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Feeding/swallowing and airway protection are complex functions, essential for survival, and continue to evolve throughout the lifetime. Medical and surgical advances across the globe have improved the long-term survival of medically complex children at the cost of increasing comorbidities, including dysfunctional swallowing (dysphagia). Dysphagia is prominent in children with histories of preterm birth, neurologic and neuromuscular diagnoses, developmental delays, and aerodigestive disorders; and is associated with medical, health, and neurodevelopmental problems; and long-term socioeconomic, caregiver, health system, and social burdens. Despite these survival and population trends, data on global prevalence of childhood dysphagia and associated burdens are limited, and practice variations are common. This article reviews current global population and resource-dependent influences on current trends for children with dysphagia, disparities in the availability and access to specialized multidisciplinary care, and potential impacts on burdens. A patient example will illustrate some questions to be considered and decision-making options in relation to age and development, availability and accessibility to resources, as well as diverse cultures and family values. Precise recognition of feeding/swallowing disorders and follow-up intervention are enhanced by awareness and knowledge of global disparities in resources. Initiatives are needed, which address geographic and economic barriers to providing optimal care to children with dysphagia., Competing Interests: Declarations. Conflict of interest: MAL-G, JCA, DF, and DSL have no relevant financial interests to disclose for completion of this manuscript. SRJ was supported in part by R01 DK 122171, R01 DK 136762, and The Nationwide Foundation Endowed Chair Grant. None of the authors have conflicts of interest to declare., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: To describe the findings of children with Robin Sequence (RS) who received sensory-motor-oral stimulation combined with early sucking during mandibular distraction osteogenesis (MDO), compared with children who did not receive the intervention., Design: A quasi-experimental study. Setting: A tertiary public hospital. Patients: Children with RS referred to MDO. A historical group from the same population but managed according to the institution's standard protocol (no sucking) served as a control group. Interventions: Sensory-motor-oral stimulation, including sucking, starting 24 h after MDO (intervention group). Main Outcome Measure: Our hypothesis is that sensory-motor-oral stimulation, including sucking during the DOM process, do not negatively affect surgical outcomes., Results: Twenty-nine children were included. Eight (72.7%) of the 11 patients in the intervention group and 13 (72.2%) of the 18 controls had MDO complications, with no significant difference between the groups ( p  = 1.000). The most common surgical outcome was antibiotic therapy for surgical site infection (76.2%). Six months after MDO, 22 (75.9%) children attained full oral feeding or associated with alternative feeding methods., Conclusion: The intervention group did not have higher complication rates, from a surgical point of view, than control group. The protocol adopted by some centers that contraindicates sucking during MDO should be revised to consider the benefits of such stimulation. Keywords: Pierre Robin Syndrome, deglutition, therapeutics, child development., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Garadacimab is a fully human immunoglobulin G4 monoclonal antibody targeting activated factor XII. This study evaluated long-term efficacy, health-related quality of life (HRQoL), and safety data for garadacimab in adults with hereditary angioedema., Methods: This global phase 2 study comprised a treatment period 1 (TP1: 12 weeks, double-blind, placebo-controlled) and a treatment period 2 (TP2: ≥44-week open-label extension). Patients aged 18-65 years with clinically confirmed hereditary angioedema were eligible. In TP1, 32 patients were randomly assigned (1:1:1:1) to receive subcutaneous garadacimab (75 mg, 200 mg, or 600 mg) or placebo every 4 weeks (once monthly). Randomisation was done using interactive response technology via block randomisation (block sizes 1-4). Subsequently, six additional patients in TP1 were assigned to open-label garadacimab 400 mg every 2 weeks. At the start of TP2, patients were re-randomised (if receiving placebo, garadacimab 75 mg, or garadacimab 400 mg) or continued to receive garadacimab 200 mg or garadacimab 600 mg once monthly. After a protocol amendment on March 20, 2020, patients originally assigned to the 600 mg dose were down-titrated to 200 mg at their next visit. The primary endpoint (published previously) was monthly attack rate for patients receiving 200 mg or 600 mg garadacimab in TP1 in the intention-to-treat population. Here, we assessed the impact of garadacimab on patient-reported and investigator-reported outcomes and HRQoL as well as long-term efficacy and safety. This trial is registered with ClinicalTrials.gov, NCT03712228, and is completed., Findings: Of 54 patients screened between Oct 29, 2018, and Aug 28, 2019, 32 randomised and six open-label patients completed TP1 and entered TP2 (20 in the garadacimab 200 mg group; 18 in the garadacimab 600 mg group; total 38 patients). Median age was 39·0 years (IQR 27·0-53·0), and 21 patients (55%) were female and 17 (45%) were male. In TP2, the median garadacimab exposure was 87·9 weeks (IQR 50·0-106·6) in the garadacimab 200 mg group and 44·1 weeks (24·1-56·1) in the garadacimab 600 mg group. Median monthly attack rates were 0·0 (IQR 0·0-0·1) in the garadacimab 200 mg group and 0·1 (0·0-0·4) in the garadacimb 600 mg group. Median reduction in monthly attack rate versus run-in was 100% (IQR 98-100) with garadacimab 200 mg. HRQoL improvements observed during TP1 with garadacimab were sustained throughout TP2. TP2 safety signals were consistent with TP1. Two patients experienced serious adverse events of diverticular perforation and asthma (not garadacimab-related). Treatment-emergent adverse events were mostly mild or moderate in severity. The most common adverse events were headache (nine of 38, 24%) and abdominal pain (seven of 38, 18%). There were no treatment-related deaths., Interpretation: Once-monthly garadacimab for more than 2 years in patients with hereditary angioedema was well tolerated and efficacious in reducing monthly attack rate and improving HRQoL. These results reveal the potential of long-term prophylactic treatment with 200 mg once-monthly garadacimab towards complete disease control of patients with hereditary angioedema., Funding: CSL Behring., Competing Interests: Declaration of interests TJC is a speaker for CSL Behring, Takeda, BioMarin, Astria, Regeneron, and Grifols, and has received research and consultancy grants from CSL Behring, Takeda, BioCryst, Ionis, BioMarin, Intellia, KalVista, Pharvaris, Ionis, Astria, and GlaxoSmithKline; he is on the Medical Advisory Board for the US Hereditary Angioedema Association and is Director of the Angioedema Centers of Reference and Excellence International Angioedema Center at Penn State University, Hershey, PA, USA. DSL received research grants from, and is a speaker and consultant for, CSL Behring, Takeda, BioCryst, Grifols, Pharming, and KalVista. AR received research grants as a principal investigator, speaker, and adviser for CSL Behring, Takeda/Shire, BioCryst, Pharming, Pharvaris, Ionis, and Shulov Innovative Science. WRL is a speaker for CSL Behring, Pharming, AstraZeneca, Sanofi and Regeneron, GlaxoSmithKline, and Takeda/Shire, and has served as a consultant for BioCryst, BioMarin, CSL Behring, Fresenius Kabi, Intellia, KalVista, Pharming, Pharvaris, and Takeda/Shire; WRL is also a board member of the US Hereditary Angioedema Association Medical Advisory Board, and has received grants or research support from ALK, BioCryst, CSL Behring, Ionis, Gossamer, KalVista, Kedrion, Therapure, and Takeda/Shire. IM-S has received honoraria, research funding, and travel grants from BioCryst, CSL Behring, Pharming, Octapharma, KalVista, and Takeda/Shire, and has served as a consultant or participated in advisory boards for these companies. JSJ is a speaker for Takeda/Shire, CSL Behring, Teva, AstraZeneca, GlaxoSmithKline, Sanofi Genzyme, and Regeneron, and has received research funding or consultancy fees from CSL Behring, Takeda/Shire, BioCryst, Novartis, Genentech, AstraZeneca, Allakos, Fresenius Kabi, GlaxoSmithKline, and Regeneron. WHY has been a speaker and advisory board member for, and has received honoraria from, CSL Behring, Takeda/Shire, Novartis, Sanofi Genzyme, and Merck; he has received research grants from CSL Behring, Takeda/Shire, BioCryst, Pharming, Aimmune, DBV Technologies, Eli Lilly, Pharvaris, AstraZeneca, Novartis, GlaxoSmithKline, Genentech/Roche, Amgen, Sanofi Genzyme, Regeneron, Galderma, AnaptysBio, Glenmark, ALK, Dermira, Ionis, and Celgene; and he also serves as a medical adviser (volunteer) for Hereditary Angioedema Canada, a patient organisation, and is a member of ACARE. BR has been a speaker and advisory board member for CSL Behring and Takeda but has not received personal reimbursement for these activities; he has participated in multiple clinical trials involving investigational drugs for CSL Behring, Takeda, BioCryst, Dyax, and Pharming; and he serves as a volunteer medical scientific adviser to Hereditary Angioedema Canada, a patient organisation. EA-P has received honoraria as a speaker, adviser, or as grant support or clinical trial investigator support from Astria Therapeutics, BioCryst, BioMarin Europe, Centogene, CSL Behring, Intellia, KalVista, Pharming Technologies, Pharvaris, and Takeda/Shire. PKK has been a speaker, advisory board member, or consultant for, and has received honoraria from, ALK, AstraZeneca, Bausch, BioCryst, Canadian Agency for Drugs and Technologies in Health, Canadian Pharmacists Association, CSL Behring, GlaxoSmithKline, Medexus, Merck, Novartis, Sanofi Genzyme, Takeda/Shire, and Valeo; has received research grants from CSL Behring and Takeda/Shire; serves as a medical adviser (volunteer) for Hereditary Angioedema Canada, a patient organisation; serves as a board member (volunteer) for the Canadian Hereditary Angioedema Network, a physician organisation; and is an employee of McMaster University. PB has been a speaker, advisory board member, or consultant for, and has received honoraria from, BioMarin, BioCryst, CSL Behring, CVS Specialty, Ionis, KalVista, Medscape, Novartis, Pharvaris, Prime, Regeneron, and Takeda; and has received research funding from CSL Behring, KalVista, and Takeda. MM has received financial support from CSL Behring for acting as a study-centre investigator during the conduct of the study, and consulting fees from CSL Behring, Takeda/Shire, Pharming Technologies, BioCryst, Novartis, Octapharma, and KalVista outside of the submitted work. At the time of the study, HF, MAB, IJ, and IP were employees of CSL Behring Innovation GmbH (HF, MAB, IP) or CSL Behring LLC (IJ) and shareholders of CSL Ltd., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Objective: To evaluate the combined impact of videofluoroscopic swallow study (VFSS) and therapeutic feeding and swallowing interventions on clinical outcomes in children with oropharyngeal dysphagia (OPD)., Methods: This was an uncontrolled longitudinal analytical study in which OPD patients were evaluated before and after VFSS. Children ≤ 24 months of age diagnosed with OPD in a clinical setting and undergoing VFSS for investigation and management of OPD were included in the study. The study participants received therapeutic feeding and swallowing interventions after having undergone VFSS, being followed at an outpatient clinic for pediatric dysphagia in order to monitor feeding and swallowing difficulties. Respiratory and feeding outcomes were compared before and after VFSS., Results: Penetration/aspiration events were observed in 61% of the VFSSs (n = 72), and therapeutic feeding and swallowing interventions were recommended for 97% of the study participants. After the VFSS, there was a reduction in the odds of receiving antibiotic therapy (OR = 0.007) and in the duration of antibiotic therapy (p = 0.014), as well as in the odds of being admitted to hospital (p = 0.024) and in the length of hospital stay (p = 0.025). A combination of oral and enteral feeding became more common than oral or enteral feeding alone (p = 0.002)., Conclusions: A high proportion of participants exhibited penetration/aspiration on VFSS. Therapeutic feeding and swallowing interventions following a VFSS appear to be associated with reduced respiratory morbidity in this population.

