Investigation of exertional dyspnoea by cardiopulmonary exercise testing with continuous laryngoscopy.

OBJECTIVES: Abnormal breathlessness at maximal exercise may be caused by a range of conditions, including exercise-induced bronchospasm, breathing pattern disorder, or exercise-induced laryngeal obstruction. These three disorders may not be detected on standard cardiopulmonary exercise testing. The aim of this study was to describe diagnostic outcomes of an expanded protocol during cardiopulmonary exercise testing. DESIGN: Retrospective cohort study. METHODS: Patients presenting with abnormal breathlessness on maximal exercise underwent continuous laryngoscopy with cardiopulmonary exercise testing on a stationary cycle ergometer. Breathing pattern disorder was evaluated by video and ventilatory data. Pre- and post-exercise spirometry was performed. RESULTS: 24 adult patients were evaluated; 10 were professional athletes. Mean age was 40 years (range 18-73). Nine of 24 (38 %) were diagnosed with exercise-induced laryngeal obstruction and referred for speech pathology. Six of these had supraglottic exercise-induced laryngeal obstruction; all were aged <30 years; 5/6 were professional athletes. One patient had breathing pattern disorder and was referred for physiotherapy; one had exercise-induced bronchospasm, requiring escalation of asthma medication; one had muscle tension dysphonia resulting in referral to an otolaryngologist who administered a laryngeal injection of botulinum toxin. A further four patients had unexplained lower maximal oxygen consumption with cardiac limitation and were referred for further cardiac investigation. CONCLUSIONS: In patients reporting abnormal breathlessness at maximal exercise, this expanded exercise protocol provided diagnostic information in 66.7 % cases which contributed to further personalised management.

Germline mutations in a G protein identify signaling cross-talk in T cells.

Humans with monogenic inborn errors responsible for extreme disease phenotypes can reveal essential physiological pathways. We investigated germline mutations in GNAI2, which encodes Gαi2, a key component in heterotrimeric G protein signal transduction usually thought to regulate adenylyl cyclase-mediated cyclic adenosine monophosphate (cAMP) production. Patients with activating Gαi2 mutations had clinical presentations that included impaired immunity. Mutant Gαi2 impaired cell migration and augmented responses to T cell receptor (TCR) stimulation. We found that mutant Gαi2 influenced TCR signaling by sequestering the guanosine triphosphatase (GTPase)-activating protein RASA2, thereby promoting RAS activation and increasing downstream extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)-AKT S6 signaling to drive cellular growth and proliferation.

Variants in IGLL1 cause a broad phenotype from agammaglobulinemia to transient hypogammaglobulinemia.

BACKGROUND: Agammaglobulinemia due to variants in IGLL1 has traditionally been considered an exceedingly rare form of severe B-cell deficiency, with only 8 documented cases in the literature. Surprisingly, the first agammaglobulinemic patient identified by newborn screening (NBS) through quantification of kappa-deleting recombination excision circles harbored variants in IGLL1. OBJECTIVE: We comprehensively reviewed clinical and immunologic findings of patients with B-cell deficiency attributed to variants in IGLL1. METHODS: NBS programs reporting the use of kappa-deleting recombination excision circle assays, the European Society for Immunodeficiencies Registry, and authors of published reports featuring patients with B-cell deficiency linked to IGLL1 variants were contacted. Only patients with (likely) pathogenic variants, reduced CD19+ counts, and no alternative diagnosis were included. RESULTS: The study included 13 patients identified through NBS, 2 clinically diagnosed patients, and 2 asymptomatic siblings. All had severely reduced CD19+ B cells (< 0.1 × 109/L) at first evaluation, yet subsequent follow-up assessments indicated residual immunoglobulin production. Specific antibody responses to vaccine antigens varied, with a predominant reduction observed during infancy. Clinical outcomes were favorable with IgG substitution. Two patients successfully discontinued substitution therapy without developing susceptibility to infections and while maintaining immunoglobulin levels. The pooled incidence of homozygous or compound heterozygous pathogenic IGLL1 variants identified by NBS in Austria, Czechia, and Switzerland was 1.3:100,000, almost double of X-linked agammaglobulinemia. CONCLUSION: B-cell deficiency resulting from IGLL1 variants appears to be more prevalent than initially believed. Despite markedly low B-cell counts, the clinical course in some patients may be milder than reported in the literature so far.

