Clinical management and outcome of head and neck paragangliomas (HNPGLs): A single centre retrospective study.

CONTEXT: Head and neck paragangliomas (HNPGLs) are rare, usually benign, slow-growing tumours arising from neural crest-derived tissue. Definitive management pathways for HNPGLs have yet to be clearly defined. OBJECTIVE: To review our experience of the clinical features and management of these tumours and to analyse outcomes of different treatment modalities. METHODS: Demographic and clinical data were obtained from The Northern Ireland Electronic Care Record (NIECR) as well from a prospectively maintained HNPGL database between January 2011 through December 2023. RESULTS: There were 87 patients; 50 females: 37 males with a mean age of 52.3 ± 14.2 years old (range 17-91 years old). 58.6% (n = 51) of patients had carotid body tumours, 25.2% (n = 22) glomus vagal tumours, 6.8% (n = 6) tumours in the middle ear, 2.2% (n = 2) in the parapharyngeal space and 1.1% (n = 1) in the sphenoid sinus. 5.7% (n = 5) of patients had multifocal disease. The mean tumour size at presentation was 3.2 ± 1.4 cm (range 0.5-6.9 cm). Pathogenic SDHD mutations were identified in 41.3% (n = 36), SDHB in 12.6% (n = 11), SDHC in 2.2% (n = 2) and SDHA in 1.1% (n = 1) of the patients. Overall treatment modalities included surgery alone in 51.7% (n = 45) of patients, radiotherapy in 14.9% (n = 13), observation in 28.7% (n = 25), and somatostatin analogue therapy with octreotide in 4.5% (n = 4) of patients. Factors associated with a significantly higher risk of recurrence included age over 60 years (p = .04), tumour size exceeding 2 cm (p = .03), positive SDHx variants (p = .01), and vagal and jugular tumours (p = .04). CONCLUSION: The majority of our patients underwent initial surgical intervention and achieved disease stability. Our results suggest that carefully selected asymptomatic or medically unfit patients can be safely observed provided lifelong surveillance is maintained. We advocate for the establishment of a UK and Ireland national HNPGL registry, to delineate optimal management strategies for these rare tumours and improve long term outcomes.

Establishing Normative Values for Healthy Term Infant Feeding Performance: Neonatal Eating Assessment Tool-Mixed, Oral Feeding Scale, and Early Feeding Skills Assessment.

PURPOSE: Infants with perceived feeding problems are frequently referred for assessment of their feeding abilities. However, little is known regarding how healthy nondysphagic infants perform on commonly used assessments, making determination of impairment difficult. The aim of this investigation was to elucidate the characteristics of healthy term infant feeding performance using three commonly employed clinical assessments: Neonatal Eating Assessment Tool-Mixed (NeoEat-Mixed), Oral Feeding Scale, and Early Feeding Skills (EFS). METHOD: In this prospective case-control study, we recruited 30 infants without feeding impairments to undergo video-monitored bottle feeds under their normal feeding conditions. Caregiver perception of infant feeding was evaluated using the NeoEat-Mixed. Milk ingestion was monitored real time using the Oral Feeding Scale for rate of milk transfer and modified proficiency as characterized by the total volume consumed out of the total volume the caregiver provided. Videos were analyzed by two speech pathologists using the EFS assessment. Descriptive statistics were used to characterize performance. RESULTS: Participants underwent feeding monitoring at an average chronological age of 4 ± 2 months. Caregivers primarily reported normal, nonconcerning feeding patterns across all of the NeoEAT-Mixed outcomes. Infants consumed milk at an average rate of transfer of 7 ± 3 ml/min, a modified proficiency of 50 ± 21%, and achieved the highest OFS score of 4 (93%, n = 28). The majority of infants scored the best EFS score (mature-3) as it related to the absence of color changes during the feed (97%, n = 29), although commonly scored in the worst EFS score (immature-1) in their presentation of one or more compelling stress cues (63%, n = 19). CONCLUSION: Establishing healthy term infant normative values for commonly used feeding assessments is critical in accurately distinguishing infants with feeding impairments from those with normal developmental variants.

Clinicoradiological outcomes after radical radiotherapy for lung cancer in patients with interstitial lung disease.

Objective: Interstitial lung disease (ILD) is relatively common in patients with lung cancer with an incidence of 7.5%. Historically pre-existing ILD was a contraindication to radical radiotherapy owing to increased radiation pneumonitis rates, worsened fibrosis and poorer survival compared with non-ILD cohorts. Herein, the clinical and radiological toxicity outcomes of a contemporaneous cohort are described. Methods: Patients with ILD treated with radical radiotherapy for lung cancer at a regional cancer centre were collected prospectively. Radiotherapy planning, tumour characteristics, and pre- and post-treatment functional and radiological parameters were recorded. Cross-sectional images were independently assessed by two Consultant Thoracic Radiologists. Results: Twenty-seven patients with co-existing ILD received radical radiotherapy from February 2009 to April 2019, with predominance of usual interstitial pneumonia subtype (52%). According to ILD-GAP scores, most patients were Stage I. After radiotherapy, localised (41%) or extensive (41%) progressive interstitial changes were noted for most patients yet dyspnoea scores (n = 15 available) and spirometry (n = 10 available) were stable. One-third of patients with ILD went on to receive long-term oxygen therapy, which was significantly more than the non-ILD cohort. Median survival trended towards being worse compared with non-ILD cases (17.8 vs 24.0 months, p = 0.834). Conclusion: Radiological progression of ILD and reduced survival were observed post-radiotherapy in this small cohort receiving lung cancer radiotherapy, although a matched functional decline was frequently absent. Although there is an excess of early deaths, long-term disease control is achievable. Advances in knowledge: For selected patients with ILD, long-term lung cancer control without severely impacting respiratory function may be possible with radical radiotherapy, albeit with a slightly higher risk of death.

