A reverse genetics and genomics approach to gene paralog function and disease: Myokymia and the juxtaparanode.

The leucine-rich glioma-inactivated (LGI) family consists of four highly conserved paralogous genes, LGI1-4, that are highly expressed in mammalian central and/or peripheral nervous systems. LGI1 antibodies are detected in subjects with autoimmune limbic encephalitis and peripheral nerve hyperexcitability syndromes (PNHSs) such as Isaacs and Morvan syndromes. Pathogenic variations of LGI1 and LGI4 are associated with neurological disorders as disease traits including familial temporal lobe epilepsy and neurogenic arthrogryposis multiplex congenita 1 with myelin defects, respectively. No human disease has been reported associated with either LGI2 or LGI3. We implemented exome sequencing and family-based genomics to identify individuals with deleterious variants in LGI3 and utilized GeneMatcher to connect practitioners and researchers worldwide to investigate the clinical and electrophysiological phenotype in affected subjects. We also generated Lgi3-null mice and performed peripheral nerve dissection and immunohistochemistry to examine the juxtaparanode LGI3 microarchitecture. As a result, we identified 16 individuals from eight unrelated families with loss-of-function (LoF) bi-allelic variants in LGI3. Deep phenotypic characterization showed LGI3 LoF causes a potentially clinically recognizable PNHS trait characterized by global developmental delay, intellectual disability, distal deformities with diminished reflexes, visible facial myokymia, and distinctive electromyographic features suggestive of motor nerve instability. Lgi3-null mice showed reduced and mis-localized Kv1 channel complexes in myelinated peripheral axons. Our data demonstrate bi-allelic LoF variants in LGI3 cause a clinically distinguishable disease trait of PNHS, most likely caused by disturbed Kv1 channel distribution in the absence of LGI3.

Oral nitrate supplementation improves cardiovascular risk markers in COPD: ON-BC, a randomised controlled trial.

BACKGROUND: Short-term studies suggest that dietary nitrate (NO3 -) supplementation may improve the cardiovascular risk profile, lowering blood pressure (BP) and enhancing endothelial function. It is not clear if these beneficial effects are sustained and whether they apply in people with COPD, who have a worse cardiovascular profile than those without COPD. Nitrate-rich beetroot juice (NR-BRJ) is a convenient dietary source of nitrate. METHODS: The ON-BC trial was a randomised, double-blind, placebo-controlled parallel group study in stable COPD patients with home systolic BP (SBP) measurement ≥130 mmHg. Participants were randomly allocated (1:1) using computer-generated, block randomisation to either 70 mL NR-BRJ (400 mg NO3 -) (n=40) or an otherwise identical nitrate-depleted placebo juice (0 mg NO3 -) (n=41), once daily for 12 weeks. The primary end-point was between-group change in home SBP measurement. Secondary outcomes included change in 6-min walk distance (6MWD) and measures of endothelial function (reactive hyperaemia index (RHI) and augmentation index normalised to a heart rate of 75 beats·min-1 (AIx75)) using an EndoPAT device. Plasma nitrate and platelet function were also measured. RESULTS: Compared with placebo, active treatment lowered SBP (Hodges-Lehmann treatment effect -4.5 (95% CI -5.9- -3.0) mmHg), and improved 6MWD (30.0 (95% CI 15.7-44.2) m; p<0.001), RHI (0.34 (95% CI 0.03-0.63); p=0.03) and AIx75 (-7.61% (95% CI -14.3- -0.95%); p=0.026). CONCLUSIONS: In people with COPD, prolonged dietary nitrate supplementation in the form of beetroot juice produces a sustained reduction in BP, associated with an improvement in endothelial function and exercise capacity.

Oscillatory positive expiratory pressure therapy in COPD (O-COPD): a randomised controlled trial.