A Novel Case of IFNAR1 Deficiency Identified a Common Canonical Splice Site Variant in DOCK8 in Western Polynesia: The Importance of Validating Variants of Unknown Significance in Under-Represented Ancestries.

Advanced genomic technologies such as whole exome or whole genome sequencing have improved diagnoses and disease outcomes for individuals with genetic diseases. Yet, variants of unknown significance (VUS) require rigorous validation to establish disease causality or modification, or to exclude them from further analysis. Here, we describe a young individual of Polynesian ancestry who in the first 13 mo of life presented with SARS-CoV-2 pneumonia, severe enterovirus meningitis and adenovirus gastroenteritis, and severe adverse reaction to MMR vaccination. Genomic analysis identified a previously reported pathogenic homozygous variant in IFNAR1 (c.1156G > T, p.Glu386* LOF), which is common in Western Polynesia. Moreover, a new and putatively deleterious canonical splice site variant in DOCK8 was also found in homozygosity (c.3234 + 2T > C). This DOCK8 variant is common in Polynesians and other under-represented ancestries in large genomic databases. Despite in silico bioinformatic predictions, extensive in vitro and ex vivo analysis revealed the DOCK8 variant likely be neutral. Thus, our study reports a novel case of IFNAR1 deficiency, but also highlights the importance of functional validation of VUS, including those predicted to be deleterious, and the pressing need to expand our knowledge of the genomic architecture and landscape of under-represented populations and ancestries.

Hereditary C1q Deficiency is Associated with Type 1 Interferon-Pathway Activation and a High Risk of Central Nervous System Inflammation.

Hereditary C1q deficiency (C1QDef) is a rare monogenic disorder leading to defective complement pathway activation and systemic lupus erythematosus (SLE)-like manifestations. The link between impairment of the complement cascade and autoimmunity remains incompletely understood. Here, we assessed type 1 interferon pathway activation in patients with C1QDef. Twelve patients with genetically confirmed C1QDef were recruited through an international collaboration. Clinical, biological and radiological data were collected retrospectively. The expression of a standardized panel of interferon stimulated genes (ISGs) in peripheral blood was measured, and the level of interferon alpha (IFNα) protein in cerebrospinal fluid (CSF) determined using SIMOA technology. Central nervous system (encompassing basal ganglia calcification, encephalitis, vasculitis, chronic pachymeningitis), mucocutaneous and renal involvement were present, respectively, in 10, 11 and 2 of 12 patients, and severe infections recorded in 2/12 patients. Elevated ISG expression was observed in all patients tested (n = 10/10), and serum and CSF IFNα elevated in 2/2 patients. Three patients were treated with Janus-kinase inhibitors (JAKi), with variable outcome; one displaying an apparently favourable response in respect of cutaneous and neurological features, and two others experiencing persistent disease despite JAKi therapy. To our knowledge, we report the largest original series of genetically confirmed C1QDef yet described. Additionally, we present a review of all previously described genetically confirmed cases of C1QDef. Overall, individuals with C1QDef demonstrate many characteristics of recognized monogenic interferonopathies: particularly, cutaneous involvement (malar rash, acral vasculitic/papular rash, chilblains), SLE-like disease, basal ganglia calcification, increased expression of ISGs in peripheral blood, and elevated levels of CSF IFNα.

Outcomes from hematopoietic stem cell transplantation following treosulfan-based conditioning: A clinical and pharmacokinetic analysis.

