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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.

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.)

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.

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.