stable or increases. A better understanding of the interactions between these two species is critical to elucidate current changes. This study aims at identifying and quantifying the niche overlap between harbour and grey seals at their Southern European limit range, in the baie de Somme (Eastern English Channel, France), in a context of exponential increase in the number of resident harbour seals and visiting grey seals. Isotopic niche overlap was quantified between both species using whisker δ13C and δ15N isotopic values, taking intra- and interindividual variability into account. Dietary overlap was quantified from scat contents using hierarchical clustering. A high degree of trophic niche overlap was identified between both species. The narrower isotopic niche of harbour seals was nested within that of grey seals (58.2% [CI95%: 22.7-100%] overlap). Six diet clusters were identified from scat content analysis. Two of them gathered most of harbour seals’ scats (85.5 % [80.3-90.2%]) and around half of grey seals’ ones (46.8% [35.1-58.4%]) that almost exclusively contained benthic flatfish. Consumption of this type of prey was identified here to be the root cause of trophic overlap. This highlighted the potential for competition between the two species at their Southern European limit range, linked to foraging on benthic flatfish, in coastal waters close to their haulout sites, especially during spring/summer. We suggest that (1) interspecific competition for prey could occur/increase in the future if the number of grey and harbour seals still increase and/or if flatfish supply decrease in this area, and (2) harbour seals would be disadvantaged in such a case if they do not adapt, as being specialised on flatfish at the colony scale.

A document by Ailish Breathnach. Click on the document to view its contents.

Bioprocess development and optimization is a challenging, costly, and time-consuming effort. In this multidisciplinary task, upstream processing (USP) and downstream processing (DSP) are conventionally considered distinct disciplines. This consideration fosters “one-way” optimization without considering interdependencies between unit operations; thus, the full potential of the process chain cannot be achieved. Therefore, it is necessary to fully integrate USP and DSP process development to provide balanced biotechnological production processes. The aim of the present study was to investigate how different host/leader/antigen binding fragment (Fab) combinations in E. coli expression systems influence USP and primary recovery performance and the final product quality. We ran identical fed-batch cultivations with 16 different expression clones to study growth and product formation kinetics, as well as centrifugation efficiency, viscosity, extracellular DNA, and endotoxin content, which are important parameters in DSP. We observed a severe influence on cell growth, product titer, extracellular product, and cell lysis, accompanied by a significant impact on the analyzed parameters of DSP performance. Our results provide the basis for establishing integrated process development considering interdependencies between USP and DSP. These interdependencies need to be understood for rational decision-making and efficient process development.

Membrane absorption (MA) has a great prospect for CO2 capture. In MA modeling, conventional 1D- and 2D- models make simplification of membrane contactor (MC) geometry. Geometry simplification allows an easy process modeling and numerical solution, however, is only reasonable for particular MCs. Here, efforts are underway to quantify the geometry effect on the MA-CO2 performance. First, we proposed a full 3D model without geometry simplification for simulating the MA-CO2 process in real MCs and then validated it with experimental data. More importantly, we highlighted a preferable hybrid model in which a correction factor (F) was introduced to the 2D simulation results to make their combination approximately equal to the 3D simulation values. The F was correlated with dimensionless parameters obtained from computational fluid dynamics (CFD) studies for characterizing the geometry effect. Such hybrid modeling contributes to characterizing the influence of geometry on the MA-CO2 performance and improving computation accuracy-efficiency combinations.

Objetives: The rate of eosinophilic esophagitis (EoE) diagnosis is increasing. This study aims to determine the incidence of EoE in the paediatric population residing in the southwestern Madrid and to analyse whether absolute monthly pollen counts, modified or not by the principal atmospheric pollutants, are associated with it. Methods: A prospective observational study was designed to calculate the incidence of EoE in children aged under 15 years who were diagnosed between September 2014 and August 2016 in twelve area hospitals. We collected clinical data, date of endoscopic diagnosis and the number of first-time endoscopies performed. Relative risk estimation was performed to assess the association between the incidence of diagnosis and monthly pollen counts and levels of atmospheric pollutants. Results: One hundred forty-eight patients were included. The most frequent symptoms were abdominal pain 42.57%, dysphagia 42.57% and impaction 39-86%. The average overall monthly incidence was 1.27 (0.41-2.67) cases/100,000 children and the annual average was 15.2. The overall analysis of the relationship between incidence and absolute monthly counts and air pollutants, corrected for the number of first-time endoscopies performed, revealed no statistically significant association. There was a higher frequency of diagnosis during the pollination period of Cupressaceae and during February and November (relative risk 1.67; p<0.01). Conclusions: This study confirms the high incidence of eosinophilic esophagitis and also suggest a period of higher incidence of diagnosis in the months of February and November as well as in the period of high pollination of Cupressaceae.