BACKGROUND: The aims of this study are to report our experience with treosulfan-based conditioning regimens for patients with non-malignant hematologic conditions, correlating clinical outcomes at different time points post-transplant with treosulfan exposure (AUC). METHODS: This study was a single-center observational study investigating overall survival (OS), disease-free survival (DFS), and event-free survival (EFS) end-points post-transplant. The consequences of treosulfan AUC with respect to toxicity, correction of underlying disease, and long-term chimerism were also explored using pharmacokinetic analysis. RESULTS: Forty-six patients received 49 transplants with treosulfan and fludarabine-based conditioning between 2005 and 2023. Twenty-four patients also received thiotepa. Donor chimerism was assessed on either whole blood or sorted cell lines at different time points post-transplant. Thirty-nine patients received treosulfan pharmacokinetic assessment to evaluate cumulative AUC, with five infants receiving real-time assessment to facilitate daily dose adjustment. OS, DFS, and EFS were 87%, 81%, and 69%, respectively. Median follow-up was 32.1 months (range 0.82-160 months) following transplant. Lower EFS was associated with patient age (<1 year; p = .057) and lower cumulative treosulfan dose (<42 g/m2; p = .003). Stable donor chimerism in B-cell, NK-cell, and granulocyte lineages at 1-year post-transplant were more prevalent in patients receiving thiotepa conditioning. Two infants required daily dose adjustment to treosulfan to avoid high AUC. CONCLUSIONS: Excellent clinical outcomes and stable chimerism were observed in this patient series. The addition of thiotepa conferred no significant toxicity and trended toward sustained ongoing donor engraftment. Correlating treosulfan AUC with long-term patient outcomes is required.

Ketogenic diet modifies ribosomal protein dysregulation in KMT2D Kabuki syndrome.

BACKGROUND: Kabuki syndrome (KS) is a genetic disorder caused by DNA mutations in KMT2D, a lysine methyltransferase that methylates histones and other proteins, and therefore modifies chromatin structure and subsequent gene expression. Ketones, derived from the ketogenic diet, are histone deacetylase inhibitors that can 'open' chromatin and encourage gene expression. Preclinical studies have shown that the ketogenic diet rescues hippocampal memory neurogenesis in mice with KS via the epigenetic effects of ketones. METHODS: Single-cell RNA sequencing and mass spectrometry-based proteomics were used to explore molecular mechanisms of disease in individuals with KS (n = 4) versus controls (n = 4). FINDINGS: Pathway enrichment analysis indicated that loss of function mutations in KMT2D are associated with ribosomal protein dysregulation at an RNA and protein level in individuals with KS (FDR <0.05). Cellular proteomics also identified immune dysregulation and increased abundance of other lysine modification and histone binding proteins, representing a potential compensatory mechanism. A 12-year-old boy with KS, suffering from recurrent episodes of cognitive decline, exhibited improved cognitive function and neuropsychological assessment performance after 12 months on the ketogenic diet, with concomitant improvement in transcriptomic ribosomal protein dysregulation. INTERPRETATION: Our data reveals that lysine methyltransferase deficiency is associated with ribosomal protein dysfunction, with secondary immune dysregulation. Diet and the production of bioactive molecules such as ketone bodies serve as a significant environmental factor that can induce epigenetic changes and improve clinical outcomes. Integrating transcriptomic, proteomic, and clinical data can define mechanisms of disease and treatment effects in individuals with neurodevelopmental disorders. FUNDING: This study was supported by the Dale NHMRC Investigator Grant (APP1193648) (R.D), Petre Foundation (R.D), and The Sydney Children's Hospital Foundation/Kids Research Early and Mid-Career Researcher Grant (E.T).

Topical treatments for atopic dermatitis (eczema): Systematic review and network meta-analysis of randomized trials.

