Misconceptions on Behavioral Cough Suppression Therapy for Pediatric Nonspecific Cough: A Response to Weinberger and Buettner’s Commentary on Fujiki et al.Laurie Slovarp, PhD, School of Speech, Language, Hearing, & Occupational Sciences, University of MontanaMarie Jette, PhD, Department of Otolaryngology – Head and Neck Surgery, University of Colorado Anschutz Medical CampusJane Reynolds, PhD, School of Speech, Language, Hearing, & Occupational Sciences, University of MontanaAmanda Gillespie, PhD, Department of Otolaryngology and Head and Neck Surgery, Emory UniversityJulie Barkmeier-Kraemer, PhD, Division of Otolaryngology – Head and Neck Surgery, University of UtahMary Sandage, PhD, Speech, Language, and Hearing Sciences, Auburn UniversityJaclyn Smith, PhD, Biology, Medical and Health Sciences, The University of ManchesterJemma Haines, BSc(Hons), Medical and Health Sciences, The University of Manchester, Manchester University NHS Foundation TrustAnne Vertigan, PhD, School of Medicine and Public Health, University of NewcastleStuart Mazzone, PhD, Department of Anatomy and Physiology, University of MelbourneCorresponding author: Laurie Slovarp, PhD,School of Speech, Language, Hearing, & Occupational Sciences, University of Montana, Missoula, MT, 59812. [email protected] (p) 406-243-2107 (f) 406-243-2362 Orcid ID: 0000-0002-3547-4092Key words : pediatric chronic cough, habit cough, suggestion therapy, speech-language pathologyFunding : noneConflicts of Interest: The authors declare no conflicts of interest.Author Contributions :Laurie Slovarp: conceptualization, writing original draft, review and editingMarie Jette: conceptualization, writing original draft, review and editingJane Reynolds: conceptualization, writing original draft, review and editingAmanda Gillespie: conceptualization, writing original draft, review and editingJulie Barkmeier-Kraemer: review and editingMary Sandage: review and editingJaclyn Smith: review and editingJemma Haines: review and editingAnne Vertigan: review and editingStuart Mazzone: writing, review, and editingAbstract/Summary : This commentary responds to Weinberger and Buettner’s critique of Fujiki et al.’s study on behavioral cough suppression therapy (BCST) for pediatric chronic cough. While acknowledging their contributions, it addresses inaccuracies and clarifies key aspects of BCST. The commentary highlights discrepancies in terminology, challenges assertions regarding diagnostic evaluations, and emphasizes the need for controlled trials to assess treatment efficacy.In their engagement with the study by Fujiki et al.1, Weinberger and Buettner2 bring attention to critical aspects of behavioral cough suppression therapy (BCST) and pediatric chronic cough treatment. While their contributions are valued, it is imperative to address certain inaccuracies and clarify key aspects of the study and BCST provided by specialized speech-language pathologists (SLPs).Firstly, Weinberger & Buettner inaccurately state that Fujiki et al. identified the children as having ”behavioral cough.” The term ”behavioral cough” in the paper was used only in the context of ”behavioral cough suppression therapy,” describing the treatment rather than the children’s cough diagnosis. The authors, in fact, used the term ”nonspecific cough/tic cough” in accordance with current CHEST and ERS guidelines3-5. Weinberger & Buettner’s assertion that ”historical evidence and current practice support “habit cough” as the appropriate diagnosis” lacks substantiation and contradicts contemporary CHEST guidelines5. We are particularly puzzled by Weinberger & Buettner’s advocacy for the term habit cough when Dr. Weinberger is listed as an author on a 2015 CHEST guidelines publication that explicitly advises against the use of these terms, deeming them ”out of date and inaccurate”5.Weinberger & Buettner also criticize the use of extensive evaluations for the children in the sample, arguing that “habit cough” can be diagnosed based on clinical presentation alone—specifically in the presence of a barking or honking cough and absence of the cough during sleep. Interestingly, the same CHEST guidelines, of which Weinberger is an author, specifically cautions against using the diagnostic terms of “psychogenic” or “habit cough” solely based on a barking or honking sound or the absence of cough during sleep, stating that these three clinical presentations lack specificity5. A barking or honking cough can occur with other diseases such as tracheomalacia or bronchiectasis6; and it is well documented that sleep inhibits the cough reflex in adults even when an organic disease process is identified7; 8. Without evidence to the contrary, it is should be assumed that sleep similarly suppresses cough in children. Further, the purpose of Fujiki et al.’s paper was to examine whether BCST improves cough in children and to describe cough characteristics and comorbidities, not to advocate for extensive assessments. Although, it is noteworthy that laryngoscopy revealed structural laryngeal pathology in several cases, challenging Weinberger & Buettner’s assertion that the described assessments were unjustified.Regarding the treatment described in Fujiki et al., Weinberger & Buettner characterize BCST as an “alternative to suggestion therapy.” This overlooks that BCST instructs in strategies to suppress cough, akin to his “suggestion therapy.” Therefore, it seems that BCST is not necessarily an alternative but rather a similar therapy with a different name. This overlap emphasizes the need for clarity in terminology. Importantly, in adults with chronic cough a loss of centrally (brain) mediated cough suppression has been demonstrated using functional brain imaging9.  