Editorial: Respiratory outcomes post Nusinersen in Spinal Muscular Atrophy Type 11 Kate Gonski1,2 Dominic A. FitzgeraldDepartment of Respiratory Medicine, The Children’s Hospital at Westmead, Sydney, NSW, Australia 2145Discipline of Child & Adolescent Health, Sydney Medical School, Faculty of Health Sciences, University of Sydney, NSW, Australia 2145Corresponding author:Dominic A. Fitzgerald MBBS PhD FRACPClinical Professor Child & Adolescent HealthDepartment of Respiratory MedicineThe Children’s Hospital at WestmeadLocked Bag 4001Westmead, NSWAustralia, 2145.1458 words15 referencesTime to wake up and smell the roses as the real world respiratory experiences have arrived for Spinal Muscular Atrophy type 1 (SMA1)! Nusinersen, the first drug to be approved for treatment of SMA1, has changed the natural history of the disease and has now been commercially available in many countries for up to four years(1). SMA 1, the most common cause of infant death attributed to respiratory insufficiency, results from a degeneration of alpha motor neurons in the spinal cord and brainstem resulting in progressive skeletal muscle weakness of the limbs, respiratory and bulbar muscles (2). Most patients with SMA1 will have respiratory complications in the first year of life requiring therapy to support airway clearance and ventilation (2). The pan-ethnic incidence is 1 in 11,000 births (3). Milder phenotypes occur as SMA types 2 and 3 in childhood with a much better prognosis (4) and countries may offer nusinersen for these patients also.In this issue, Lavie and colleagues (5) offer insights into clinicalrespiratory outcomes from 3 years of prospective data collection in their cohort of 20 SMA1 patients treated before and after 2 years of nusinersen in Israel. Their work builds on the scientific evidence of efficacy of nusinersen primarily for motor outcomes over the last decade. A phase 3 randomised, double-blinded, sham controlled clinical trial in patients with SMA 1 showed that those treated with nusinersen had a significant motor milestone response with a higher likelihood of event-free survival(6). This group did not show a difference in the frequency of serious respiratory adverse events between the groups, thereby leaving unanswered questions about the effect of the medication on respiratory morbidity. Over the past few years, the translatability of outcomes from randomized controlled studies to current real-world outcomes has been questioned (7-9).A letter to the editor by LoMauro et al. involving children with SMA1 described a milder subset of children with SMA 1 [Described as type SMA 1c: onset between 3 and 6 months] treated with nusinersen who had an improvement in accessory muscle use and reduced daily hours of ventilation when compared to a natural history cohort (7). This was not reported in the more severe SMA 1a and 1b groups. Sansone et al. (8) published an observational, longitudinal cohort study looking at respiratory support requirements at baseline, 6 months and 10 months after nusinersen treatments in 118 children with SMA1. Semi-structured qualitative interviews from caregivers were collected at each interval. They showed that 77% of the cohort’s respiratory requirements remained stable and more than 80% of children treated before 2 years survived in contrast to the lower survival reported in natural history studies. The limitation of this study is that they used modality and number of hours of ventilation as the surrogate for respiratory function which can be influenced significantly by respiratory care, management and patient compliance. Chen et al. (9) also published follow-up data (single-centre) in SMA 1 children treated with nusinersen in order to further understand the comprehensive real-world outcomes of this new treatment. While this study was limited by its small sample size of 9, it highlighted that children with SMA1 treated with nusinersen continued to develop considerable respiratory comorbidities. Although a large amount of data has been collected over the past 5 years, there remain