BACKGROUND: Atopic dermatitis (AD) is a common skin condition with multiple topical treatment options, but uncertain comparative effects. OBJECTIVE: We sought to systematically synthesize the benefits and harms of AD prescription topical treatments. METHODS: For the 2023 American Academy of Allergy, Asthma & Immunology and American College of Allergy, Asthma, and Immunology Joint Task Force on Practice Parameters AD guidelines, we searched MEDLINE, EMBASE, CENTRAL, CINAHL, LILACS, ICTRP, and GREAT databases to September 5, 2022, for randomized trials addressing AD topical treatments. Paired reviewers independently screened records, extracted data, and assessed risk of bias. Random-effects network meta-analyses addressed AD severity, itch, sleep, AD-related quality of life, flares, and harms. The Grading of Recommendations Assessment, Development and Evaluation approach informed certainty of evidence ratings. We classified topical corticosteroids (TCS) using 7 groups-group 1 being most potent. This review is registered in the Open Science Framework (https://osf.io/q5m6s). RESULTS: The 219 included trials (43,123 patients) evaluated 68 interventions. With high-certainty evidence, pimecrolimus improved 6 of 7 outcomes-among the best for 2; high-dose tacrolimus (0.1%) improved 5-among the best for 2; low-dose tacrolimus (0.03%) improved 5-among the best for 1. With moderate- to high-certainty evidence, group 5 TCS improved 6-among the best for 3; group 4 TCS and delgocitinib improved 4-among the best for 2; ruxolitinib improved 4-among the best for 1; group 1 TCS improved 3-among the best for 2. These interventions did not increase harm. Crisaborole and difamilast were intermediately effective, but with uncertain harm. Topical antibiotics alone or in combination may be among the least effective. To maintain AD control, group 5 TCS were among the most effective, followed by tacrolimus and pimecrolimus. CONCLUSIONS: For individuals with AD, pimecrolimus, tacrolimus, and moderate-potency TCS are among the most effective in improving and maintaining multiple AD outcomes. Topical antibiotics may be among the least effective.

Systemic treatments for atopic dermatitis (eczema): Systematic review and network meta-analysis of randomized trials.

BACKGROUND: Atopic dermatitis (AD) is an inflammatory skin condition with multiple systemic treatments and uncertainty regarding their comparative impact on AD outcomes. OBJECTIVE: We sought to systematically synthesize the benefits and harms of AD systemic treatments. METHODS: For the 2023 American Academy of Allergy, Asthma & Immunology and American College of Allergy, Asthma, and Immunology Joint Task Force on Practice Parameters AD guidelines, we searched MEDLINE, EMBASE, CENTRAL, Web of Science, and GREAT databases from inception to November 29, 2022, for randomized trials addressing systemic treatments and phototherapy for AD. Paired reviewers independently screened records, extracted data, and assessed risk of bias. Random-effects network meta-analyses addressed AD severity, itch, sleep, AD-related quality of life, flares, and harms. The Grading of Recommendations Assessment, Development and Evaluation approach informed certainty of evidence ratings. This review is registered in the Open Science Framework (https://osf.io/e5sna). RESULTS: The 149 included trials (28,686 patients with moderate-to-severe AD) evaluated 75 interventions. With high-certainty evidence, high-dose upadacitinib was among the most effective for 5 of 6 patient-important outcomes; high-dose abrocitinib and low-dose upadacitinib were among the most effective for 2 outcomes. These Janus kinase inhibitors were among the most harmful in increasing adverse events. With high-certainty evidence, dupilumab, lebrikizumab, and tralokinumab were of intermediate effectiveness and among the safest, modestly increasing conjunctivitis. Low-dose baricitinib was among the least effective. Efficacy and safety of azathioprine, oral corticosteroids, cyclosporine, methotrexate, mycophenolate, phototherapy, and many novel agents are less certain. CONCLUSIONS: Among individuals with moderate-to-severe AD, high-certainty evidence demonstrates that high-dose upadacitinib is among the most effective in addressing multiple patient-important outcomes, but also is among the most harmful. High-dose abrocitinib and low-dose upadacitinib are effective, but also among the most harmful. Dupilumab, lebrikizumab, and tralokinumab are of intermediate effectiveness and have favorable safety.

Use of adrenaline to manage suspected anaphylaxis following COVID-19 vaccination: An Australian retrospective cohort study.