Although empirical data in children is not available, it seems conceivable that similar mechanisms may be in operation, providing a neurobiological basis for why cough suppression training is often beneficial and supporting the use of terminology that emphasizes this aspect of the therapy.Additionally, Weinberger & Buettner’s argument that 45 pediatric pulmonologists ”already indicate they readily diagnose habit cough and successfully treat with suggestion therapy,” implies a stance against SLP treatment. However, considering there are thousands of pediatric pulmonologists in the U.S. alone, the sample size of 45 falls short of substantiating the claim that ”many” pulmonologists universally adopt this approach or that additional clinicians, such as SLPs, are unnecessary to assist these patients effectively. The argument lacks robust evidence and fails to account for the role of additional clinicians, such as SLPs, to address pediatric chronic cough effectively. Further, a substantial proportion of children in Fujiki et al.’s sample presented with phonotraumatic lesions (e.g., vocal nodules), which SLPs are specifically trained to address through behavioral treatment.Lastly, Weinberger & Buettner suggest that conducting a controlled trial for suggestion therapy is impractical due to the reported low frequency of referrals. We disagree that the size of the population is a valid argument for not conducting a randomized controlled trial. A control group is needed to robustly assess the efficacy of any treatment, particularly in the case of cough interventions which are particularly vulnerable to placebo effect10; 11. Weinberger & Buettner suggest that it would be unethical to withhold suggestion therapy for the sake of a randomized clinical trial; however, one could easily design a study that allowed for those randomized to a control treatment to be eligible for suggestion therapy upon completion of the control arm. Given Dr. Weinberger’s data suggests suggestion therapy eliminates nonspecific/tic cough in less than one week, such children would need to wait no more than one to two weeks before becoming eligible for suggestion therapy and it should be possible to demonstrate such a substantial effect in a relatively small number of subjects in a randomized controlled trial.We agree with Dr. Weinberger that SLP skills vary. As is the case with any clinical discipline, there are many subspecialties in the field of speech-language pathology and varying levels of skill and expertise within those subspecialties. BCST training is not standard in SLP training programs, and, therefore, requires special training.In conclusion, we think these clarifications underscore the importance of understanding Fujiki et al.’s paper in its correct context, and will advance a more nuanced and informed discussion on pediatric cough disorders and BCST’s role in treatment. We acknowledge Weinberger & Buettner’s contribution to pediatric cough management. The data reported in this letter and other publications12; 13, although anecdotal, suggests that behavioral treatment focused on cough suppression is effective. Given this, we encourage Weinberger and Buettner to complete a randomized controlled efficacy trial. If the data confirms efficacy, the study would significantly elevate the legitimacy of the treatment, increasing its use by other practitioners and benefitting pediatric patients with chronic cough.REFERENCES1. Fujiki RB, Wright ML, Fujiki AE, Thibeault SL. 2023. Factors influencing behavioral cough suppression therapy in children with nonspecific chronic cough. Pediatr Pulmonol. 58(12):3466-3477.2. Weinberger M, Buettner D. 2024. The habit cough syndrome. Pediatr Pulmonol. 59(2):260-262.3. Chang AB, Oppenheimer JJ, Irwin RS, Panel CEC. 2020. Managing chronic cough as a symptom in children and management algorithms: CHEST guideline and expert panel report. Chest. 158(1):303-329.4. Morice AH, Millqvist E, Bieksiene K, Birring SS, Dicpinigaitis P, Domingo Ribas C, Hilton Boon M, Kantar A, Lai K, McGarvey L et al. 2020. ERS guidelines on the diagnosis and treatment of chronic cough in adults and children. Eur Respir J. 55(1).5. Vertigan AE, Murad MH, Pringsheim T, Feinstein A, Chang AB, Newcombe PA, Rubin BK, McGarvey LP, Weir K, Altman KW et al. 2015. Somatic cough syndrome (previously referred to as psychogenic cough) and tic cough (previously referred to as habit cough) in adults and children: CHEST guideline and expert panel report. Chest. 148(1):24-31.6. Spinou A, Lee KK, Sinha A, Elston C, Loebinger MR, Wilson R, Chung KF, Yousaf N, Pavord ID, Matos S et al. 2017. The objective assessment of cough frequency in bronchiectasis. Lung. 195(5):575-585.7. Lee KK, Birring SS. 2010. Cough and sleep. Lung. 188 Suppl 1:S91-94.8. Power JT, Stewart IC, Connaughton JJ, Brash HM, Shapiro CM, Flenley DC, Douglas NJ. 1984. Nocturnal cough in patients with chronic bronchitis and emphysema. Am Rev Respir Dis. 130(6):999-1001.9. Ando A, Smallwood D, McMahon M, Irving L, Mazzone SB, Farrell MJ. 2016. Neural correlates of cough hypersensitivity in humans: Evidence for central sensitisation and dysfunctional inhibitory control. Thorax. 71(4):323-329.10. Eccles R. 2009. Central mechanisms iv: Conscious control of cough and the placebo effect. Handb Exp Pharmacol. (187):241-262.11. Eccles R. 2010. Importance of placebo effect in cough clinical trials. Lung. 188 Suppl 1:S53-61.12. Lokshin B, Lindgren S, Weinberger M, Koviach J. 1991. Outcome of habit cough in children treated with a brief session of suggestion therapy. Ann Allergy. 67(6):579-582.13. Weinberger M, Hoegger M. 2016. The cough without a cause: Habit cough syndrome. J Allergy Clin Immunol. 137(3):930-931.

