Craniofacial, craniocervical, and pharyngeal morphology in bilateral cleft lip and palate and obstructive sleep apnea patients.

OBJECTIVE: The aim of this study was to analyze craniofacial, craniocervical, and pharyngeal morphology in surgically treated bilateral cleft lip and palate (BCLP) men, untreated men with obstructive sleep apnea (OSA), and a reference group of men. SUBJECTS AND METHODS: Lateral cephalograms were obtained of 27 male BCLP patients (mean age 29.0 +/- 8.3 years), 27 untreated male OSA patients (mean age 38.6 +/- 5.3 years), and 27 male controls serving as a reference group (mean age 30.8 +/- 9.2 years). Tracings were made, and 26 variables representing craniofacial, craniocervical, and pharyngeal dimensions were obtained using Viewbox 3.1.1.6. software. The groups were compared using a one-way analysis of variance. RESULTS: Craniofacial, craniocervical, and pharyngeal morphology of BCLP and OSA patients was similar except for a significantly more retrusive maxilla in the BCLP group. Compared to the reference group, the BCLP and OSA groups had significantly larger craniocervical angulations, smaller depth of the oropharynx at the tip of the velum, and a more inferiorly positioned hyoid bone. Significantly larger vertical dimensions were found in the BCLP group compared to the reference group. CONCLUSIONS: Craniofacial, craniocervical, and pharyngeal morphology of BCLP and OSA patients demonstrate substantial similarities except for a significantly more retrusive maxilla in the BCLP group. It is suggested that airway obstruction and postural adaptation to the obstruction may possibly be related to the aberrant craniofacial, craniocervical, and pharyngeal morphology in OSA and in BCLP patients.     

SARS-CoV-2 Vaccine Responses in Individuals with Antibody Deficiency: Findings from the COV-AD Study

Background

Vaccination prevents severe morbidity and mortality from COVID-19 in the general population. The immunogenicity and efficacy of SARS-CoV-2 vaccines in patients with antibody deficiency is poorly understood.

Objectives

COVID-19 in patients with antibody deficiency (COV-AD) is a multi-site UK study that aims to determine the immune response to SARS-CoV-2 infection and vaccination in patients with primary or secondary antibody deficiency, a population that suffers from severe and recurrent infection and does not respond well to vaccination.

Methods

Individuals on immunoglobulin replacement therapy or with an IgG less than 4 g/L receiving antibiotic prophylaxis were recruited from April 2021. Serological and cellular responses were determined using ELISA, live-virus neutralisation and interferon gamma release assays. SARS-CoV-2 infection and clearance were determined by PCR from serial nasopharyngeal swabs.

Results

A total of 5.6% (n?=?320) of the cohort reported prior SARS-CoV-2 infection, but only 0.3% remained PCR positive on study entry. Seropositivity, following two doses of SARS-CoV-2 vaccination, was 54.8% (n?=?168) compared with 100% of healthy controls (n?=?205). The magnitude of the antibody response and its neutralising capacity were both significantly reduced compared to controls. Participants vaccinated with the Pfizer/BioNTech vaccine were more likely to be seropositive (65.7% vs. 48.0%, p?=?0.03) and have higher antibody levels compared with the AstraZeneca vaccine (IgGAM ratio 3.73 vs. 2.39, p?=?0.0003). T cell responses post vaccination was demonstrable in 46.2% of participants and were associated with better antibody responses but there was no difference between the two vaccines. Eleven vaccine-breakthrough infections have occurred to date, 10 of them in recipients of the AstraZeneca vaccine.

Conclusion

SARS-CoV-2 vaccines demonstrate reduced immunogenicity in patients with antibody deficiency with evidence of vaccine breakthrough infection.

     

Biomechanical effects of a mandibular advancement device on the temporomandibular joint

Purpose

Mandibular advancement devices are commonly used in the treatment of patients with mild to moderate obstructive sleep apnea (OSA). Designed to maintain the mandible in forced protrusion while being worn, mandibular advancement devices (MADs) are intended to increase the upper airway during sleep, thereby reducing OSA symptoms. Depending on the extent of mandibular protrusion, side effects including temporomandibular joint dysfunction are frequently reported. These are likely to reduce overall treatment success by affecting therapeutic adherence.