BACKGROUND: The rate of anaphylaxis following COVID-19 vaccinations is estimated to be 2-11 cases per million doses administered. However, adrenaline is occasionally used in individuals who are later diagnosed with immunisation stress-related responses, as their initial presenting signs and symptoms can appear similar to that of anaphylaxis. This study aims to describe the clinical profile of individuals who had received adrenaline following a COVID-19 vaccine and their subsequent revaccination outcomes. METHODS: We examined notifications of cases who had received adrenaline following a COVID-19 vaccine in New South Wales, Australia. The cases were classified into Brighton Collaboration Case Definition (BCCD) for anaphylaxis, their clinical presentation, management and subsequent revaccination outcomes were compared. RESULTS: From 22 February 2021 to 30 September 2021, there were 222 cases where adrenaline was administered. Of these, 32 (14 %) fulfilled Level 1 BCCD, 59 (27%) Level 2, 2 (1%) Level 3, 97 (44%) Level 4 and 32 (14 %) Level 5. The most commonly reported symptoms were sensation of throat closure (n = 116, 52%), difficulty breathing (n = 82, 37%) and nausea (n = 55, 25 %). Of the 176 (79%) individuals who proceeded to further vaccination, 89 (51%) received the same vaccine formulation and only 14 (8%) experienced another allergic adverse event with 9 (5%) receiving adrenaline. CONCLUSION: Less than one in five individuals who received adrenaline met Level 1 BCCD criteria for anaphylaxis. Many reactions that were treated with adrenaline had little to no diagnostic certainty of anaphylaxis and in such cases repeat vaccination had a high likelihood of being tolerated. Increased awareness and education on objective signs and symptoms of anaphylaxis is required to ensure appropriate use of adrenaline.

A Delayed Presentation of Late Dumping Syndrome After Ivor Lewis Procedure.

An accurate and timely diagnosis of dumping syndrome after gastric and oesophageal surgery is often difficult. A delay in making this diagnosis and instituting therapy can result in significant morbidity and avoidable complications. As bariatric surgery becomes more prevalent, the importance of a timely diagnosis of dumping syndrome is increasing. We present a case of a 77-year-old man who was admitted into the intensive care unit with a reduced conscious state secondary to hypoglycemia. The patient was subsequently diagnosed with late dumping syndrome in the context of an Ivor Lewis procedure seven years prior. Despite having a history of recurrent neuroglycopenic symptoms, there was a delay in diagnosis as dumping syndrome had not previously been considered until this admission. After confirmation of the diagnosis, the patient was commenced on dietary adjustments and acarbose, with a resolution of post-prandial hypoglycaemia. The authors discuss dietary and pharmacological therapy to manage hypoglycaemia associated with dumping syndrome.

Facilitators and Barriers to the Implementation of BETTER WISE, a Chronic Disease and Prevention Intervention in Canada: A Qualitative Study.

The aim of the BETTER WISE intervention is to address cancer and chronic disease prevention and screening (CCDPS) and lifestyle risks in patients aged 40-65. The purpose of this qualitative study is to better understand facilitators and barriers to the implementation of the intervention. Patients were invited for a 1-h visit with a prevention practitioner (PP), a member of a primary care team, with specific skills in prevention, screening, and cancer survivorship. We collected and analyzed data from 48 key informant interviews and 17 focus groups conducted with 132 primary care providers and from 585 patient feedback forms. We analyzed all qualitative data using a constant comparative method informed by grounded theory and then employed the Consolidated Framework for Implementation Research (CFIR) in a second round of coding. The following key elements were identified: (1) Intervention characteristics-relative advantage and adaptability; (2) Outer setting-PPs compensating for increased patient needs and decreased resources; (3) Characteristics of individuals-PPs (patients and physicians described PPs as compassionate, knowledgeable, and helpful); (4) Inner setting-network and communication (collaboration and support in teams or lack thereof); and (5) Process-executing the implementation (pandemic-related issues hindered execution, but PPs adapted to challenges). This study identified key elements that facilitated or hindered the implementation of BETTER WISE. Despite the interruption caused by the COVID-19 pandemic, the BETTER WISE intervention continued, driven by the PPs and their strong relationships with their patients, other primary care providers, and the BETTER WISE team.

Opportunistic coeliac disease screening in undifferentiated presentations to paediatric acute care.