Editorial comment on the Special Issue “Omics in Food Allergy”Riccardo Castagnoli1,2, Ivan Taietti1,2,*, Agnes Sze-Yin Leung3, Philippe Eigenmann41. Pediatric Unit, Department of Clinical, Surgical, Diagnostic, and Pediatric Sciences, University of Pavia, Pavia, Italy2. Pediatric Clinic, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy3. Department of Paediatrics, Faculty of Medicine, The Chinese University of Hong Kong, China4. Pediatric Allergy Unit, Department of Pediatrics, Gynecology and Obstetrics, University Hospitals of Geneva, Geneva, SwitzerlandORCID:Riccardo Castagnoli: 0000-0003-0029-9383Ivan Taietti: 0000-0002-0372-523XAgnes Sze-Yin Leung: 0000-0001-8249-4478Philippe Eigenmann: 0000-0003-1738-1826Corresponding author:Ivan Taietti, MD;Pediatric Unit, Department of Clinical, Surgical, Diagnostic, and Pediatric Sciences, University of Pavia, 27100 Pavia, [email protected]; +39 340 7092400.Food allergy (FA), defined as an adverse reaction to food mediated by the immune system, is a significant public health issue with increasing prevalence over the past decades. Although FA affects up to 10% of children, the precise mechanisms underlying FA development and persistence remain inadequately understood1. Food immunotherapy has been successful in increasing the threshold of tolerance in individuals with persistent FA (desensitization), and in a subset, sustained unresponsiveness (remission) can be achieved. A combination of environmental and genetic factors is considered to be involved in the tolerance induction to food allergens. However, to date, it has been difficult to fully dissect the complexity of the biological determinants involved in FA.The emergence of “omics” sciences, including genomics, transcriptomics, proteomics, and metabolomics, is revolutionizing the basic and translational research approach, allowing for the comprehensive study of biological processes through analyzing and integrating multiple datasets from various biological perspectives.Moreover, epigenetic studies that evaluate the role of gene expression modifiers are deepening our understanding of the interaction between genetic predisposition and environmental influences.The Special Issue “Omics in Food Allergy” aims to present current knowledge and future perspectives in the field of FA through the lenses of omics sciences.Chun et al. and Lehmann et al. provide a detailed overview of epigenetic mechanisms involved in FA, including DNA methylation and microRNA (miRNAs)2,3. DNA methylation refers to the covalent addition of a methyl group, typically to a cytosine in a CpG dinucleotide in DNA. This limits access for transcription, frequently in the promoter region, leading to reduced gene expression. Moreover, miRNAs are small RNAs transcribed from intergenic or intronic genomic loci that decrease gene expression by mRNA degradation and translational inhibition. Of note, Chun et al. described two different approaches in investigating FA mechanisms: (i) the epigenome-wide research approach and (ii) candidate-gene investigations. The epigenome-wide research approach identified genomic regions differently methylated and regulated, involved in FA causation, antigen presentation, T cell development, and reaction severity. Candidate-gene investigations focused on Th1, Th2, T regulatory, and innate genes of interest in FA, highlighting the importance of methylation changes in specific candidate genes. In this context, for cow’s milk allergy (CMA), the attention is focused on novel genetic loci involved in Th1/Th2 differentiation pathways and potential B-cell dysfunction4. Of note, miRNA seems to be involved in CMA as demonstrated by the downregulation of mi193a-5p, a post-transcriptional regulator of IL-4 expression, in infants with CMA5. Moreover, methylation levels in peripheral blood mononuclear cells for IL-4, IL-5, IL-10, and IFN-γ negatively correlate with their respective serum cytokine concentrations and vary according to CMA status (active, resolved, or non-CMA). Finally, Chun et al. reviewed ongoing research aimed at finding DNA methylation predictors of food challenges. Initial work based on the concept of epigenetic markers as biomarkers of disease and treatment demonstrated promise for applying DNA methylation markers to potentially improve how we assess and manage patients with FA, but further validation in larger cohorts and work to practically translate such biomarkers to clinical practice is advocated2.Metabolomics may reflect the integration of genetic, transcriptomic, and proteomic variations with environmental factors, thus reflecting molecular processes of diseases. A metabolome approach would facilitate the identification of surrogate metabolite markers correlating with the disease activity and prognosis. Lee et al. reported an updated overview of metabolomics’s current application in the FA field. Alterations to the gut microbiota induced by Western dietary patterns are likely to profoundly affect host immunity and play a significant role in FA. Metabolites of interest include short-chain fatty acids (SCFAs), bile acid metabolites, and tryptophan metabolites due to their essential roles in normal immune development and homeostasis. SCFAs appear to be reduced in FA patients. Of note, it has been shown that bacterial SCFAs could protect against FA as a consequence of a high-fiber diet in mice. Accordingly, a reduction in Bifidobacterium during infancy, with a consequent reduction in SCFA levels is associated with an increased risk of allergy6. In peanut allergy, oral dysbiosis, reduced oral SCFA levels, and increased oral mucosal Th2 cytokine secretion characterize patients affected, and low fecal SCFAs at a young age could raise the risk of developing FA. Bile acid levels in stool seem to be involved in FA development and persistence, but blood level measurements are advocated to better characterize their role. Moreover, sphingolipids may modulate the function of invariant natural killer T cells and contribute to maintaining intestinal balance and protecting against FA through the modulation of the mast cells’ responsiveness. Sphingolipid dysmetabolism is involved in FA development as a consequence of immune dysregulation in modulating the differentiation of regulatory T cells and Th17 cells that is relevant in FA. Interestingly, some fecal sphingolipids seem to confer protection against FA while reduction of other of them seems to be associated with increased risk of FA, likewise the reduction in serum sphingolipids. Unfortunately, no definitive evidence is available to distinguish whether the sphingolipids modulating this FA effect are dietary or microbial-derived. Metabolites of tryptophan from kynurenine and indole pathways are linked to the function of the intestinal barrier and mucosal immune responses (mainly T regulatory cells) and contribute to intestinal homeostasis. A reduction in these pathways is linked to multiple FA in children. To date, the role of omega-3-polyunsaturated fatty acids metabolites is not clearly defined in FA. However, 17-hydroxy-docosahexaenoic acid (17-HDHA) has been reported to inhibit IgE production by B cells and to suppress the differentiation of naïve B cells into IgE-secreting cells7.The gut microbiome (GM) and its metabolic product, as previously mentioned, play an important role in FA development. TheBifidobacteriaceae family and bacteria of theLactobacillales order are consistently reported lower in CMA children. At the same time, the Firmicutes phylum, primarily associated with the Clostridia class, is consistently increased in mice and human studies. It seems discordant with the observation that infants with resolved CMA were reported to have enrichedClostridia class at 3-6 months but with non-conclusive data. However, Savova et al. showed that GM with enriched Clostridiaclass, reduced Lactobacillales order, and reducedBifidobacterium genus is associated with CMA in early life. Emerging evidence shows that prebiotics, probiotics, and symbiotics, may be a promising adjuvant in promoting tolerance acquisition. ElevatedBifidobacterium genus and reduced Clostridia class members were consistently observed post-treatment with Bifidobacteriumstrains probiotics or after lactose-supplemented extensively hydrolyzed formula (EHF) treatment strategy but with decreased levels ofLactobacillus genus in those treated with Bifidobacteriumstrains probiotics. Gaps remain in understanding the relationship between microbiome and immune response and between transcriptomics (including genes related to the immune response) and GM. In vivo ,Bifidobacterium bifidum has been shown to reduce allergy symptoms, lower serum IgE and raise IgG2 levels, decrease the pro-inflammatory cytokines (TNFα, IL- 1β, and IL-6), and increase the anti-inflammatory cytokine IL-10 in CMA-patients8. Recently, fiber diet has been shown to modulate the disease course of FA through diet-driven changes in the GM9. It is necessary to conduct further research on the impact of GM on FA development and persistence.Lastly, oral immunotherapy (OIT) may provide an active treatment that enables to increase the amount of food that the patient can intake without reaction during treatment (i.e., desensitization), and reduces the risk of potential life-threatening allergic reaction in the event of accidental ingestion10 Unfortunately, there are still significant gaps in understanding the immune mechanisms following OIT, but increasing knowledge about transcriptional pathways associated with its outcomes is available to date11. Ashley et al.12 show that OIT-induced remission of FA is linked to the anergic T cell state mediated by anergy of memory T cells associated with mantained T regulatory cell activity. Suppression of the Th2 transcriptional signals in Th2A-like cells was linked to desensitization following OIT. Moreover, the dampened Th2 and Th1 signatures in effector cells are linked with FA remission, while baseline inflammatory signals in Th1 and Th17 effector cells were associated with poorer outcomes following OIT. Type I interferons were recently identified as potential regulators of remission following OIT because of their key role in the suppression of the Th2 antigen response through regulatory action on GATA3 and the high-affinity IgE receptor. Moreover, an early transient increase in TGF-β producing cells one year into treatment seems to be associated with good clinical outcomes. In addition, persistent activation of FOXP3, expressed by T regulatory cells, may be a critical requirement for lasting persistence of remission12.Comprehensive multi-omics studies are essential to understand FA mechanistically, as highlighted by this Special Issue. “Omics” studies of FA are of great interest as they allow for a thorough understanding of the complexity of FA development and therapeutic outcomes. This has a fundamental impact on approaches to precision medicine.