Background: Hereditary angioedema (HAE) is a rare condition marked by swelling episodes in various body parts, including the extremities, upper airway, face, intestinal tract, and genitals. Long-term prophylaxis (LTP), prescribed to control recurring HAE attacks, is integral to its management. Previously, attenuated androgens (AAs) were the only oral LTP options. However, in 2020, berotralstat, an oral plasma kallikrein inhibitor, was approved in the United States. A 2018 survey of adults with HAE type I or type II showed that almost all the patients who used prophylactic HAE medication preferred oral treatment (98%) and felt that it fit their lifestyle better than injectable treatment (96%). Still, guidelines lack consensus on transitioning patients from AAs to alternative oral prophylactic therapy. Objective: This paper aims to share expert insights and patient feedback on transitioning from AAs to berotralstat, an alternative oral prophylactic therapy, from the perspective of clinicians with extensive experience in treating patients with HAE. Methods: A panel of five HAE specialists convened for a virtual half-day roundtable discussion in April 2023. Results: Discussions about transitioning from AAs to berotralstat were prompted by routine consultations, patient inquiries based on independent research, ineffective current treatment, or worsening AA-related adverse effects. For patients who switched from AAs, the physicians reported that the decision was influenced by the alternative therapy's ability to prevent HAE attacks, its safety, and the once-daily administration schedule. All expert panel members identified fewer AA-related adverse effects; better quality of life; and less severe, shorter, and less frequent HAE attacks as clinical or patient goals they hoped to achieve through the treatment switch. Conclusion: The emergence of new, highly specific LTP drugs for HAE calls for the development of comprehensive recommendations and guidelines for transitioning from AAs to alternative oral prophylactic therapy. The expert panel highlighted key factors to consider during the development of such guidelines.