gaps in the understanding of many aspects of the use of nusinersen in SMA beyond modest increases in peripheral muscle strength and in particular whether these improvements will translate into reduced respiratory morbidity and less respiratory failure with dependence upon non-invasive ventilation (NIV) (10).The paper by Lavie et al. (5) contributes to our understanding with its focus on ‘real-world’ variables including starting or ongoing need for assisted ventilation, the use of mechanical insufflation-exsufflation, respiratory complications, and treatment cessation due to respiratory reasons, or death in around 15% of cases attributed to pulmonary aspiration. In essence, it is a source of modest encouragement for clinicians as the majority of children demonstrated stability of respiratory support over the first two years of treatment with nusinersen which is in itself much better than the natural history of the condition with progressive decline and death in 90% by the age of 2 years. However, there are some gaps in knowledge in this paper which will require further studies. It is unclear exactly why children started ventilation specifically, who went to tracheostomy and why others went to NIV and what their initial ventilator pressures were. Management algorithms have been available to outline this in neuromuscular diseases [11]. Further, it is unclear how many children had polysomnograms and what the results were in terms of apnoea indices, measures of hypoventilation, alterations in oxygenation and extent of transcutaneous CO2 abnormalities, other than that they were consistent with the standards of care for the treatment of children with SMA published in 2007 [12]. Further guidelines have since emerged in the nusinersen era [13]. Certainly, the positive impact of the use of NIV on respiratory outcomes, including hospitalisations, albeit in the broader neuromuscular population, has been established [14]. As would be hoped, a reduction in admissions was seen in the present study in SMA1. Nonetheless, as all clinicians appreciate, what is prescribed and what is used for the treatment of anything in “the real world” varies widely. Think of asthma preventers or any therapies in cystic fibrosis including expensive correctors. In a prospective study on real world respiratory outcomes, the absence of information on adherence with average daily hours of support from memory cards inside the NIV devices is a short-coming of the study of Lavie et al. (5). This is something which, with serial assessment of polysomnography parameters, should be addressed in future studies in SMA1 treated patients to ascertain the true rather than potentially perceived benefit of NIV.Lavie et al. (5) provide insight into the everyday clinical respiratory burden of patients with SMA1 treated with nusinersen while highlighting further areas of research. Specifically, they rightly suggest a beneficial effect with the earliest initiation of nusinersen due to the possibility that nusinersen may have an effect on preserving respiratory function if started at a younger age. This mirrors data in the larger RCT where earlier treatment was associated with better motor outcomes. Logically, this could be readily achieved with emerging increase in new born screening programs including SMA genes in countries such as Australia and Belgium [15]. This would also enable quantification of the number of copies of SMN2 genes present, missing in 30% of cases in the series of Lavie et al. (5). This stratification of genotype may be more important than ever in the nusinersen era as we improve our ability to predict outcomes beyond age of presentation [Types 1a, 1b and 1c] [13]. The argument for newborn screening for SMA, with earlier diagnosis and improved outcomes for such an expensive therapy seems persuasive.This article explores patient outcomes in a real-world setting and found that the need for assisted ventilation did not worsen as would be with the natural progression of SMA1. However, they showed no improvement either. Therefore, nusinersen