Chronic inflammatory demyelinating polyneuropathy. A case descriptionGarcia-Castillo M.Written informed consent was obtained from the patient to publish this report in accordance with the journal’s patient consent policy.

The study focused on the impact and action mechanism of different organic selenium products on the bioactivity of two strains of Lactobacillus paracasei. The growth, antioxidant activity, extracellular polysaccharide secretion, quorum sensing and biofilm formation of the strains before and after the addition of organic selenium crude products and three organic selenium standard were evaluated. The results showed that the addition of crude organic selenium had a promoting effect on the growth, antioxidant activity, extracellular polysaccharide, biofilm formation, and AI-2 activity of the strain. The organic selenium standards had a regulatory effect (positive and negative) on biofilm formation and the activity of the QS signal molecule AI-2 in the strain. L-selenocysteine had the strongest regulatory effect, with maximum GIM1.80 biofilm formation when it reached a critical concentration of 0.4 μg/ml; L-selenomethionine resulted in the highest activity of the signal molecule AI-2 of GDMCC1.155, when it reached a critical concentration of 0.4 μg/ml. The results of scanning electron microscopy demonstrated that organic selenium effectively improved the morphology and structure of the bacterial cells of the two strains. Molecular docking revealed that the mechanism by which organic selenium regulates quorum sensing in Lactobacillus was achieved by binding two crucial receptor proteins (histidine protein kinase HKP and periplasmic binding protein LuxP) from specific sites. It provides a new alternative (organic selenium) for regulating the viability and beneficial activity of Lactobacillus paracasei. Significance statement: The study found that organic selenium can both positively and negatively regulate quorum sensing and biofilm formation of Lactobacillus, and the critical concentrations have also been obtained. Meanwhile, it was found that organic selenium can promote the growth, antioxidant activity, and biofilm formation of Lactobacillus by activating quorum sensing, so as to better exert its probiotic properties. Furthermore, the regulating mechanism of organic selenium on the activity of Lactobacillus was revealed. This study provides a new alternative for regulating and stimulating the beneficial activity of probiotics.