BACKGROUND: Oscillatory positive expiratory pressure (OPEP) devices are intended to facilitate sputum clearance and reduce cough, but there is limited evidence for their effectiveness in COPD, or to guide patient selection. We aimed to assess the impact of OPEP therapy on quality of life and objective measures of cough and sleep disturbance in patients with COPD with regular sputum production. METHODS: We enrolled stable patients with COPD, who reported sputum production every day or most days, into an assessor-blind, parallel-group, randomised controlled trial comparing 3 months of using an Acapella device against usual care (including use of the active cycle of breathing technique). The primary outcome was cough-related quality of life measured using the Leicester Cough Questionnaire (LCQ). Secondary outcomes included fatigue (Functional Assessment of Chronic Illness Therapy, FACIT score) and generic quality of life (EuroQol-5 Dimensions, EQ-5D). In a substudy (n=45), objective monitoring of cough and disturbance/movement during sleep were also available. RESULTS: 122 participants (61/61 OPEP/control) were recruited, 40% female, 17% smokers, FEV1 38 (25-56)% predicted, and age 62±10 years. 103 completed the study (55/48 OPEP/control). Use of OPEP was associated with an improvement in LCQ compared with controls; MD (95% CI) 1.03 (0.71 to 2.10); (p=0.03), FACIT score 4.68 (1.34 to 8.02); (p<0.001) and EQ-5D 4.00 (0.49 to 19.75); (p=0.04). There was also an improvement in cough frequency -60 (-43 to -95) coughs/24 hours (p<0.001), but no statistically significant effect on sleep disturbance was identified. CONCLUSIONS: Regular use of an Acapella device improves symptoms and quality of life in people with COPD who produce sputum daily or most days. TRIAL REGISTRATION NUMBER: ISRCTN44651852.

Use of oscillatory positive expiratory pressure (OPEP) devices to augment sputum clearance in COPD: a systematic review and meta-analysis.

INTRODUCTION: Oscillating positive expiratory pressure (OPEP) devices are intended to facilitate sputum clearance in chronic obstructive pulmonary disease (COPD), but there is uncertainty as to their place in treatment pathways. We aimed to review the existing literature to establish the evidence base for their use. METHODS: A systematic search of records up to March 2020 was performed on PubMed, CINAHL, Medline (Ovid), Cochrane and Embase to retrieve clinical trials that evaluated the efficacy of OPEP devices in patients with COPD. Two independent reviewers retrieved the titles, abstracts and full texts, and completed the data extraction. RESULTS: Following full-text review of 77 articles, eight (six randomised control trials and 2 cross-over studies) were eligible for inclusion. Pooled analysis showed low-grade evidence that the use of OPEP devices was associated with decreased COPD symptoms and exacerbations (OR 0.37, 95% CI 0.19 to 0.72), and enhanced exercise capacity; 6 min walk distance (mean difference (95% CI), 49.8 m (14.2 m to 85.5 m); p=0.009]). However, studies were mostly short term with the majority having a high risk of bias. The average acceptance, completion and drop-out rates were 82%, 91% and 8%, respectively. CONCLUSION: The use of OPEP devices can have a positive impact in COPD, but confidence in effect sizes is low and there is a need for further, higher quality studies to examine their long-term efficacy in COPD as well as to identify specific patient phenotypes that are more likely to respond. PROSPERO REGISTRATION NUMBER: CRD 42016041835.

Incidence of Inborn Errors of Metabolism and Endocrine Disorders Among 40965 Newborn Infants at Riyadh Second Health Cluster of the Ministry of Health Saudi Arabia.