is a small step forward with the promise of much more to come from gene therapy and potentially combinations of therapies. Longer term studies with international prospective data registries are warranted and should be funded by international neuromuscular societies at arm’s length from pharmaceutical companies. It is as important to document respiratory outcomes rather than just predominantly modest motor outcomes not only for SMA1 but also SMA2 and SMA3, because at the end of the day in the real world, your respiratory wellbeing determines morbidity and mortality.References1. LoMauro A, Mastella C, Alberti K, Masson R, Aliverti A, Baranello G. Effect of nusinersen on respiratory muscle function in different subtypes of type 1 spinal muscular atrophy. American Journal of Respiratory and Critical Care Medicine. 2019;200(12):1547-1550.2. Kolb SJ, Coffey CS, Yankey JW, Krosschell K, Arnold WD, Rutkove SB, et al. Natural history of infantile-onset spinal muscular atrophy. Ann Neurol. 2017; 82(6):883-8913. Sugarman EA, Nagan N, Zhu H, Akmaev VR, Zhou Z, Rohlfs EM, et al. Pan-ethnic carrier screening and prenatal diagnosis for spinal muscular atrophy: Clinical laboratory analysis of >72 400 specimens. Eur J Hum Genet. 2012; 20 (1):27-324. Farrar MA, Park SB, Vucic S, Carey KA, Turner BJ, Gillingwater TH, et al. Emerging therapies and challenges in spinal muscular atrophy. Annals of Neurology. 2017; 81(3):355-3685. Lavie M, Diamant N, Cahal M, Sadot E, Be’er M, Fatal A, Sagi L, Domany KA, Amirav I. Nusinersen for Spinal muscular Atrophy Type 1: real World Respiratory Experience. Pediatr Pulmonol 2020; XXXX; doi xxxx6. Finkel RS, Mercuri E, Darras BT, Connolly AM, Kuntz NL, Kirschner J, et al. Nusinersen versus sham control in infantile-onset spinal muscular atrophy. N Engl J Med. 2017; 377:1723-17327. LoMauro A, Mastella C, Alberti K, Masson R, Aliverti A, Baranello G. Effect of nusinersen on respiratory muscle function in different subtypes of type 1 spinal muscular atrophy. American Journal of Respiratory and Critical Care Medicine. 2019 Dec 15;200(12):1547-508. Sansone VA, Pirola A, Albamonte E, Pane M, Lizio A, et al Respiratory Needs in Patients with Type 1 Spinal Muscular Atrophy Treated with Nusinersen. The Journal of Pediatrics. 2020; 219 P223-228. E49. K-A. Chen, J. Widger, A. Teng, D.A. Fitzgerald, A. D’Silva, M. Farrar, Real-world respiratory and bulbar comorbidities of SMA type 1 children treated with nusinersen: 2-year single centre Australian experience, Paediatric Respiratory Reviews (2020), doi: httpds://doi.org/10.1016/j.prrv.2020.09.00210. Fitzgerald DA, Doumit M, Abel F. Changing respiratory expectations with the new disease trajectory of nusinersen treated spinal muscular atrophy [SMA] type 1. Paediatric Respiratory Reviews. 2018 Sep 1;2 8:11-7.11. Hull J, Aniapravan R, Chan E, Chatwin M, Forton J, Gallagher J, Gibson N, Gordon J, Hughes I, McCulloch R, Russell RR. British Thoracic Society guideline for respiratory management of children with neuromuscular weakness. Thorax. 2012 Jul 1;67(Suppl 1):i1-40.12. Wang CH, Finkel RS, Bertini ES, Schroth M, Simonds A, Wong B, Aloysius A, Morrison L, Main M, Crawford TO, Trela A. Consensus statement for standard of care in spinal muscular atrophy. Journal of child neurology. 2007 Aug;22(8):1027-49.13. Finkel RS, Mercuri E, Meyer OH, Simonds AK, Schroth MK, Graham RJ, Kirschner J, Iannaccone ST, Crawford TO, Woods S, Muntoni F. Diagnosis and management of spinal muscular atrophy: Part 2: Pulmonary and acute care; medications, supplements and immunizations; other organ systems; and ethics. Neuromuscular Disorders. 2018 Mar 1;28(3):197-207.14. Young HK, Lowe A, Fitzgerald DA, Seton C, Waters KA, Kenny E, Hynan LS, Iannaccone ST, North KN, Ryan MM. Outcome of noninvasive ventilation in children with neuromuscular disease. Neurology. 2007 Jan 16;68(3):198-201.15. Boemer F, Caberg JH, Dideberg V, Dardenne D, Bours V, Hiligsmann M, Dangouloff T, Servais L. Newborn screening for SMA in Southern Belgium. Neuromuscular Disorders. 2019 May 1;29(5):343-9.