Evaluation of flow dynamics in dSINE (distal Stent graft-induced New Entry) using 4D flow MRIKenji Sakakibara1), Hiroyuki Nakajima1), Yudai Hagihara1), Chie Nakamura1), Daichi Shikata1), Yuki Takesue1), Satoru Shiraiwa1),Yoshihiro Honda1),Shigeaki Kaga1)Masahiro Hamasaki2), Hisashi Johno2)1) Department of Surgery (II), Faculty of Medicine, University of Yamanashi2) Department of Radiology, Faculty of Medicine, University of Yamanashi

Roegneria yenchiana sp. nov. (Triticeae) is described as a new species collected from Shangri-la of Yunnan Province in China based on morphological, cytological, and molecular data. It is morphologically characterized by one spikelet per node, rectangular glums, awns flanked by two short mucros in lemmas, which is distinguished from other species of Roegneria. The genomic in situ hybridization results indicate that R. yenchiana is an allotetraploid, and its genomic constitution is StY. Phylogenetic analyses based on multiple loci suggested that R. yenchiana is closely related to Pseudoroegneria and Roegneria, and the Pseudoroegneria served as the maternal donors during its polyploid speciation.

Microfiltration is an essential step during biopharmaceutical manufacturing. However, unexpected flux decay can occur. Although the flux decay profile and initial flux are important factors determining microfiltration filterability, predicting them accurately is challenging since the root cause of unexpected flux decay remains elusive. In this study, the methodology for developing a prediction model of flux decay profiles was established. First, the filtration profiles of different monodisperse polystyrene latex and silica beads of various sizes were evaluated. These results revealed that the size and surface electrostatic properties of the beads affect the flux decay profile. Taking the size and surface electrostatic properties of protein aggregates into account, we constructed a predictive model using model bead filtration profiles. We showed that this methodology was applicable to two different microfiltration filters to predict the flux decay profile of therapeutic proteins. Since this prediction model is based on normalized flux, the initial flux must be predicted. We therefore successfully developed a method to predict initial flux based on the Hagen-Poiseuille equation using sample viscosity values for both filters. These prediction models can be used for effective microfiltration scale-up assessment and can be applied during early stage of process development.