Inborn errors of metabolism (IEM) and endocrine disorders are common genetic conditions in the Saudi population with the incidence rate often underestimated. Newborn screening (NBS) using various disease panels provides the first line in the early detection and intervention among infants with a high risk of IEM. Here we aim to assess the incidence of screening disorders and provide an overview of the NBS program at the Ministry of Health Tertiary Care King Fahad Medical City. Dried blood spots (DBS) from 40,965 newborn infants collected on the second day after birth were analyzed for 20 disorders. The total number of positive screen ("repeat") samples over 10 years was about 1% (n = 382/40,965). The true positive result rate was 15.3% (n = 46/301) with the recall rates of individual disorders ranging from 0.26% (95% CI, 0.17-0.69) to 2.6% (95% CI, 2.19-3.05). The false positive result rate was 84.7% (n = 255/301) with biotinidase activity found to be the most common cause of the second sample repeat. The overall incidence of the screened diseases was 1:891 (95% CI, 11.61-12.47). CH and CAH are the most prevalent among endocrine disorders with an incidence of 1:4097 (95% CI, 2.19-3.05), and PA and ASA among the IEM with an incidence of 1:10,241 (95% CI, 0.09-0.95). In summary, we provide updated data and our experience on the incidence of various IEM and endocrine disorders among the Saudi population, highlight the role of false positive results of biotinidase activity that can increase the recall rate and lead to overestimation of the incidence data, and recommend multicenter studies to achieve a successful national NBS program.

Retraction: Mesenteric Panniculitis and COVID-19: A Rare Association.

[This retracts the article DOI: 10.7759/cureus.21314.].

Singing for lung health in COPD: a multicentre randomised controlled trial of online delivery.

BACKGROUND: Singing for lung health (SLH) is an arts-based breathing control and movement intervention for people with long-term respiratory conditions, intended to improve symptoms and quality of life. Online, remotely delivered programmes might improve accessibility; however, no previous studies have assessed the effectiveness of this approach. METHODS: We conducted an assessor-blind randomised controlled trial comparing the impact of 12 weeks of once-weekly online SLH sessions against usual care on health-related quality of life, assessed using the RAND 36-Item Short Form Health Survey (SF-36) Mental Health Composite (MHC) and Physical Health Composite (PHC) scores. RESULTS: We enrolled 115 people with stable chronic obstructive pulmonary disease (COPD), median (IQR) age 69 (62-74), 56.5% females, 80% prior pulmonary rehabilitation, Medical Research Council dyspnoea scale 4 (3-4), forced expiratory volume in 1 s % predicted 49 (35-63). 50 participants in each arm completed the study. The intervention arm experienced improvements in physical but not mental health components of RAND SF-36; PHC (regression coefficient (95% CI): 1.77 (95% CI 0.11 to 3.44); p=0.037), but not MHC (0.86 (95% CI -1.68 to 3.40); p=0.504). A prespecified responder analysis based on achieving a 10% improvement from baseline demonstrated a response rate for PHC of 32% in the SLH arm and 12.7% for usual care (p=0.024). A between-group difference in responder rate was not found in relation to the MHC (19.3% vs 25.9%; p=0.403). DISCUSSION AND CONCLUSION: A 12-week online SLH programme can improve the physical component of quality of life for people with COPD, but the overall effect is relatively modest compared with the impact seen in research using face-to-face group sessions. Further work on the content, duration and dose of online interventions may be useful. TRIAL REGISTRATION NUMBER: NCT04034212.

Perception and clinical practice regarding mucus clearance devices with chronic obstructive pulmonary disease: a cross-sectional study of healthcare providers in Saudi Arabia.