Dysphagia in Robin Sequence can be present in varying degrees, requiring multidisciplinary management and specific swallowing assessment by a specialist. Most studies published to date have evaluated only respiratory outcomes, and the available evidence on the improvement of swallowing is questionable. To conduct a systematic review and meta-analysis of studies evaluating swallowing in children with Robin Sequence before and after airway clearance procedures. The research question was developed based on the PICO strategy. The literature search was performed in electronic databases and gray literature. Studies were selected by 3 independent reviewers. The risk of bias and level of evidence of the studies were assessed. A proportion meta-analysis was performed to calculate the prevalence of dysphagia after airway clearance procedures. The search identified 4938 studies, 5 of which were included. All studies had limitations in terms of design and sample size. The prevalence of dysphagia after airway clearance was obtained by analyzing treatment subgroups: mandibular distraction osteogenesis, mandibular distraction osteogenesis + tracheostomy tube, and nasopharyngeal tube. Clinical and/or instrumental assessment was assessed by a swallowing specialist. The meta-analysis was precluded by the limitations of the studies, especially regarding sample size, which affected the accuracy of the findings. Dysphagia remained unresolved in 55% of children (95% CI 1-99%). The methodological quality of the studies indicated a high risk of bias and very low level of evidence. It was not possible to confirm that airway clearance techniques used in Robin Sequence improve dysphagia., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The objective of this study is to investigate in infants submitted to videofluoroscopic swallowing study (VFSS) during the first year of life, the association between aspiration and later tube feeding, and to identify potential risk factors related to feeding route outcome. Retrospective cohort study with data from electronic health records was performed. Data were collected from infants < 12 months of age who underwent VFSS during inpatient hospital stay in the period between 2013 and 2018. Patient charts after 24 months of age were reviewed to ascertain the outcome and study factors, including VFSS findings, neonatal data, clinical comorbidities, nutritional status, ICU admissions, and hospital readmissions. Relative risk (RR) for tube feeding was calculated, and a Poisson regression with robust variance was used to identify potential risk factors. VFSS data from 164 patients < 1 year old were retrieved, of whom 112 (68%) contributed with data about feeding route after 2 years of age. Most infants were preterm < 37 weeks (66%), with a median age of 9.28 weeks at the time of the exam. Aspiration occurred in 33% of the patients, with no statistically significant difference between full-term or premature infants (p = 0.173). The relative risk of tube feeding after the age of 2 among infants who aspirated in VFSS was 0.74 (CI 0.25-2.16, p = 0.573). Poisson regression analysis showed that number of hospital readmissions (RR 1.04, 95%CI 1.01-1.07, p = 0.005) and gestational age < 34 weeks (RR 0.26, 95%CI 0.07-0.089, p = 0.032) were associated with later tube feeding. Early VFSS findings have low predictive value regarding later feeding route. Aspiration events should be considered as complementary information for clinical decision., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The scientific scope of swallowing disorders in the neonatal and pediatric populations is growing exponentially; however, the preponderance of evidence for evaluation protocols has been concentrated in non-instrumental evaluations creating a lack of research about protocols for instrumental swallowing assessment. Thus, the purpose of this study was to systematically review the literature to identify and to report protocols used in instrumental assessments through videofluoroscopic swallow study (VFSS) and fiberoptic endoscopic evaluation of swallowing (FEES) in the neonatal and pediatric populations to support clinical decision making. The search strategy was applied in five online databases, no filters were applied to restrict languages or publication dates and the gray literature was reviewed. PRISMA statement was used to guide the construction of this review. The studies included validated and unvalidated protocols, the validated protocols had their risk of bias estimated using the QUADAS-2. In total, 13 studies were included in the final review, of these eleven assessed through QUADAS-2, and two classified with low risk of bias. One study is in the process of standardization and validation of an instrumental assessment protocol for swallowing in bottle-fed infants through VFSS. Information about validity and reliability of published protocols for instrumental evaluation in the neonatal and pediatric populations is limited. Therefore, further research is needs to development studies aiming to standardize and validate protocols for instrumental assessments in these populations., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The purpose of this study was to translate and adapt the Feeding/Swallowing Impact Survey (FS-IS) into Brazilian Portuguese and provide a validated instrument for caregivers of children with feeding/swallowing disorders. This cross-cultural study involved initial translation, synthesis of translations, back-translation, Committee of Experts, and pre-test. The sample consisted of 95 primary caregivers of children with feeding/swallowing disorders classified by Pediatric Dysphagia Evaluation Protocol (PDEP) in mild (n = 9), moderate-severe (n = 40), or profound (n = 46) dysphagia. Reliability and evidence of validity based on test content, response processes, internal structure and the relations to other variables were investigated. Internal consistency, test-retest, exploratory and confirmatory factor analysis were performed, in addition to the correlation with PedsQL™ Family Impact Module (PedsQL TM FIM). The pre-test participants did not report any difficulties in understanding the translated version. The Brazilian Portuguese version of FS-IS (Pt-Br-FS-IS) presented Cronbach's Alpha of 0.83, Exploratory Factor Analysis verified that the instrument would not be unifactorial (KMO = 0.74 and Bartlett's sphericity test p < 0.001) and Confirmatory Factor Analysis confirmed the original model in three subscales with χ 2 /df = 1.23, CFI = 0.92, TLI = 0.90, RMSEA (90% CI) 0.049 (0.011-0.073) adjustment indexes and the ICC was excellent in all subscales and total score. The correlation with PedsQL™FIM was significant in the total score and subscales. This study successfully translated and cross-culturally adapted the FS-IS instrument to the Brazilian Portuguese language and the investigation of its reliability and validity evidence suggests that the Pt-Br-FS-IS is a reliable and valid tool to measure the impact of feeding/swallowing disorders on the quality of life of caregivers of affected children., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Hereditary angioedema is associated with dysregulation of the kallikrein-kinin system. Factor XII (FXII) is a key initiator of the kallikrein-kinin system, which produces bradykinin, a central mediator of angioedema. Garadacimab (CSL Behring) is a first-in-class, fully human, immunoglobulin G4 monoclonal antibody targeting activated FXII, intended to prevent attacks in patients with C1-esterase inhibitor-deficient hereditary angioedema (HAE-C1-INH). We aimed to investigate garadacimab as a treatment every 4 weeks for patients with HAE-C1-INH., Methods: In this double-blind, placebo-controlled, phase 2 study, patients with HAE-C1-INH were recruited from 12 research centres in Canada, Germany, Israel, and the USA. Eligible patients were aged 18-65 years and must have had at least four attacks of any severity over a consecutive 2-month period during the 3 months before screening or initiation of previous hereditary angioedema prophylaxis. After a run-in period of 4-8 weeks, patients were randomly assigned (1:1:1:1), using an interactive response technology via block randomisation (block sizes of 1-4), to either placebo or 75 mg, 200 mg, or 600 mg garadacimab. Patients were given an initial intravenous loading dose, and then, on day 6 and every 4 weeks for 12 weeks, they were given a subcutaneous dose of their allocated treatment. The primary endpoint was the number of monthly attacks in the intention-to-treat population (defined as all patients who underwent screening, provided consent, and were assigned to treatment) during the 12-week subcutaneous administration period assessed in the 200 mg and 600 mg garadacimab groups versus placebo. Safety was assessed in all patients who received at least one dose or partial dose of study treatment. This study is registered with ClinicalTrials.gov, NCT03712228., Findings: Between Oct 29, 2018, and Aug 28, 2019, 54 patients were screened, of whom 32 were randomly assigned to either placebo (n=8) or 75 mg (n=9), 200 mg (n=8), or 600 mg (n=7) garadacimab. The median age was 39·5 years (28·0-52·5) and 18 (56%) of 32 patients were female and 14 (34%) were male. The median number of monthly attacks during the 12-week subcutaneous treatment period was 4·6 (IQR 3·1-5·0) with placebo, 0·0 (0·0-0·4) with 75 mg garadacimab, 0·0 (0·0-0·0) with 200 mg garadacimab, and 0·3 (0·0-0·7) with 600 mg garadacimab. Compared with placebo, the rate of attacks was significantly reduced with garadacimab at 200 mg (reduced by 100% [95% CI 98-101]; p=0·0002) and 600 mg (reduced by 93% [54-110]; p=0·0003). No serious adverse events, deaths, or adverse events of special interest (anaphylaxis, thromboembolic events, and bleeding events) were observed., Interpretation: Garadacimab 200 mg and 600 mg every 4 weeks significantly reduced the number of monthly attacks versus placebo and was well tolerated during the study. Garadacimab is an efficacious, subcutaneous prophylaxis in patients with HAE-C1-INH and warrants phase 3 evaluation., Funding: CSL Behring., Competing Interests: Declaration of interests TC is a speaker for Pharming, CSL Behring, Takeda, Fresenius Kabi, and Grifols; has received research and consultancy grants from CSL Behring, Takeda, BioCryst, Ionis, Spark, BioMarin, Fresenius Kabi, and Grifols; and is on the medical advisory board for the US Hereditary Angioedema Association, the Board of Directors for the Mid-Atlantic American Lung Association, and the Board of Directors for the American Academy of Allergy, Asthma and Immunology. EA-P has received honoraria as a speaker or advisor from Adverum Biotechnologies, BioCryst, BioMarin, Centogene, CSL Behring, KalVista, Pharming, Pharvaris, and Shire/Takeda; and has received grants or clinical trial investigator support from BioCryst, CSL Behring, KalVista, Pharvaris, and Shire/Takeda. PB has consulted for CSL Behring, Takeda, Pharming, Pearl Therapeutics, BioCryst, CVS Health, Novartis, AstraZeneca and GlaxoSmithKline; and has received clinical trial support from CSL Behring, Takeda, BioCryst, and Novartis. MKD and DP are former full-time employees of CSL Behring and own stocks in CSL Behring. HF, IJ, and IP are full-time employees of CSL Behring and own stocks in CSL Behring. JSJ is a speaker for Takeda/Shire, CSL Behring, Teva, AstraZeneca, GlaxoSmithKline, Sanofi Genzyme, and Regeneron; and has received research funding or consultancy fees from CSL Behring, Takeda/Shire, BioCryst, Novartis, Genentech, AstraZeneca, Allakos, Fresenius Kabi, GlaxoSmithKline, and Regeneron. PKK is or recently was a speaker or an advisor for ALK Pharma, AstraZeneca, CSL Behring, GlaxoSmithKline, Kaleo, Merck, Mylan, Novartis, Pediapharm/Medexus, Sanofi and Takeda/Shire; and has received research funding from CSL Behring, Green Cross, and Takeda/Shire. DSL is a speaker, researcher, and consultant for CSL Behring, Takeda, Pharming, BioCryst, and Grifols. WRL is a speaker for CSL Behring, Pharming, AstraZeneca, Sanofi/Regeneron, GlaxoSmithKline, and Shire/Takeda; has served as a consultant for BioCryst, BioMarin, CSL Behring, Fresenius Kabi, Intellia, KalVista, Pharming, Pharvarius, and Shire/Takeda; is a board member of the US Hereditary Angioedema Association Medical Advisory Board; and has received grants or research support from ALK, BioCryst, CSL Behring, Ionis, Gossamer, KalVista, Kedrion, Therapure, and Takeda/Shire. MM has received financial support from CSL Behring for acting as a study centre investigator during the conduct of the study, and personal fees from CSL Behring, Shire/Takeda, Pharming, BioCryst, Novartis, Octapharma, and KalVista. IM-S has received honoraria, research funding, and travel grants from BioCryst, CSL Behring, Pharming, Octapharma, KalVista, and Takeda/Shire. IM-S served as a consultant for BioCryst, CSL Behring, Pharming, Octapharma, KalVista, and Takeda/Shire; and participated in advisory boards for BioCryst, CSL Behring, Pharming, Octapharma, KalVista, and Takeda/Shire. AR is a speaker, researcher, and advisor for CSL Behring, Takeda/Shire, BioCryst, Pharming, and Shulov Innovative Science. BR has been a speaker and advisory board member for CSL Behring and Takeda and has not received personal reimbursement for these activities; has participated in multiple clinical trials involving investigational drugs for CSL Behring, Takeda, BioCryst, Dyax, and Pharming and he does not hold patents or investments with these companies or involving this product; and he serves as a volunteer medical scientific advisor to the patient organisation Hereditary Angioedema Canada. WHY has received fees for consulting services from CSL Behring, Takeda/Shire, Novartis, Sanofi Genzyme, and Merck, and research grants from CSL Behring, Takeda/Shire, BioCryst, Pharming, AstraZeneca, Novartis, Sanofi Genzyme, Regeneron, Galderma, AnaptysBio, Glenmark, ALK Pharma, and Dermira., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Videofluoroscopy swallow studies (VFSS) and high-resolution manometry (HRM) methods complement to ascertain mechanisms of infant feeding difficulties. We hypothesized that: (a) an integrated approach (study: parent-preferred feeding therapy based on VFSS and HRM) is superior to the standard-of-care (control: provider-prescribed feeding therapy based on VFSS), and (b) motility characteristics are distinct in infants with penetration or aspiration defined as penetration-aspiration scale (PAS) score ≥ 2. Feeding therapies were nipple flow, fluid thickness, or no modification. Clinical outcomes were oral-feeding success (primary), length of hospital stay and growth velocity. Basal and adaptive HRM motility characteristics were analyzed for study infants. Oral feeding success was 85% [76-94%] in study (N = 60) vs. 63% [50-77%] in control (N = 49), p = 0.008. Hospital-stay and growth velocity did not differ between approaches or PAS ≥ 2 (all P > 0.05). In study infants with PAS ≥ 2, motility metrics differed for increased deglutition apnea during interphase (p = 0.02), symptoms with pharyngeal stimulation (p = 0.02) and decreased distal esophageal contractility (p = 0.004) with barium. In conclusion, an integrated approach with parent-preferred therapy based on mechanistic understanding of VFSS and HRM metrics improves oral feeding outcomes despite the evidence of penetration or aspiration. Implementation of new knowledge of physiology of swallowing and airway protection may be contributory to our findings., (© 2021. The Author(s).)