Opportunities for Trauma-Informed Medical Care in Cystic FibrosisTo the Editor:People living with Cystic Fibrosis (PwCF) face a lifetime of potentially traumatic medical experiences. These experiences can range from invasive medical treatments (e.g. venipuncture, nasogastric tube placement) to daily illness-related events (e.g. illness related bullying). These experiences place PwCF at high risk for a type of posttraumatic stress called Medical Traumatic Stress (MTS)[1]. With the growing recognition of the high prevalence and impact of MTS, we anticipate that cystic fibrosis care teams may soon be tasked with integrating trauma-informed medical care into their clinical practices. CF care teams are well poised to prevent and screen for MTS because they 1) create the environment for many illness-related experiences; 2) have established workflows for mental health screening; and, in many cases, 3) have trusting relationships with PwCF and their families. Here, we seek to highlight the opportunities for implementing trauma-informed medical care within the cystic fibrosis-specific context.MTS is defined as the psychological and physiological responses of children and their families to pain, injury, serious illness, medical procedures, and invasive or frightening treatment experiences[2]. MTS is common in PwCF – 55% of these youth report experiencing potentially traumatic medical experiences and 30% report MTS symptoms[1]. MTS symptoms have the potential to impact medical care, health outcomes and quality of life[3].While highly effective modulator therapies may decrease the frequency and severity of medical care, PwCF have identified these therapies as an additional source of potentially traumatic experiences[4]. New potentially traumatic medical experiences in modulator-eligible PwCF can include lost sense of purpose as their identity shifts from a “sick” person to a “well” person; survivor guilt from benefiting from therapies not available to others; and financial distress as they face planning for a longer than anticipated life expectancy [4]. The challenge of navigating the healthcare system, such as advocating with care teams and insurance companies, has been identified as potentially traumatic by PwCF, particularly those who are modulator-ineligible[4].A trauma-informed approach to medical care may be helpful for cystic fibrosis care teams to mitigate MTS. The Pediatric Psychosocial Preventive Health Model (PPPHM) provides a framework for tiered implementation of trauma-informed medical care[5]. It includes recommendations for universal practices gauged towards all children and families, targeted approaches for those at high risk of developing MTS, and treatment for those with severe, escalating, or persistent MTS symptoms (Figure 1).Universal MTS interventions for PwCF include prevention and screening. Preventive interventions can include MTS awareness education for all PwCF, family members of PwCF and cystic fibrosis care team members. This education can highlight approaches to modifying potentially traumatic medical experiences and identifying MTS symptoms that indicate the need for further support. Universal systems interventions may also include the implementation of workflows to minimize the traumatic potential of healthcare experiences (e.g. workflows to minimize needle distress with comfort positioning, numbing cream, and distraction as part of standard care. Care teams can also integrate shared decision-making processes to optimize patient perception of control and implement systems that facilitate communication between cystic fibrosis care team and PwCF.While annual mental health screening for depression and anxiety is the current recommendation for all PwCF, healthcare providers should consider integrating routine MTS screening into their practice. Screening workflows can include screening for patient risk factors and MTS symptoms, as well as family member symptoms of MTS. Currently, there are no screening tools designed to specifically capture the cystic fibrosis experience of MTS; however, acute stress screeners such as the Acute Stress Checklist for Children can aid in the identification of MTS, thereby guiding providers on who to refer for further mental health assessments or support. One common concern regarding screening for MTS is managing the burden of time as well as supporting those PwCF who screen at-risk. Thus, in planning for MTS screening, teams ought to consider the time required for screening, appropriate training for those performing the screening, and the development of a clear workflow for management and referrals. While these barriers require a thoughtful approach to processes and care, the benefits outweigh the consequences of not screening. MTS is present for many regardless of if screening occurs and screening allows the medical team to optimize overall healthcare.The second tier of the PPPHM recommends targeted approaches to MTS for those with risk factors or early symptoms. Possible MTS risk factors in PwCF include parent posttraumatic stress disorder, high daily medication burden, and emergency room and intensive care [1]. Interventions for PwCF who have MTS risk factors or early symptoms may include increasing support during potentially traumatic medical experiences (e.g. having a child life expert prepare a patient before a procedure); altering the medical care plan when possible (e.g. minimizing daily medication burden); educating family members on what to say to PwCF before, during, and after potentially traumatic medical experiences; and integrating patient-specific resilience factors into individualized coping and support plans. In some cases, brief therapeutic psychological interventions may help address specific symptoms (e.g., targeted CBT needle phobia interventions, behavioral sleep interventions, brief psychoeducation interventions).The third tier of the PPPHM recommends treatment for MTS symptoms that impact medical care or impair daily functions. PwCF with significant MTS symptoms should be referred to a mental health provider with expertise in the treatment of trauma symptoms. Ideally, the provider should have familiarity with chronic medical conditions, and, ideally, cystic fibrosis specifically. While we do not yet have evidence-based MTS-specific interventions for PwCF, approaches may include cognitive behavioral techniques such as restructuring of hospital-related thoughts, behavioral activation, or trauma-focused cognitive behavioral therapy. Mental health providers could also collaborate with families and cystic fibrosis care teams to develop an individualized plan for minimizing re-traumatization and reducing the impact of MTS on medical care and quality of life.In summary, given the substantial impact that MTS can have on PwCF, cystic fibrosis care teams should consider integrating trauma-informed approaches into the medical care of PwCF to optimize overall health (including mental health). Comprehensive approaches to MTS mitigation in PwCF include 1) universal awareness, prevention, and screening, 2) targeted interventions for those at high risk, and 3) individualized MTS treatment administered by mental health professionals. To optimize cystic fibrosis care with attention to MTS, future research should prioritize more definitive identification of MTS risk factors, the development of validated cystic fibrosis-specific MTS screening tools, the creation and dissemination of evidence-based MTS prevention programs, and the development of evidence-based MTS mental health interventions tailored to PwCF.Figure 1: Application of the Pediatric Psychosocial Preventative Health Model to Cystic Fibrosis. Adapted with permission from the Center for Healthcare Delivery Science at Nemours Children’s Health System 2018-2019. All rights reserved[5].