Background: Ventilated neonates with respiratory distress may show a ventilation-perfusion (V/Q) mismatch. Objective: To evaluate the difference between the Bohr (Vd,Bohr) and Enghoff (Vd,Enghoff) dead spaces in infants by using volumetric capnography (Vcap) based on ventilator graphics and capnograms. Methods: This study enrolled 46 ventilated infants (mean birth weight, 2239 ± 640 g; mean gestational age, 35.5 ± 3.3 weeks). We performed Vcap and calculated Vd,Bohr and Vd,Enghoff when arterial blood sampling was necessary for treatment. Each measurement was classified according to the severity of acute respiratory distress syndrome (ARDS) by using the Berlin definition: severe or moderate ARDS, ratio of partial pressure of oxygen to fraction of inspired oxygen (P/F ratio) ≤ 200; mild ARDS, 200 < P/F ratio ≤ 300; and non-ARDS, 300 < P/F ratio. Next, regression analysis was performed to evaluate the correlation between the P/F ratio and the difference between Vd,Enghoff and Vd,Bohr. Results: Median Vd,Enghoff/tidal volume (VT) was significantly higher in the ARDS groups (severe or moderate: 0.60 [IQR, 0.49–0.68]; mild: 0.50 [0.43-0.59]) than in the non-ARDS group (0.45 [0.36-0.56]). The ARDS groups showed a large difference between Vd,Enghoff and Vd,Bohr (severe or moderate: median, 0.23 [0.15-0.30]; mild: median, 0.14 [0.09-0.21] vs. control: median, 0.09 [0.06-0.13]). The regression analysis for the relationship between P/F ratio and Vd,Enghoff - Vd,Bohr showed a negative correlation (r = -0.55, p < 0.001). Conclusion: Ventilated neonates with respiratory distress showed a large difference between Vd,Enghoff and Vd,Bohr, possibly reflecting a low V/Q mismatch and right-to-left shunting.

An Unusual Case of Necrotizing Pneumonia Presenting with Acute Kidney InjuryUgur Berkay Balkanci, MDSchool of Public Health, University of Minnesota, Minneapolis, MNDavid J. Sas, DODivision of Pediatric Nephrology and Hypertension, Department of Pediatrics and Adolescent Medicine, Mayo Clinic, Rochester, MinnesotaNadir Demirel, MDDivision of Pediatric Pulmonology, Department of Pediatrics and Adolescent Medicine, Mayo Clinic, Rochester, MinnesotaCorresponding Author:Nadir Demirel, MDDivision of Pediatric Pulmonology200 First Street SWRochester, MN 55906Tel. No.: 5075380754Fax No.: [email protected] words: postinfectious glomerulonephritis, pneumothorax, complications, complicated pneumoniaFinancial Disclosure: The authors have indicated they have no financial relationships relevant to this article to disclose.Funding: No external funding.Short title: “An unusual case of necrotizing pneumonia”To the Editor:Lower respiratory tract infections are the most common reason for hospitalization in the pediatric age group in the United States. Although pneumonia is prevalent, complicated pneumonia such as empyema, lung abscess and necrotizing pneumonia (NP) is uncommon in children1. The prevalence of complicated pneumococcal pneumonia decreased significantly after the introduction of the thirteen-valent pneumococcal vaccine in 20101. NP in the pediatric population is a severe disease characterized by extensive destruction and liquefaction of the lung tissue resulting in loss of the pulmonary parenchymal architecture, cavitation of the lung, and pleural involvement. Renal complications of complicated pneumonia are rare and mostly reported as atypical hemolytic uremic syndrome (HUS)2. Post-infectious glomerulonephritis (PIGN) is an unexpected complication of bacterial pneumonia3.We report a six-year-old otherwise healthy fully vaccinated girl with a 4-day history of fever, abdominal pain, vomiting, non-bloody diarrhea, and poor oral intake. Parents reported decreased urine output and dark-colored urine on the day of admission. Initial evaluation revealed serum creatinine of 5.01 mg/dL and blood urea nitrogen of 86 mg/dL, elevated acute phase reactants suggesting acute kidney injury (AKI) in the setting of an undiagnosed acute infectious process. The patient was admitted with decreased effective circulatory volume. Urinalysis revealed hematuria with <25% dysmorphic red blood cells (RBCs), proteinuria, pyuria, and RBC casts and granular casts, suggestive of acute glomerulonephritis.She was started on intermittent hemodialysis at day 2 of admission to address uremia, fluid overload, and hyperphosphatemia. A renal biopsy revealed diffuse exudative glomerulonephritis, consistent with infection-related glomerulonephritis. ASO, Anti-DNase B were negative; C3, C4 levels were low. She was treated with pulse IV methylprednisolone 10mg/kg/day for three days. The first 5 days in the hospital, the patient remained afebrile and her lung exam was normal