Background: While many studies of effective hereditary angioedema (HAE) therapy have demonstrated improved health-related quality of life (HRQoL) using validated instruments, specific reasons behind the improved scores have never been investigated using qualitative methods. A non-interventional, qualitative research study was designed to investigate the reasons for improvements in HRQoL while using effective prophylaxis, in this case subcutaneous C1INH (C1INH[SC]) replacement therapy., Methods: Adult patients with HAE-C1INH type 1 or 2 who had been using C1INH(SC) for ≥ 3 consecutive months were recruited through four HAE specialty practices in the US to participate in a 60-min phone interview performed by a trained qualitative research specialist (ICON plc) using a semi-structured interview guide with open-ended questions developed with the Angioedema Quality of Life (AE-QoL) items in mind. Interview transcripts were analyzed using thematic analysis methods to identify concepts (specific symptoms/impacts) and themes (higher-level categories grouping related concepts). A cross-mapping exercise was performed between interview-identified concepts and items included in the AE-QoL., Results: Fourteen patients were interviewed and included in the analysis (age range, 28-82 years [mean 47.5 years]; 64% female; 93% white). In 10 interviews, patients mentioned having no or nearly no HAE attacks, no longer feeling limited by HAE, less HAE-related anxiety/worry and depression, an improved ability to travel, fewer emergency room/hospital visits, and ease of administration of C1INH(SC), including not requiring assistance from others. Other commonly expressed concepts included: increased feelings of confidence, independence, optimism, and normalcy; less absence from work/school; better productivity; improved sleep and energy; healthier family relationships; and improved cognition. While all AE-QoL items emerged from patient interviews, a number of identified concepts were not addressed by the AE-QoL, including sensitivity to various potential attack-triggers (e.g., stress/anxiety, sports), attack frequency, not having to cancel social plans, improvements in ability to perform day-to-day tasks, and a lower burden from medical visits., Conclusions: From these interviews, a large number of common themes and concepts emerged: a greater sense of freedom and normalcy, increased productivity, and improved interpersonal relationships while using convenient and effective prophylaxis. These findings provide insights into real-world experiences and the many facets of HRQoL that are important to patients with HAE-C1INH.