Letter to the Editor

Most plant thermal tolerance studies focus on single critical thresholds, which limit the capacity to generalise across studies and predict heat stress under natural conditions. In animals and microbes, thermal tolerance landscapes describe the more realistic, cumulative effects of temperature. We tested this in plants by measuring the decline in leaf photosynthetic efficiency (FV/FM) following a combination of temperatures and exposure times, then modelled these physiological indices alongside recorded environmental temperatures. We demonstrate that a general relationship between stressful temperatures and exposure durations can be effectively employed to quantify and compare heat tolerance within and across plant species and over time. Importantly, we show how FV/FM curves translate to plants under natural conditions, suggesting that environmental temperatures often impair photosynthetic function. Our findings provide more robust descriptors of heat tolerance in plants and suggest that heat tolerance in disparate groups of organisms can be studied with a single predictive framework.

Introduction. Precise electrocardiographic localization of accessory pathways (AP) can be challenging. Seminal AP localization studies were limited by complexity of algorithms and sample size.We aimed to create a non-algorithmic method for AP localization based on color-coded maps of AP distribution generated by a web-based application. Methods. APs were categorized into 19 regions/types based on invasive electrophysiologic mapping. Preexcited QRS complexes were categorized into 6 types based on polarity and notch/slur. For each QRS type in each lead the distribution of APs was visualized on a gradient map. The principle of common set was used to combine the single lead maps to create the distribution map for AP with any combination of QRS types in several leads. For the validation phase, a separate cohort of APs was obtained. Results. A total of 804 patients with overt APs were studied. The application used the exploratory dataset of 552 consecutive APs and the corresponding QRS complexes to generate AP localization maps for any possible combination of QRS types in 12 leads. Optimized approach (on average 3 steps) for evaluation of preexcited ECG was developed. The area of maximum probability of AP localization was pinpointed by providing the QRS type for the subsequent leads. The exploratory dataset was validated with the separate cohort of APs (n = 260); p = 0.23 for difference in AP distribution. Conclusions. In the largest dataset of APs to-date, a novel probabilistic and semi-automatic approach to electrocardiographic localization of APs was highly predictive for anatomic localization.

A Symphony of Anomalies: Isolated Pulmonary Artery Agenesis Meets Congenital Lung HypoplasiaNida Ansari, D.O.1, Sacide S. Ozgur, M.D.1, Alan Alcantara, M.D.1, Yasmeen Sultana, M.D.1Disclosure of Interest: The authors report no conflict of interest. An ethical review is not necessary because this is a case report. This research received no specific grant from funding agencies in the public, commercial, or not-for-profit sectors.Consent: As this is a case report, consent was obtained for the purpose of this paper.Acknowledgments: We would like to acknowledge the patient and his family for allowing us to share this case with our colleagues.Author affiliation: Ansari, N, Ozgur, S, Alcantara, A, performed the literature review and wrote the manuscript, and all authors contributed to the writing, the final editing, and the collection of the patient’s clinical data. All work was performed at St. Joseph’s University Medical Center at the following address:St. Joseph’s University Medical Center Department of Internal Medicine 703 Main Street Paterson, NJ USA 07503 973-754-2000All authors, including the corresponding author, may be reached using the aforementioned contact information.