without respiratory symptoms.On day six of admission, she developed acute right-sided chest pain and shortness of breath during hemodialysis. Chest x-ray (CXR) revealed a large right-sided tension pneumothorax, prompting therapeutic chest tube placement. Repeat CXR revealed reexpansion of the right lung and a significant right upper lobe consolidation with an ovoid hyperlucency and an air-fluid level. A chest CT scan confirmed the diagnosis of NP with multiple cavities (Image).Flexible bronchoscopy was performed with bronchoalveolar lavage revealing 42% neutrophils and negative cultures. She was treated with broad spectrum intravenous antibiotics.During admission, she developed hypertension, well-controlled with scheduled enalapril and amlodipine, as well as isradipine as needed. On day 14 of admission, hemodialysis was discontinued as kidney function improved, and chest tube was removed. She was discharged at day 26 of admission on intravenous ceftriaxone and oral metronidazole to complete 30 days of treatment. A repeat chest CT at end of treatment showed complete resolution of NP. Renal functions and blood pressure normalized on follow up.NP is characterized by persistent high fevers and prolonged hospitalizations even with appropriate antibiotic treatment1. Most often, NP affects immunocompetent children with no underlying risk factors4. The pathophysiology of this complication is acute liquefactive necrosis of the lung parenchyma which results in the development of pneumatoceles4. The most common pathogen causing NP is Streptococcus pneumoniae followed by Staphylococcus aureus and Streptococcus pyogenes. Other rarer bacterial and viral pathogens are Mycoplasma pneumonia, Influenza, and Adenovirus1. Identifying the microbiologic pathogen can be challenging and is only made in 50% of cases1. In our case, we did not isolate the causative microorganism. NP typically resolves without residual morbidity, even after a protracted course1,4.Pleural involvement is almost universal in NP, and the course of pleural disease often determines duration and outcome, particularly as it relates to the complication of bronchopleural fistula (BPF)1. BPF is most likely due to the necrotic development of a connection between bronchial space and pleural space4. BPF formation is associated with a significantly longer hospital stay in children with NP4. Yet, most cases heal without surgical intervention4. Tension pneumothorax has been observed as a rare complication of NP1.Renal involvement in complicated pneumonia is rare. Atypical HUS has been reported as a complication of pneumonia, particularly associated with empyema. (most commonly due to invasive Streptococcus pneumoniae)2. In a case series of 37 cases of atypical HUS, 34 patients (92%) had pneumonia with 10 patients (29%) with NP5. Less commonly, pneumonia can be associated with PIGN. PIGN is the most common glomerulonephritis in children worldwide. Pneumonia-associated PIGN is rare. In a case series from the US, PIGN accounted for 0.15% of admissions for pneumonia and 0.39% of admissions for glomerulonephritis6. Pneumonia-associated PIGN is known to be caused by various bacterial pathogens including Streptococcus pneumoniae, Staphylococcus aureus, Mycoplasma pneumoniae, Chlamydia pneumoniae, Nocardia, and Coxiella burnetii3. Different from the usual presentation of the PIGN (in which the time interval between a pharyngeal group A Streptococcal infection and PIGN is 6 to 10 days), pneumonia-associated PIGN is usually concomitant with the pulmonary disease3,6.Our case is unusual in several ways: pneumonia-associated PIGN typically presents with respiratory symptoms first, and acute kidney injury developing during the course of pneumonia3. More surprisingly, the patient developed NP which is characterized by even more severe respiratory symptoms1. Yet, our patient presented without respiratory complaints and pneumonia became apparent only after the development of pneumothorax. We could only identify 2 cases of pneumonia-associated PIGN who presented with renal involvement before pulmonary complaints6,7. Also, previous cases in the literature of pneumonia-associated PIGN report mostly a non-complicated course of pulmonary disease3,6. In a case series of 11 children with pneumonia-associated PIGN, only one case developed a small empyema6. Similarly, the majority of the reported cases of pneumonia-associated PIGN describe a benign course of renal disease3,6. Our patient’s kidney failure progressed rapidly, and she required 2 weeks of intermittent hemodialysis and a three-day course of pulse steroid therapy. At present, systemic corticosteroids are not recommended for patients with complicated