Background: Long-term prophylaxis with subcutaneous C1-inhibitor (C1-INH[SC]; HAEGARDA, CSL Behring) in patients with hereditary angioedema (HAE) due to C1-INH deficiency (C1-INH-HAE) was evaluated in an open-label extension follow-up study to the international, double-blind, placebo-controlled COMPACT study. The current analysis evaluated patient-reported health-related quality of life (HRQoL) data from 126 patients in the open-label extension study randomized to treatment with C1-INH(SC) 40 IU/kg (n = 63) or 60 IU/kg (n = 63) twice weekly for 52 weeks. HRQoL was evaluated at the beginning of the open-label study and at various time points using the European Quality of Life-5 Dimensions Questionnaire (EQ-5D), the Hospital Anxiety and Depression Scale (HADS), the Work Productivity and Activity Impairment Questionnaire (WPAI), and the Treatment Satisfaction Questionnaire for Medication. The disease-specific Angioedema Quality of Life Questionnaire (AE-QoL) and HAE quality of life questionnaire (HAE-QoL) instruments were administered in a subset of patients. Statistical significance was determined by change-from-baseline 95% confidence intervals (CIs) excluding zero. No adjustment for multiplicity was done., Results: Mean baseline EQ-5D scores (Health State Value, 0.90; Visual Analog Scale, 81.32) were slightly higher (better) than United States population norms (0.825, 80.0, respectively) and mean HADS anxiety (5.48) and depression (2.88) scores were within "normal" range (0-7). Yet, patients using C1-INH(SC) 60 IU/kg demonstrated significant improvement from baseline to end-of-study on the EQ-5D Health State Value (mean change [95% CI], 0.07 [0.01, 0.12] and Visual Analog Scale (7.45 [3.29, 11.62]). In the C1-INH(SC) 60 IU/kg group, there were significant improvements in the HADS anxiety scale (mean change [95% CI], - 1.23 [- 2.08, - 0.38]), HADS depression scale (- 0.95 [- 1.57, - 0.34]), and WPAI-assessed presenteeism (mean change [95% CI], - 23.33% [- 34.86, - 11.81]), work productivity loss (- 26.68% [- 39.92, - 13.44]), and activity impairment (- 16.14% [- 26.36, - 5.91]). Clinically important improvements were achieved in ≥ 25% of patients for all domains except WPAI-assessed absenteeism (which was very low at baseline). Mean AE-QoL total score by visit ranged from 13.39 to 17.89 (scale 0-100; lower scores = less impairment). Mean HAE-QoL global scores at each visit (115.7-122.3) were close to the maximum (best) possible score of 135., Conclusions: Long-term C1-INH(SC) replacement therapy in patients with C1-INH-HAE leads to significant and sustained improvements in multiple measures of HRQoL. Trial registration A Study to Evaluate the Long-term Clinical Safety and Efficacy of Subcutaneously Administered C1-esterase Inhibitor in the Prevention of Hereditary Angioedema, NCT02316353. Registered December 12, 2014, https://clinicaltrials.gov/ct2/show/NCT02316353 .

Vascular calcification is a known complication of chronic kidney disease (CKD). The prevalence of vascular calcification in patients with non-dialysis-dependent CKD stages 3-5 has been shown to be as high as 79% (20). Vascular calcification has been associated with increased risk for mortality, hospital admissions, and cardiovascular disease (6, 20, 50, 55). Alterations in mineral and bone metabolism play a pivotal role in the pathogenesis of vascular calcification in CKD. As CKD progresses, levels of fibroblast growth factor-23, parathyroid hormone, and serum phosphorus increase and levels of 1,25-(OH) 2 vitamin D decrease. These imbalances have been linked to the development of vascular calcification. More recently, additional factors have been found to play a role in vascular calcification. Matrix G1a protein (MGP) in its carboxylated form (cMGP) is a potent inhibitor of vascular calcification. Importantly, carboxylation of MGP is dependent on the cofactor vitamin K. In patients with CKD, vitamin K deficiency is prevalent and is exacerbated by warfarin, which is frequently used for anticoagulation. Insufficient bioavailability of vitamin K reduces the amount of cMGP available, and, therefore, it may lead to increased risk of vascular calcification. In vitro studies have shown that in the setting of a high-phosphate environment and vitamin K antagonism, human aortic valve interstitial cells become calcified. In this article, we discuss the pathophysiological consequence of vitamin K deficiency in the setting of altered mineral and bone metabolism, its prevalence, and clinical implications in patients with CKD.

Objective: To evaluate the effect of an oral stimulation program in preterm on the performance in the first oral feeding, oral feeding skills and transition time from tube to total oral intake., Study Designer: Double-blind randomized clinical trial including very preterm newborns. Congenital malformations, intracranial hemorrhage grade III or IV, bronchopulmonary dysplasia, and necrotizing enterocolitis were excluded. Intervention group (GI) received an oral stimulation program of tactile extra-, peri-, and intraoral tactile manipulation once a day for 15 minutes, during a 10-day period. Control group (GII) received sham procedure with same duration of time. Feeding ability was assessed by a speech-language pathologist blinded to group assignment. The classification of infants' oral performance was determined by Oral Feeding Skills (OFS). Neonates were monitored until hospital discharge., Results: Seventy-four (37 in each group) were randomized. Mean gestational ages and birth weights were 30±1.4 and 30±1.5 weeks, and 1,452±330g and 1,457±353g for intervention and control groups, respectively. Infants in the intervention group had significantly better rates than infants in the control group on: mean proficiency (PRO) (41.5%±18.3 vs. 19.9%±11.6 (p<0.001)), transfer rate (RT) (2.3 mL/min and 1.1 mL/min (p<0.001)) and overall transfer (OT) (57.2%±19.7 and 35.0%±15.7 (p<0.001)). Median transition time from tube to oral feeding was 4 (3-11) and 8 (7-13) days in intervention and control groups, respectively (p = 0.003). Intake of breast milk was found to reduce transition time from tube feeds to exclusive oral feeding (p<0.001, HR 1.01, 95%CI 1.005-1.019), but the impact of the study intervention remained significant (p = 0.007, HR 1.97, 95%CI 1.2-3.2)., Conclusion: Infants who were breast-fed and an oral stimulation program proved beneficial in reducing transition time from tube feeding to oral feeding., Trial Registration: ClinicalTrials.gov number NCT03025815., Competing Interests: The authors have declared that no competing interests exist.

Background: Women with hereditary angioedema due to C1-inhibitor deficiency (HAE-C1INH) experience more frequent and severe angioedema attacks compared with men. Fluctuations in female sex hormones can influence HAE attack frequency and severity. Subcutaneous C1-INH (C1-INH [SC]) is indicated as routine prophylaxis to prevent HAE attacks. In this post hoc subgroup analysis, we evaluated the efficacy and safety of C1-INH (SC) in female subjects with HAE-C1INH enrolled in an open-label extension of the pivotal phase III COMPACT trial., Methods: In this multicenter, randomized, parallel-arm trial, eligible subjects (age ≥ 6 years with ≥ 4 attacks over 2 consecutive months) received C1-INH (SC) 40 IU/kg or 60 IU/kg twice weekly for 52 to 140 weeks. Analyses of efficacy endpoints were performed for all female subjects and those of childbearing age (age ≥ 15 to ≤ 45 years), including subjects who became pregnant during the evaluation period., Results: Overall, 91% (69/76) of female subjects were classified as responders (≥ 50% reduction in HAE attacks relative to the pre-study period); 82% experienced < 1 attack/4 weeks. The median number of attacks/month was 0.10, with 96% median reduction in attacks relative to the pre-study period. Results were similar in the subgroup of subjects of childbearing age. Four women who became pregnant during the trial and were exposed to C1-INH (SC) during the first trimester delivered healthy babies with no congenital abnormalities., Conclusions: C1-INH (SC) prophylaxis was safe and effective in women with HAE-C1INH, including those of childbearing age. Four women exposed to C1-INH (SC) during the first trimester had uneventful pregnancies and delivered healthy babies. Trial registration Clinicaltrials.gov identifier NCT02316353 (Registered December 10, 2014); https://clinicaltrials.gov/ct2/show/NCT02316353., Competing Interests: Competing interestsD. Levy has served on the speaker’s bureau, as a consultant, on a steering committee, and as a clinical investigator for CSL Behring; consultant for BioCryst; and speaker for Takeda. H. Farkas received institutional support for a clinical trial for this study from CSL Behring; advisory board/consultancy fees and/or speaker’s honoraria from BioCryst, CSL Behring, Shire, and Sobi (Swedish Orphan Biovitrum); and travel support from CSL Behring. M. Riedl reports grant support from CSL Behring during the conduct of the study and has received research grants from BioCryst, CSL Behring, Dyax, Ionis Pharmaceuticals, Pharming Technologies, and Shire; has served as a consultant and/or speaker for Adverum Biotechnologies, Alnylam Pharmaceuticals, Arrowhead Pharmaceuticals, BioCryst, CSL Behring, Dyax, Global Blood Therapeutics, Ionis Pharmaceuticals, KalVista Pharmaceuticals, Pharming Technologies, Salix Pharmaceuticals, and Shire; and is an uncompensated advisory board member for the US Hereditary Angioedema Association, outside the submitted work. F. Hsu reports serving as a consultant for BioCryst; serving as a speaker for CSL Behring, Pharming Technologies BV, and Takeda Pharmaceutical Company Ltd; and performing contracted research for Hoffman-La Roche. J.P. Brooks declares that he has no competing interests. M. Cicardi received grants from Shire and personal fees from Alnylam, BioCryst, CSL Behring, Dyax, KalVista, Pharming Technologies, Shire, Sobi (Swedish Orphan Biovitrum), and ViroPharma. H. Feuersenger and I. Pragst are employees of CSL Behring. A. Reshef reports grant support from CSL Behring during the conduct of the study and has received grant support from Pharming., (© The Author(s) 2020.)