Intracellular plant defense against pathogens is mediated by a class of disease resistance genes known as NB-LRRs or NLRs (R genes). Many of the diseases these genes protect against are more prevalent in regions of higher rainfall, which provide better growth conditions for the pathogens. As such, we expect a higher selective pressure for the maintenance and proliferation of R genes in plants adapted to wetter conditions. In this study, we enriched libraries for R genes using RenSeq from baits primarily developed from the common sunflower (Helianthus annuus) reference genome. We sequenced the R gene libraries of Silphium integrifolium Michx, a perennial relative of sunflower, from 12 prairie remnants across a rainfall gradient in the Central Plains of the United States, with both Illumina short-read (n=99) and PacBio long-read (n=10) approaches. We found a positive relationship between the mean effective annual precipitation of a plant’s source prairie remnant and the number of R genes in its genome, consistent with intensity of plant pathogen coevolution increasing with precipitation. We show that RenSeq can be applied to the study of ecological hypotheses in non-model relatives of model organisms.

The knowledge of soil moisture spatio-temporal variability is highly relevant for water resources management. This is especially significant in highly demanding areas of arid and semiarid regions where sensitive ecosystems, agriculture and recreational areas are competing for water resources. This study reports an analysis of the spatial-temporal variability of soil moisture data for a small to medium-scale network in a coastal wetland of southwestern Spain. Measurements were taken from 5 sites located in the Doñana National Park, with an extension of approx. 25 × 3 km over the time-period of one hydrological year from September 2017 to September 2018. Absolute soil moisture was separated in two components: the temporal mean (time-invariant term) and the deviations from the mean or anomalies (time-variant term). The time-invariant component was generally the main contributor to the total spatial variance of absolute soil moisture data and it was mostly controlled by the groundwater levels in the area. Nevertheless, the time variant terms have a huge effect on soil moisture variability in very dry states at all 5 sites. Time-dependent patterns were found between average soil moisture state and the variance and covariance of both the time-variant and time-invariant components of soil moisture, which could be used for the up and downscaling of soil moisture from satellite data. Those patterns were only affected by heavy rainfalls giving rise to hysteretic behavior. This study shows that even though groundwater level is a time-variant variable, it significantly affects soil moisture’s time-variant and time-invariant terms.

The prospect of preventing HIV infection with broadly neutralising monoclonal antibodies (bNAbs) has generated unprecedented enthusiasm in the scientific community and hope among people living with HIV around the world. HIV bNAbs could be a game changer in the prevention of HIV acquisition. Some of these bNAbs are being tested in early phase clinical trials, and the debate is now about the priorities for strategic large-scale efficacy trials. The prevailing view is that only a fixed combination of at least three bNAbs could prevent HIV, regardless of target populations or routes of transmission. We propose an alternative strategy consisting of evaluating the tolerability and efficacy of one or two bNAbs cocktails tailored to different target populations and indications. The rationale for this alternative strategy is based on ethical, pathophysiological and practical facts and is illustrated by the possibility of preventing HIV transmission through breastfeeding in high incidence/prevalence areas such as southern Africa. There is a prospect of eliminating paediatric HIV acquisition through breastfeeding by using single/dual long-acting bNAb regimens.

A document by Michael Stellon. Click on the document to view its contents.

Understanding animal movement and behaviour can aid spatial planning and inform conservation management. However, it is difficult to directly observe behaviours in remote and hostile terrain such as the marine environment. Behaviours can be inferred from telemetry data using hidden Markov models (HMMs), but model predictions are not typically validated due to difficulty obtaining ‘ground truth’ behavioural information. We investigate the accuracy of HMM-inferred behaviours by considering a unique dataset provided by Joint Nature Conservation Committee. The data consist of simultaneous proxy movement tracks of the boat (defined as visual tracks as birds are followed by eye) and seabird behaviour obtained at the same time-frequency by observers on the boat. We use these data to assess whether (i) visual track is a good proxy for true bird locations in relation to HMM-inferred behaviours, and (ii) inferred behaviours from HMMs fitted to visual tracking data accurately represent true behaviours as identified by behavioural observations taken from the boat. We demonstrate that visual tracking data can be regarded as a good proxy for true movement data of birds in terms of similarity in inferred behaviours. Accuracy of HMMs ranging from 71% to 87% during chick-rearing and 54% to 70% during incubation was generally insensitive to model choice, even when AIC values varied substantially across different models. Finally, we show that for foraging, a state of primary interest for conservation purposes, identified missed foraging bouts lasted for only a few seconds. We conclude that HMMs fitted to tracking data can accurately identify important conservation-relevant behaviours, demonstrated using visual tracking data. Therefore, confidence in using HMMs for behavioural inference should increase even when validation data are unavailable. This has important implications for animal conservation, where the size and location of protected areas are often informed by behaviours identified using HMMs fitted to movement data.

Key Clinical MessageSturge–Weber syndrome (SWS) is a neurocutaneous syndrome characterized by angiomas. This report presents airway management using submental intubation in sagittal split ramus osteotomy under general anesthesia and aimed to explore better anesthetic management for avoiding the rupture of angiomas in a patient with SWS.