Differential sensitivity of mouse strains to an N-alkylated imino sugar: glycosphingolipid metabolism and acrosome formation

This review deals with the pharmacological properties of an alkylated monosaccharide mimetic, N-butyldeoxynojirimycin (NB-DNJ). This compound is of pharmacogenetic interest because one of its biological effects in mice - impairment of spermatogenesis, leading to male infertility - depends greatly on the genetic background of the animal. In susceptible mice, administration of NB-DNJ perturbs the formation of an organelle, the acrosome, in early post-meiotic male germ cells. In all recipient mice, irrespective of reproductive phenotype, NB-DNJ has a similar biochemical effect: inhibition of the glucosylceramidase beta-glucosidase 2 and subsequent elevation of glucosylceramide, a glycosphingolipid. The questions that we now need to address are: how can glucosylceramide specifically affect early acrosome formation, and why is this contingent on genetic factors? Here we discuss relevant aspects of reproductive biology, the metabolism and cell biology of sphingolipids, and complex trait analysis; we also present a speculative model that takes our observations into account.     

Long-term non-hormonal male contraception in mice using N-butyldeoxynojirimycin

BACKGROUND: The imino sugar N-butyldeoxynojirimycin (NB-DNJ) causes reversible infertility in male mice. This compound may have promise as a male contraceptive, because it is already in clinical use, for a non-reproductive condition. As contraceptives need to be taken for extended periods of time, it was essential to evaluate NB-DNJ for its reproductive effects over a long period of administration. METHODS: We have assessed the imino sugar for its long-term effects on the fertility of male C57BL/6 mice, reversibility and potential cumulative toxicity by monitoring various reproductive and systemic parameters over 12 months. RESULTS: Long-term low-dose (15 mg/kg/day) administration of NB-DNJ was sufficient to maintain infertility in male mice. In contrast to short-term drug treatment, imino sugar exposure for more than 3 months resulted in reduced sperm counts. Male mice that had been administered imino sugar for 6, 10 or 12 months and were then maintained without drug administration regained their fertility within 9 weeks after withdrawal of the drug. Prolonged NB-DNJ intake did not affect reproductive hormone levels, serum biochemistry or animal behaviour. CONCLUSION: Low-dose treatment with NB-DNJ over a long period is an effective approach for the regulation of fertility in a male mammal by non-hormonal means, without causing overt adverse effects.     

Long‐term safety and effectiveness of berotralstat for hereditary angioedema: The open‐label APeX‐S study

BackgroundBerotralstat (BCX7353) is an oral, once‐daily inhibitor of plasma kallikrein recently approved for prevention of angioedema attacks in adults and adolescents with hereditary angioedema (HAE). The objective of this report is to summarize results from an interim analysis of an ongoing long‐term safety study of berotralstat in patients with HAE.MethodsAPeX‐S is an ongoing, phase 2, open‐label study conducted in 22 countries (ClinicalTrials.gov, {"type":"clinical-trial","attrs":{"text":"NCT03472040","term_id":"NCT03472040"}}NCT03472040). Eligible patients with a clinical diagnosis of HAE due to C1 inhibitor deficiency (HAE‐C1‐INH) were centrally allocated to receive berotralstat 150 or 110 mg once daily. The primary objective was to determine long‐term safety and the secondary objective was to evaluate effectiveness.ResultsEnrolled patients (N = 227) received berotralstat 150 mg (n = 127) or 110 mg (n = 100) once daily. The median (range) duration of exposure was 342 (11–540) and 307 (14–429) days for the 150‐mg and 110‐mg groups, respectively. Treatment‐emergent adverse events (TEAEs) occurred in 91% (n = 206) of patients. The most common TEAEs across treatment groups were upper respiratory tract infection (n = 91, 40%), abdominal pain (n = 57, 25%), headache (n = 40, 18%), and diarrhea (n = 31, 14%) and were mostly mild to moderate. Fifty percent (n = 113) of patients had at least one drug‐related adverse event (AE; 150 mg, n = 57 [45%]; 110 mg, n = 56 [56%]), and discontinuations due to AEs occurred in 19 (8%) patients (150 mg, n = 13 [10%]; 110 mg, n = 6 [6%]). Three (1.3%) patients experienced a drug‐related serious TEAE. Among patients who received berotralstat through 48 weeks (150 mg, n = 73; 110 mg, n = 30), median HAE attack rates were low in month 1 (150 mg, 1.0 attacks/month; 110 mg, 0.5 attacks/month) and remained low through 12 months (0 attacks/month in both dose groups). Mean HAE attack rates followed a similar trend, and no evidence for patient tolerance to berotralstat emerged. In both dose groups, angioedema quality of life scores showed clinically meaningful changes from baseline.ConclusionsIn this analysis, both berotralstat doses, 150  and 110 mg once daily, were generally well tolerated. Effectiveness results support the durability and robustness of berotralstat as prophylactic therapy in patients with HAE.Trial registrationThe study is registered with ClinicalTrials.gov ({"type":"clinical-trial","attrs":{"text":"NCT03472040","term_id":"NCT03472040"}}NCT03472040).     