A large body of work in animals and human beings supports the hypothesis that metabolic acidosis has a deleterious effect on the progression of kidney disease. Alkali therapy, whether pharmacologically or through dietary intervention, appears to slow CKD progression, but an appropriately powered randomized controlled trial with a low risk of bias is required to reach a more definitive conclusion. Recent work on urinary ammonium excretion has shown that the development of prognostic tools related to acidosis is not straightforward, and that application of urine markers such as ammonium may require more nuance than would be predicted based on our understanding of the pathophysiology., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: A common osmolality threshold for feedings is to stay <450 mOsm/kg for normal infants. Preterm formulas are frequently modified to improve growth, modify nutrition, and manage gastroesophageal reflux (GER) or dysphagia. Relationships between osmolality and additives to ready-to-feed preterm formulas are unclear. Our aims were to evaluate and compare the effects of caloric density, thickening agent recipes, and supplements to ready-to-feed preterm formula on osmolality., Methods: A freezing point osmometer was used to measure the osmolality of 47 preterm infant formula combinations with varying caloric densities (ready-to-feed 22 and 30 cal/oz), thickening agents (rice vs oatmeal cereal), thickener amounts (0.0, 0.5, 1.0, 1.5, 2.0, 2.5, and 3.0 tsp/oz), and combinations of supplements (saline, iron, vitamin D, or multivitamin). Ten samples per combination were tested using a 10-μL pipette. Comparisons were made using analysis of variance and t-tests for group and pair-wise comparisons, respectively., Results: A total of 470 osmolality samples were analyzed: (1) raters had high agreement (r = 0.98; P < .001); (2) for every 0.5 tsp/oz of thickener, the osmolality increases by 30 mOsm/kg (P < .001); (3) osmolality was higher with the oatmeal (vs rice) thickening agent (P < .001); and (4) vitamin and electrolyte supplement combinations increase osmolality., Conclusions: Alteration of ready-to-feed preterm formulas may significantly increase osmolality and have unintended consequences. Caution and monitoring should be exercised with modifying ready-to-feed preterm formulas for regurgitation, rumination, GER, dysphagia, feeding intolerance, or emesis. This study supports the concept of achieving volume tolerance before further manipulation of additives., (© 2018 American Society for Parenteral and Enteral Nutrition.)

Background: Hereditary angioedema with C1-inhibitor deficiency (C1-INH-HAE) impairs health-related quality of life (HRQoL)., Objective: The objective of this study was to assess HRQoL outcomes in patients self-administering subcutaneous C1-INH (C1-INH[SC]; HAEGARDA) for routine prevention of HAE attacks., Methods: Post hoc analysis of data from the placebo-controlled, crossover phase III COMPACT study (Clinical Studies for Optimal Management of Preventing Angioedema with Low-Volume Subcutaneous C1-Inhibitor Replacement Therapy). Ninety patients with C1-INH-HAE were randomized to 1 of 4 treatment sequences: C1-INH(SC) 40 or 60 IU/kg twice weekly for 16 weeks, preceded or followed by 16 weeks of twice weekly placebo injections. All HAE attacks were treated with open-label on-demand treatment as necessary. HRQoL assessments at week 14 (last visit) included the European Quality of Life-5 Dimensions Questionnaire (EQ-5D-3L), the Hospital Anxiety and Depression Scale (HADS), the Work Productivity and Activity Impairment Questionnaire (WPAI), and the Treatment Satisfaction Questionnaire for Medication (TSQM)., Results: Compared with placebo (on-demand treatment alone), treatment with twice weekly C1-INH(SC) (both doses combined) was associated with better EQ-5D visual analog scale general health, less HADS anxiety, less WPAI presenteeism, work productivity loss, and activity impairment, and greater TSQM effectiveness and overall treatment satisfaction. More patients self-reported a "good/excellent" response during routine prevention with C1-INH(SC) compared with on-demand only (placebo prophylaxis) management. For each HRQoL measure, a greater proportion of patients had a clinically meaningful improvement during C1-INH(SC) treatment compared with placebo., Conclusions: In patients with frequent HAE attacks, a treatment strategy of routine prevention with self-administered twice weekly C1-INH(SC) had a greater impact on improving multiple HAE-related HRQoL impairments, most notably anxiety and work productivity, compared with on-demand treatment alone (placebo prophylaxis)., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: To investigate the accuracy of clinical evaluation of swallowing in a sample of children with laryngomalacia or glossoptosis and describe the prevalence of dysphagia in each of these diseases, as well as characterize the swallow response to speech and language therapy interventions., Study Design: Children aged 1 month to 11 years receiving care at the Department of Otolaryngology, Hospital de Clínicas de Porto Alegre, Brazil, were evaluated in a cross-sectional design. Evaluation of swallowing was performed at two time points by two blinded speech-language pathologists, one responsible for clinical evaluation and the other for videofluoroscopic study. The protocols employed were based on the instruments proposed by DeMatteo et al. (DeMatteo C, Matovich D, Hjartarson A. Comparison of clinical and videofluoroscopic evaluation of children with feeding and swallowing difficulties. Dev Med Child Neurol 2005;47:149-157.)., Results: The study sample consisted of 29 patients: 10 patients with laryngomalacia and 19 patients with glossoptosis. The sensitivity of clinical evaluation did not exceed 50% in any of the evaluations, but specificity reached 100% in some cases, using thickened liquids. The prevalence of dysphagia was 100%, and the use of thickened liquids significantly reduced tracheal aspiration., Conclusions: Dysphagia was highly prevalent in this sample. The sensitivity of clinical evaluation to detect laryngeal penetration and tracheal aspiration was low, as the majority of aspiration events were silent. The videofluoroscopic study is important in order to determine a safest method to feed the patient. Pediatr Pulmonol. 2017;52:41-47. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Objective: To evaluate the performance of two glossoptosis airway obstruction classifications in predicting symptom severity and laryngeal exposure difficulty in Robin Sequence (RS) patients., Setting: Public tertiary hospital otolaryngology section (Hospital de Clínicas de Porto Alegre - HCPA)., Patients: All RS patients diagnosed at HCPA from October 2012 to February 2015 were enrolled, a total of 58 individuals. They were classified in isolated RS, RS-Plus and syndromic RS., Intervention: Patients were submitted to sleep endoscopy and a score was attributed according to Yellon and de Sousa by a blinded researcher. Symptom severity evaluation was performed as defined by Cole classification., Main Outcome Measure: Association between endoscopic findings and clinical symptoms severity and laryngeal exposure difficulty., Results: Twenty four patients were identified as isolated RS (41.4%), 19 patients presented as RS-Plus (32.7%) and 15 patients had well defined diagnosed syndromes (25.9%). Concomitant airway anomalies were found in 18 patients (31%). Specifically 17.4% in isolated RS, 55.6% in RS- Plus and 28.6% in the syndromic group had such anomalies (P = 0,03). Probability of presenting severe clinical symptoms as graded by Cole was higher in grade 3 Yellon classification (68.4%, P = 0.012) and in moderate and severe de Sousa classification (61.5% and 62.5%, respectively, P = 0.015) than in milder grades of obstruction. This findings were considered significant even after controlling for patient age. Laryngeal exposure difficulty was correlated with de Sousa and Yellon (Rho = 0,41 and Rho = 0,43, respectively; P < 0,05)., Conclusion: Patients with higher degrees of obstruction in sleep endoscopy had a higher probability of presenting a more severe clinical manifestation and a more difficult laryngeal exposure. Since the number of patients included in this study was small for subgroup analyses, it is not clear if this association is restricted to a specific group of RS., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Introduction Surgical repair of congenital heart disease in the first years of life compromises the coordination of the suction, breathing, and swallowing functions. Objective To describe the alterations in swallowing found in infants with congenital heart defect during their hospitalization. Methods Prospective, cross-sectional study in a reference hospital for heart disease. The sample consisted of 19 postsurgical patients who underwent an evaluation of swallowing. The infants included were younger than 7 months and had a diagnosis of congenital heart defect and suspected swallowing difficulties. Results Of the 19 infants with congenital heart defect, the median age was 3.2 months. A significant association was found between suction rhythm and dysphagia (p = 0.036) and between oral-motor oral feeding readiness and dysphagia (p = 0.014). Conclusions The data suggest that dysphagia often occurs after surgery in infants with congenital heart defect. Infants with congenital heart defect had very similar behavior to preterm infants in terms of oral feeding readiness.