AIM: Coeliac disease (CD) can remain undiagnosed due to absent/atypical symptoms. We evaluated screening for CD in undifferentiated paediatric patients in the emergency department (ED). METHODS: Subjects were all patients presenting to a children's hospital ED during the study period who had blood taken. Plasma remaining after routine care was tested for tissue transglutaminase IgA (tTG IgA) and deamidated gliadin IgG (DGP IgG) antibodies. Patients with positive results were counselled and offered confirmatory testing, then gastroenterology review if warranted. RESULTS: An initial positive result for either DGP IgG or tTG IgA was found in 4.2% (44/1055). There was a normalisation of 76% (19/25) of positive DGP IgG and 44% (4/9) of tTG IgA results on repeat testing, which was not available in 27% (12/44). The prevalence of biopsy-confirmed CD was 0.7% (7/1055), including two new diagnoses and five subjects with known CD. Three likely cases could not be confirmed. All confirmed and likely cases were >10 years old. In children >10 years old, the prevalence of either biopsy-confirmed or likely CD was 3.3% (10/302). A family history of CD, growth concerns, recurrent abdominal pain and lethargy were associated with persistence of positive tests. CONCLUSION: Opportunistic testing for CD in ED requires further investigation as a CD screening strategy. Our results suggest optimal screening in this setting should be by initially testing for tTG IgA and total IgA in children >10 years old (minimising transiently positive tests). Transiently positive coeliac antibodies may also warrant further investigation as a predictor of future CD.

Human PIK3R1 mutations disrupt lymphocyte differentiation to cause activated PI3Kδ syndrome 2.

Heterozygous loss-of-function (LOF) mutations in PIK3R1 (encoding phosphatidylinositol 3-kinase [PI3K] regulatory subunits) cause activated PI3Kδ syndrome 2 (APDS2), which has a similar clinical profile to APDS1, caused by heterozygous gain-of-function (GOF) mutations in PIK3CD (encoding the PI3K p110δ catalytic subunit). While several studies have established how PIK3CD GOF leads to immune dysregulation, less is known about how PIK3R1 LOF mutations alter cellular function. By studying a novel CRISPR/Cas9 mouse model and patients' immune cells, we determined how PIK3R1 LOF alters cellular function. We observed some overlap in cellular defects in APDS1 and APDS2, including decreased intrinsic B cell class switching and defective Tfh cell function. However, we also identified unique APDS2 phenotypes including defective expansion and affinity maturation of Pik3r1 LOF B cells following immunization, and decreased survival of Pik3r1 LOF pups. Further, we observed clear differences in the way Pik3r1 LOF and Pik3cd GOF altered signaling. Together these results demonstrate crucial differences between these two genetic etiologies.

Real world impact of 13vPCV in preventing invasive pneumococcal pneumonia in Australian children: A national study.

BACKGROUND: We aimed to assess the direct protective effect of 13 valent pneumococcal conjugate vaccine (13vPCV) against invasive pneumococcal pneumonia (IPP; including pneumonia and empyema) in children using a nation-wide case-control study across 11 paediatric tertiary hospitals in Australia. METHODS: Children < 18 years old admitted with pneumonia were eligible for enrolment. IPP was defined as Streptococcus pneumoniae (SP) cultured or detected by polymerase chain reaction (PCR) from blood or pleural fluid. Causative SP serotype (ST) was determined from blood or pleural fluid SP isolates by molecular methods in PCR positive specimens or else inferred from nasopharyngeal isolates. For each IPP case, 20 population controls matched by age and socio-economic status were sampled from the Australian Immunisation Register. Conditional logistic regression was used to estimate the adjusted odds ratio (aOR) of being fully vaccinated with 13vPCV (≥3 doses versus < 3 doses) among IPP cases compared to controls, adjusted for sex and Indigenous status. RESULTS: From February 2015 to September 2018, we enrolled 1,168 children with pneumonia; 779 were 13vPCV-eligible and were individually matched to 15,580 controls. SP was confirmed in 195 IPP cases, 181 of whom had empyema. ST3 and ST19A were identified in 52% (102/195) and 11% (21/195) of IPP cases respectively. The aOR of being fully vaccinated with 13vPCV was 0.8 (95% CI 0.6-1.0) among IPP cases compared to matched controls. CONCLUSION: We failed to identify a strong direct protective effect of 13vPCV against IPP among Australian children, where disease was largely driven by ST3.