Beneficial effects of substrate reduction therapy in a mouse model of GM1 gangliosidosis

GM1 gangliosidosis is an inherited neurodegenerative disorder caused by lysosomal beta-galactosidase deficiency, resulting in the storage of GM1 and GA1, primarily in the central nervous system. This disease typically afflicts infants and young children and there is currently no effective therapy. Substrate reduction therapy (SRT) could be of potential benefit. The imino sugars N-butyldeoxynojirimycin (NB-DNJ, miglustat, Zavesca) and N-butyldeoxygalactonojirimycin (NB-DGJ) used for SRT inhibit glucosylceramide synthase (GlcCerS) that catalyses the first committed step in glycosphingolipid biosynthesis. We have compared the efficacy and tolerability of NB-DNJ and NB-DGJ in the beta-galactosidase knockout mouse. NB-DGJ was better tolerated than NB-DNJ, due to intrinsic gastrointestinal tract dysfunction that was exacerbated by NB-DNJ. However, functional improvement was greatest with NB-DNJ treatment which may potentially be caused by novel anti-inflammatory properties of NB-DNJ.     

Prevalence of obstructive sleep apnoea following head and neck cancer treatment: a cross-sectional study

The obstructive sleep apnoea-hypopnoea syndrome (OSAHS) is a sleep-related breathing disorder characterised by repetitive pharyngeal collapse. OSAHS is associated with a reduced quality of life. A high OSAHS prevalence has been reported in patients treated for head and neck cancer (HNC). The aim of the present study was to identify the prevalence of OSAHS within a Dutch population of patients treated for HNC. Consecutive HNC patients with a follow-up of 6 months to 5 years after treatment of an oral or oropharynx carcinoma were eligible for inclusion. Two questionnaires were used to assess the presence of OSAHS-related complaints. Subsequently, polysomnography was used in patients with OSAHS-related complaints to confirm the diagnosis of OSAHS. Four out of 33 included patients were diagnosed with OSAHS, yielding a prevalence of 12%. Since recognition and treatment of OSAHS might play an important role in improving quality of life of HNC patients, we suggest screening all patients with an oral or oropharynx carcinoma for the presence of OSAHS-related complaints prior to and following HNC treatment.     

Efficacy and comorbidity of oral appliances in the treatment of obstructive sleep apnea–hypopnea: a systematic review and preliminary results of a randomized trial

The obstructive sleep apnea–hypopnea syndrome (OSAHS) is a common sleep-related breathing disorder characterized by repetitive obstructions of the upper airway during sleep. The modification of pharyngeal patency by oral appliance therapy has been suggested as an alternative to various treatment modalities for OSAHS. To determine the evidence base with respect to the efficacy and comorbidity of the oral appliance therapy in OSAHS, a systematic review of the available literature was conducted. In addition, the preliminary results of a randomized parallel trial are reported on the effectiveness and specific indication of, respectively, the oral appliance and continuous positive airways pressure therapy in OSAHS.Presented at the EDESA Meeting, 15 October 2005, Berlin, Germany