OBJECTIVES: Clearing secretions from the airway can be difficult for people with chronic obstructive pulmonary disease (COPD). Mucus clearance devices (MCDs) are an option in disease management to help with this, but healthcare provider awareness and knowledge about them as well as current clinical practice in Saudi Arabia are not known. DESIGN: A cross-sectional online survey consisting of four themes; demographics, awareness, recommendations and clinical practice, for MCDs with COPD patients. SETTING: Saudi Arabia. PARTICIPANTS: 1188 healthcare providers including general practitioners, family physicians, pulmonologists, nursing staff, respiratory therapists and physiotherapists. PRIMARY OUTCOME MEASURES: Healthcare providers' level of awareness about MCDs, and the identification of current clinical practices of COPD care in Saudi Arabia. RESULTS: 1188 healthcare providers (44.4% female) completed the survey. Regarding devices, 54.2% were aware of the Flutter, 23.8% the Acapella and 5.4% the positive expiratory pressure mask. 40.7% of the respondents identified the Acapella, and 22.3% the Flutter as first choice for COPD management. 75% would usually or always consider their use in COPD patients reporting daily difficulty clearing mucus, whereas 55.9% would sometimes or usually consider the use of MCDs with COPD patients who produced and were able to clear mucus with cough. In clinical practice, 380 (32%) of the respondents would prescribe MCDs, 378 (31.8%) would give MCDs without prescriptions, 314 (26.4%) would not provide them at all and 116 (9.8%) would only advise patients about them. CONCLUSION: Healthcare providers are aware of the existence of MCDs and their benefits for sputum clearance and believe that MCDs are beneficial for sputum clearance in some COPD patients. TRIAL REGISTRATION NUMBER: ISRCTN44651852.

The Status of Respiratory Care Education in Saudi Arabia: A National Survey of Program Directors.

Background: Respiratory Care Practitioner (RCP) is a vital healthcare professional in Saudi Arabia (SA). Many factors regarding the education of RCPs in SA are unknown, including the number of active institutions, levels of education and barriers to promoting the profession. Methods: A cross sectional-based survey was conducted between June 1st, 2020 and September 20th, 2020 in SA to explore the status of RCPs education. Institutions that offered RCP programs were identified through the Ministry of Education and Ministry of Defense academic programs websites. The RCP program directors were invited to participate in an electronic survey. Results: Among the 74 institutions searched, 23 indicated that they offered RC programs. Only 13 (56.52%) responded to the survey. Among all programs, four (17.39%) were inactive, 17 (73.91%) were governmental institutions, and only one (4.35%) obtained a national accreditation. From the 13 respondents, there were 1297 students enrolled and 123 full-time faculty members. None of the institutions reported offering postgraduate RC degrees. The respondents reported many barriers; however, shortage of staff (76.92%), lack of postgraduate programs (69.23%), lack of research activity (69.23%), and ineffective communications between institutions (61.54%) were the most reported barriers. Conclusion: The RC education in SA is developing but not well distributed throughout the country. The shortage of staff and the limited number of postgraduate degree holders potentially contributed to the delay in establishing postgraduate RC degrees, obtaining accreditation, and implementing subspecialties to advance the profession in terms of research and quality of care.

Mesenteric Panniculitis and COVID-19: A Rare Association.

Coronavirus disease 2019 (COVID-19) typically involves the respiratory system, but gastrointestinal involvement is common. Further, patients with severe COVID-19 are at high risk to develop gastrointestinal complications, including bowel ischemia, ileus, and deranged liver enzymes. We present the case of a 44-year-old woman with mild COVID-19 pneumonia who was in home isolation. Ten days after the isolation, the patient presented to the emergency department complaining of generalized abdominal pain that was sharp in nature and associated with nausea and recurrent episodes of vomiting. The patient did not complain of any respiratory symptoms. Physical examination showed diffuse tenderness with no clinical signs to suggest generalized peritonitis. The laboratory parameters showed normal hematological, renal, and hepatic profiles. No elevation in the inflammatory markers was observed. The amylase level was within the normal range. Abdominal computed tomography scan demonstrated the presence of misty mesentery with increased density of the mesentery with fat stranding encasing the mesenteric vessels along with mesenteric adenopathy. Such radiological features suggested the diagnosis of mesenteric panniculitis. Subsequently, intravenous corticosteroid therapy was initiated and the patient exhibited significant improvement after 24 hours. The patient was discharged after nine days of hospitalization. She was followed up after one month and she had no complaints. Mesenteric panniculitis is a rare idiopathic inflammatory condition involving the mesenteric adipose tissue. The case shed a light on the possible association of COVID-19 with mesenteric panniculitis. The clinical manifestations of mesenteric panniculitis are non-specific and imaging studies are essential to suggest the diagnosis.