Introduction:  Stroke is considered one of the most frequent neurological causes of oropharyngeal dysphagia., Aim:  To determine the effect of cryostimulation on oropharyngeal sensitivity and, subsequently, on the swallowing reaction and premature escape of food in patients with neurogenic dysphagia after stroke., Methods:  Clinical and experimental study. The study enrolled 7 adult subjects, 6 men and 1 woman ranging from 28 to 64 years of age, with a diagnosis of stroke and current oropharyngeal dysphagia without any other underlying disease. The selected subjects underwent speech-language pathology evaluation and videofluoroscopic assessment of the dysphagia. The subjects were then treated with cryostimulation consisting of 10 applications to each structure (anterior faucial pillar, posterior oropharyngeal wall, soft palate, and back tongue) 3 times a day (for a total of 30 daily applications per structure) for 4 consecutive days. The patients were then re-evaluated based on the same criteria. The pre- and post-cryostimulation results of the clinical and videofluoroscopic evaluations were analyzed descriptively and statistically using Student's t-test and Fisher's exact test., Results:  Cryostimulation had beneficial effects on oropharyngeal sensitivity in 6 of the 7 subjects. There was also a significant improvement in swallowing and in the premature escape in six subjects., Conclusion:  Cryostimulation increased sensitivity and subsequently improved the swallowing reaction and premature escape of food in patients with neurogenic dysphagia after stroke. These effects were evident by both speech-language pathology and videofluoroscopic evaluation.

Objective: Transient receptor potential vanilloid 4 (TRPV4) is a Ca(2+)-permeable channel that can be gated by tonicity (osmolarity) and mechanical stimuli. Chondrocytes, the cells in cartilage, respond to their osmotic and mechanical environments; however, the molecular basis of this signal transduction is not fully understood. This study was undertaken to demonstrate the presence and functionality of TRPV4 in chondrocytes., Methods: TRPV4 protein expression was measured by immunolabeling and Western blotting. In response to TRPV4 agonist/antagonists, osmotic stress, and interleukin-1 (IL-1), changes in Ca(2+) signaling, cell volume, and prostaglandin E(2) (PGE(2)) production were measured in porcine chondrocytes using fluorescence microscopy, light microscopy, or immunoassay, respectively., Results: TRPV4 was expressed abundantly at the RNA and protein levels. Exposure to 4alpha-phorbol 12,13-didecanoate (4alphaPDD), a TRPV4 activator, caused Ca(2+) signaling in chondrocytes, which was blocked by the selective TRPV4 antagonist, GSK205. Blocking TRPV4 diminished the chondrocytes' response to hypo-osmotic stress, reducing the fraction of Ca(2+) responsive cells, the regulatory volume decrease, and PGE(2) production. Ca(2+) signaling was inhibited by removal of extracellular Ca(2+) or depletion of intracellular stores. Specific activation of TRPV4 restored the defective regulatory volume decrease caused by IL-1. Chemical disruption of the primary cilium eliminated Ca(2+) signaling in response to either 4alphaPDD or hypo-osmotic stress., Conclusion: Our findings indicate that TRPV4 is present in articular chondrocytes, and chondrocyte response to hypo-osmotic stress is mediated by this channel, which involves both an extracellular Ca(2+) and intracellular Ca(2+) release. TRPV4 may also be involved in modulating the production or influence of proinflammatory molecules in response to osmotic stress.

The PI3K/AKT signaling is activated in various hematologic malignancies. We evaluated the effect of a novel, pan-AKT kinase inhibitor, GSK690693, on the proliferation of 112 cell lines representing different hematologic neoplasia. Fifty-five percent of all cell lines tested were sensitive to AKT inhibitor (EC(50)<1 microM), with acute lymphoblastic leukemia (ALL), non-Hodgkin lymphoma, and Burkitt lymphoma showing 89%, 73%, and 67% sensitivity to GSK690693, respectively. The antiproliferative effect was selective for the malignant cells, as GSK690693 did not inhibit the proliferation of normal human CD4(+) peripheral T lymphocytes as well as mouse thymocytes. Phosphorylation of downstream substrates of AKT was reduced in both sensitive and insensitive cell lines on treatment with GSK690693, suggesting that the cause of resistance was not related to the lack of AKT kinase inhibition. Consistent with the role of AKT in cell survival, GSK690693 also induced apoptosis in sensitive ALL cell lines. Overall, our data provide direct evidence for the role of AKT signaling in various hematologic malignancies, especially ALL and some lymphomas.

Background and Purpose: The human, rat, and mouse P2X(7) receptors have been previously characterized, and in this study we report the cloning and pharmacological properties of the guinea pig orthologue., Experimental Approach: A cDNA encoding for the guinea pig P2X(7) receptor was isolated from a guinea pig brain library. The receptor was expressed in U-2 OS cells using the BacMam viral expression system. A monoclonal antibody was used to confirm high levels of cell surface expression and the functional properties were determined in ethidium bromide accumulation studies., Key Results: The predicted guinea pig protein is one amino acid shorter than the human and rat orthologues and over 70% identical to the rat and human receptors. In contrast to human and rat P2X(7) receptors, 2'-&3'-O-(4benzoylbenzoyl)ATP (BzATP) was a partial agonist of the guinea pig P2X(7) receptor when compared to ATP and acted as an antagonist in some assays. However, as at other species orthologues, BzATP was more potent than ATP. The guinea pig P2X(7) receptor possessed higher affinity for 1-[N,O-bis(5-isoquinoline sulphonyl)-N-methyl-L-tyrosyl]-4-phenylpiperazine (KN62), suramin and Coomassie Brilliant Blue than human or rat P2X(7) receptors suggesting that it is pharmacologically different to other rodent or human P2X(7) receptors., Conclusions and Implications: The guinea pig recombinant P2X(7) receptor displays a number of unique properties that differentiate it from the human, rat and mouse orthologues and this structural and functional information should aid in our understanding of the interaction of agonists and antagonist with the P2X(7) receptor.