pneumonia. A Cochrane review including 17 randomized controlled trials, of which four were conducted on children, found that corticosteroid therapy reduced mortality and morbidity in adults with severe CAP, and morbidity, but not mortality, in adults and children with non-severe CAP1. We speculate that pulse steroid treatment may have modified the course of NP in our patient.This case suggests an atypical presentation of NP with predominant renal complications is possible. Pediatricians should be aware of renal complications of respiratory diseases. Systemic steroids should be considered in the treatment of NP.References:1. de Benedictis FM, Kerem E, Chang AB, Colin AA, Zar HJ, Bush A. Complicated pneumonia in children. Lancet 2020;396:786-798.2. Spinale JM, Ruebner RL, Kaplan BS, Copelovitch L. Update on Streptococcus pneumoniae associated hemolytic uremic syndrome. Curr Opin Pediatr 2013;25:203-208.3. Carceller Lechón F, de la Torre Espí M, Porto Abal R, Écija Peiró JL. Acute glomerulonephritis associated with pneumonia: a review of three cases. Pediatr Nephrol 2010;25:161-164.4. Sawicki GS, Lu FL, Valim C, Cleveland RH, Colin AA. Necrotising pneumonia is an increasingly detected complication of pneumonia in children. Eur Respir J 2008;31:1285-1291.5. Banerjee R, Hersh AL, Newland J, Beekmann SE, Polgreen PM, Bender J, Shaw J, Copelovitch L, Kaplan BS, Shah SS. Streptococcus pneumoniae-associated Hemolytic Uremic Syndrome Among Children in North America. Pediatr Infect Dis J 2011;30:736-739.6. Srivastava T, Warady BA, Alon US. Pneumonia-associated acute glomerulonephritis. Clin Nephrol 2002;57:175-182.7. Schachter J, Pomeranz A, Berger I, Wolach B. Acute glomerulonephritis secondary to lobar pneumonia. Int J Pediatr Nephrol 1987;8:211-214.

Background: Patient-reported outcomes (PROs) that assess health-related quality of life (HRQoL) are increasingly important components of cancer care and research that have been infrequently used in sub-Saharan Africa (SSA). We aimed to longitudinally measure HRQoL among pediatric lymphoma patients in Malawi. Methods: We administered the Chichewa Pediatric Patient-Reported Outcome Measurement Information System Pediatric (PROMIS)-25 at diagnosis, active treatment, and follow-up among pediatric lymphoma patients in Lilongwe, Malawi. Mean scores were calculated for the six PROMIS-25 HRQoL domains (Mobility, Anxiety, Depressive Symptoms, Fatigue, Peer Relationships, and Pain Interference) using the PROMIS scoring manual. Results: Seventy-five children completed PROMIS-25 surveys at diagnosis, 35 (47%) during active treatment, and 24 (32%) at follow-up. The majority of patients died (n= 37, 49%) or were lost-to-follow-up (n=8, 11%). Most (n=51, 68%) were male, median age was 10 (IQR 8-12), 48 (66%) presented with advanced Stage III/IV, 61 (81%) were diagnosed with Burkitt lymphoma and 14 (19%) had Hodgkin lymphoma. At diagnosis, HRQoL was poor across all domains, except for Peer Relationships. Improvements in HRQoL during active treatment and follow-up exceeded the minimally important difference. Poor Lanksy performance status ≤ 70 and Pain Intensity = 10 at diagnosis were associated with increased mortality risk and worse survival. Conclusions: Our experience suggests incorporating assessments of HRQoL via PROs in oncology care is feasible in SSA, can provide prognostic information, and generates clinically meaningful data to inform supportive care interventions. Further, PROs offer an opportunity to include patient voices and prioritize holistic patient-centered care even in low-resource settings.

COVID-19 has created challenges for society and the medical community. While the pandemic continues to unfold, the transplant community has had to pivot to keep recipients, donors, and transplant teams safe given these unprecedented times. This has resulted in a decrease in the number of transplants performed in the United States and an increased number of inactive patients on the UNOS waiting list.1 Waitlist and transplant recipients have an increased risk for acquiring COVID-19. It is speculated that this patient population is particularly vulnerable given their immunocompromised status and the high prevalence of comorbidities.2 Given the uncertainty surrounding the risk of transplant patients contracting COVID-19, there is interest in describing these cases in the literature.

In reconstructive rhinoplasty, the nasal framework must be securely fixated to the facial bony skull. We present a surgical technique to fixate the nasal L-strut to the facial skull by using exclusively titanium L-shaped micro-plates in cases where the anterior nasal spine and the nasal bones cannot be used