Impact of dietary nitrate supplementation on exercise capacity and cardiovascular parameters in chronic respiratory disease: a systematic review and meta-analysis.

BACKGROUND: Dietary nitrate supplementation, usually in the form of beetroot juice, may improve exercise performance and endothelial function. We undertook a systematic review and meta-analysis to establish whether this approach has beneficial effects in people with respiratory disease. METHODS: A systematic search of records up to March 2021 was performed on PubMed, CINAHL, MEDLINE (Ovid), Cochrane and Embase to retrieve clinical trials that evaluated the efficacy of dietary nitrate supplementation on cardiovascular parameters and exercise capacity in chronic respiratory conditions. Two authors independently screened titles, abstracts and full texts of potential studies and performed the data extraction. RESULTS: After full-text review of 67 papers, eleven (two randomised controlled trials and nine crossover trials) involving 282 participants met the inclusion criteria. Three were single dose; seven short term; and one, the largest (n=122), done in the context of pulmonary rehabilitation. Pooled analysis showed that dietary nitrate supplementation reduced systolic blood pressure (BP), diastolic BP and mean arterial pressure (mean difference (95% CI), -3.39 mm Hg (-6.79 to 0.01); p=0.05 and -2.20 mm Hg (-4.36 to -0.03); p=0.05 and -4.40 mm Hg (-7.49 to -1.30); p=0.005, respectively). It was associated with increased walk distance in the context of pulmonary rehabilitation (standardised mean difference (95% CI), 0.47 (0.11 to 0.83), p=0.01), but no effect was identified in short-term studies (0.08 (-0.32 to 0.49). CONCLUSION: Dietary nitrate supplementation may have a beneficial effect on BP and augment the effect of pulmonary rehabilitation on exercise capacity. Short-term studies do not suggest a consistent benefit on exercise capacity. PROSPERO REGISTRATION NUMBER: CRD42019130123.

Substance Use and Misuse among Adults with Chronic Obstructive Pulmonary Disease in the United States, 2015-2019: Prevalence, Association, and Moderation.

BACKGROUND: Despite the advancements in chronic obstructive pulmonary disease (COPD) treatment, complications related to COPD exacerbation remain challenging. One associated factor is substance use/misuse among adults with COPD. Fewer studies, however, examined the prevalence and association between COPD and substance use and misuse. In addition, limited knowledge existed about the moderation effects of serious psychological distress and gender among adults with COPD and substance use/misuse. We aimed, therefore, to measure such prevalence, association, and moderation from nationally representative samples in the United States. METHOD: Data were drawn from the 2015-2019 National Survey on Drug Use and Health. Weighted logistic regressions were used to measure the associations of last-month tobacco (cigarettes, cigars, pipe, and smokeless tobacco products), other licit and illicit substance use (alcohol, marijuana, cocaine, crack, heroin, hallucinogens, and inhalants), and substance misuse (pain relievers, tranquilizers, stimulants, and sedatives) among adults with COPD. Serious psychological distress and gender were tested as moderators in the association between COPD and substance use/misuse. RESULTS: The findings revealed that adults with COPD [Weighted N = 53,115,718) revealed greater odds of cigarettes [adjusted odds ratio (aOR) = 2.48 (95%CI = 1.80-3.42)) and smokeless tobacco (aOR = 3.65 (95%CI = 1.75-7.65)). However, they were less likely to use alcohol (aOR = 0.61 (95%CI = 0.45-0.84)). Adults with COPD who had serious psychological distress were more likely to use pipe tobacco and alcohol; however, they were less likely to use hallucinogens and inhalants. Finally, males compared to females with COPD were less likely to use smokeless tobacco. CONCLUSION: Adults with COPD in the United States were more likely to use tobacco products and less likely to use alcohol. In addition, serious psychological distress and gender were moderators in associations between COPD and substance use but not in substance misuse. Future studies should longitudinally assess the factors that may contribute to the initiation and progression of substance use and misuse among adults with COPD.