Objective: To test the repeatability of sonography in the assessment of fetal sucking and swallowing movements., Methods: Eighty normal fetuses of pregnant women with no systemic abnormalities were examined sonographically at 30-38 weeks of gestation. Sucking and swallowing movements were observed for 15 min and the face was visualized in frontal and lateral views. The examinations were recorded for later analysis by two independent observers and the 95% limits of agreement (Bland and Altman) method was used for inter- and intraobserver comparison., Results: The mean +/- SD number of swallowing movements, sucking bursts and total sucking movements recorded by Observer 1 were 8.3 +/- 4.7, 9.9 +/- 9.3 and 35.8 +/- 48.0 and the equivalent values for Observer 2 were 8.2 +/- 4.8, 9.8 +/- 9.3 and 36.4 +/- 49.0, respectively. The mean (95% limits of agreement) interobserver difference was 0.1 (-1.4; 1.6), 0.1 (-2.2; 2.3) and -0.6 (-9.0; 7.9), and the mean (95% limits of agreement) intraobserver difference was 0.4 (-3.1; 3.9), 0.1 (-2.0; 2.2) and 1.0 (-10.7; 12.7) for swallowing movements, sucking bursts and total sucking movements, respectively., Conclusions: The high degree of intra- and interobserver repeatability disclosed in the sonographic analysis of fetal sucking and swallowing movements supports the applicability of sonographic assessment in normal fetuses.

Numerous human studies have separately observed the effects of auditory stimuli at brain stem and cortical levels, but little research has focused on possible functional coupling between these diverse brain areas. The present study recorded the cortical C-process [5] evoked by a pitch change between two successive tones, as well as the brain stem frequency-following response (FFR) evoked by each tone. The results replicated expected C-process component waveforms, including a late, negative (N2) component. FFR spectral intensity differences between the two tones were significantly correlated with N2 amplitude. These results suggest that signal processing reflected in long-latency auditory evoked response components is not exclusively a cortical phenomenon, but also depends upon patterns of neural processing occurring in brain stem pathways.

Melanin-concentrating hormone (MCH) is involved in the regulation of feeding and energy homeostasis. Recently, a 353-amino acid splice variant form of the human orphan receptor SLC-1 () (hereafter referred to as MCH(1)) was identified as an MCH receptor. This report describes the cloning and functional characterization of a novel second human MCH receptor, which we designate MCH(2), initially identified in a genomic survey sequence as being homologous to MCH(1) receptors. Using this sequence, a full-length cDNA was generated with an open reading frame of 1023 base pairs, encoding a polypeptide of 340 amino acids, with 38% identity to MCH(1) and with many of the structural features conserved in G protein-coupled receptors. This newly discovered receptor belongs to class 1 (rhodopsin-like) of the G protein-coupled receptor superfamily. HEK293 cells transfected with MCH(2) receptors responded to nanomolar concentrations of MCH with an increase in intracellular Ca(2+) levels and increased cellular extrusion of protons. In addition, fluorescently labeled MCH bound with nanomolar affinity to these cells. The tissue localization of MCH(2) receptor mRNA, as determined by quantitative reverse transcription-polymerase chain reaction, was similar to that of MCH(1) in that both receptors are expressed predominantly in the brain. The discovery of a novel MCH receptor represents a new potential drug target and will allow the further elucidation of MCH-mediated responses.

Quantitative antibody levels to three herpesviruses in acute and chronic sera from six patients with clinical signs of the acute retinal necrosis syndrome were consistent with a specific etiologic diagnosis only in the two cases associated with cutaneous herpes zoster. Available data on acute and convalescent antibody titers to herpes group viruses from these six patients in addition to data from 27 acute retinal necrosis cases from the literature disclosed that only 13 of the 33 patients (39%) had a diagnostic increase or decrease in herpes group viral antibody levels on serial sampling. Three patients had nondiagnostic changes in viral antibody levels despite positive vitreous cultures for herpesviruses. In contrast, a review of 25 cases from the literature with paired antiviral serum and intraocular fluid antibody levels suggested a more promising approach to the etiologic diagnosis of the acute retinal necrosis syndrome. By calculating the ratio of antiviral antibodies in intraocular fluid and serum, an etiologic diagnosis could be made in 12 of 14 (86%) of subacute and convalescent samples. The sensitivity of this method decreased to 72% (13 of 18) when fluids were obtained earlier in the course of the disease.

All cases of uterine perforation occurring during intracavitary application for carcinoma of the cervix over a 13-year period (1968-1981) were reviewed. There were 14 perforations out of 799 applications in 622 patients, for an incidence of 2.25% of patients and 1.75% of applications. In most cases, it is sufficient to halt the application and carefully monitor the patient, as supported by the uneventful post-perforation course in 12 cases. Nine patients (64%) underwent subsequent intracavitary application without further complications; of these, 8 are still living or died without evidence of tumor. In the other 5, it was impossible to locate the cervical canal on subsequent applications. Alternative treatments, results of therapy, and analysis of failures are presented. The authors conclude that there is no direct evidence that uterine perforation alters the prognosis following radiation therapy for carcinoma of the cervix.

Metastatic tumors of the oral cavity are uncommon. Most of them are located in the mandible while only a small percentage are found within the soft tissues. Two cases of metastatic bronchogenic carcinomas to the tongue are described. Review of the literature showed that cancer of the lung was the most common primary lesion that metastasized to the soft tissues of the oral cavity. The base of the tongue was the most prevalent site of metastases to soft tissue within the oral cavity.

Bladder dysfunction is a recognized complication following radical hysterectomy, however, the effect of radiation alone or in combination with surgery on bladder function has received little attention. Thirty patients who underwent radical hysterectomy with postoperative whole pelvis radiation (RH + RT) were matched for age, stage of disease, and time interval since therapy, with 30 patients who had radical hysterectomy alone (RH) and 30 patients who were treated with pelvic radiotherapy (RT). Bladder function was assessed by symptoms and urodynamic evaluation. Altered bladder sensation and voiding problems were associated with surgery, and were more frequent after RH or RH + RT than RT (P = 0.002). fifty percent of RH patients voided by abdominal straining compared to 10% who had only RT. No greater problem was seen after RH + RT compared to RH. Urinary incontinence was present in 15% of patients prior to therapy. After treatment, incontinence requiring protection developed in 23% of RT patients, 26% of RH patients, and 63% of RH + RT patients. The severity of the incontinence was greater after RH + RT. Bladder neck and urethral function was similar in all groups, however, bladder compliance was reduced in RT patients and significantly (P = 0.0001) reduced after RH + RT compared to RH alone. This reduction was related to the bladder dose of external radiation and was a factor in the etiology of the urinary incontinence seen in RH + RT patients.

Low dose superficial x-irradiation to the incisional site after surgical excision of a keloid prevented keloid or hypertrophic scar formation in 31 of 35 patients evaluated (88%). The clinical manifestation of keloids, physiology of wound healing, pathophysiology of keloid formation, and the radiation technique utilized are presented. This study shows that the method is well tolerated, easily administered, and efficient in inhibiting recurrence of keloid or hypertrophic scar formation.

A case of a 10-year-old asthmatic patient who had cardiac arrest during induction for elective ear surgery is presented. The patient's serum theophylline level was 21.6 micrograms/mL one hour after surgery. It is likely that, since other factors that can contribute to cardiac arrest during the perioperative period were not present, the combined use of aminophylline and halothane was responsible.