The impact of climate change related extreme weather events on people with pre-existing disabilities and chronic conditions: a scoping review.

PURPOSE: People with disabilities experience a disproportionate impact of extreme weather events and there is a critical need to better understand the impact that climate change has for them. Most previous reviews focus on the risk of acquiring a new disability or injury after a climate-related event and not the impact on people with pre-existing disabilities or chronic conditions, which is the purpose of this study. METHODS: We conducted a scoping review while searching seven international databases that identified 45 studies meeting our inclusion criteria. RESULTS: The studies included in our review involved 2 337 199 participants with pre-existing disabilities and chronic conditions across 13 countries over a 20-year period. The findings demonstrated the following trends: (1) the impact on physical and mental health; (2) the impact on education and work; (3) barriers to accessing health and community services (i.e., lack of access to services, lack of knowledge about people with disabilities, communication challenges, lack of adequate housing); and (4) coping strategies (i.e., social supports and connecting to resources) and resilience. CONCLUSIONS: Our findings highlight the critical need for rehabilitation clinicians and other service providers to explore opportunities to support their clients in preparing for climate-related emergencies.

Rehabilitation clinicians and community service providers are in a good position to potentially assess people with disabilities for their preparedness for extreme weather events.Rehabilitation clinicians could look for opportunities to educate themselves and their clients about available resources related to extreme weather events and preparedness.Rehabilitation and community service providers could seek to partner with local organizations to support their clients with disabilities.Rehabilitation health care providers might consider advocating for the inclusion of people with disabilities in climate justice responses at all levels of government (e.g., local, regional and national).

Successful living kidney donation from a patient with a Gitelman's syndrome.

Living kidney donation from Gitelman's syndrome (GS) patients remains very rare. Long-term renal prognosis of donor and recipient patients remains unknown. We report a 67-year-old man with GS, harbouring a mutation of the SLC12A3 gene, who donated his kidney for transplant. Five years post-transplantation, his clinical condition and biochemical parameters remained stable with close monitoring and follow-up. Patients with non-complicated GS can be considered eligible to donate their kidney for transplant.

Corticotroph Aggressive Pituitary Tumors and Carcinomas Frequently Harbor ATRX Mutations.

CONTEXT: Aggressive pituitary tumors (APTs) are characterized by unusually rapid growth and lack of response to standard treatment. About 1% to 2% develop metastases being classified as pituitary carcinomas (PCs). For unknown reasons, the corticotroph tumors are overrepresented among APTs and PCs. Mutations in the alpha thalassemia/mental retardation syndrome X-linked (ATRX) gene, regulating chromatin remodeling and telomere maintenance, have been implicated in the development of several cancer types, including neuroendocrine tumors. OBJECTIVE: To study ATRX protein expression and mutational status of the ATRX gene in APTs and PCs. DESIGN: We investigated ATRX protein expression by using immunohistochemistry in 30 APTs and 18 PCs, mostly of Pit-1 and T-Pit cell lineage. In tumors lacking ATRX immunolabeling, mutational status of the ATRX gene was explored. RESULTS: Nine of the 48 tumors (19%) demonstrated lack of ATRX immunolabelling with a higher proportion in patients with PCs (5/18; 28%) than in those with APTs (4/30;13%). Lack of ATRX was most common in the corticotroph tumors, 7/22 (32%), versus tumors of the Pit-1 lineage, 2/24 (8%). Loss-of-function ATRX mutations were found in all 9 ATRX immunonegative cases: nonsense mutations (n = 4), frameshift deletions (n = 4), and large deletions affecting 22-28 of the 36 exons (n = 3). More than 1 ATRX gene defect was identified in 2 PCs. CONCLUSION: ATRX mutations occur in a subset of APTs and are more common in corticotroph tumors. The findings provide a rationale for performing ATRX immunohistochemistry to identify patients at risk of developing aggressive and potentially metastatic pituitary tumors.

Detection of vertebral fracture in an acute hospital setting: an intervention to reduce future fracture risk through fracture liaison service intervention?

We introduced a standardised reporting system in the radiology department to highlight vertebral fractures and to signpost fracture prevention services. Our quality improvement project achieved improved fracture reporting, access to the FLS service, bone density assessment and anti-fracture treatment. PURPOSE: Identification of vertebral fragility fractures (VF) provides an opportunity to identify individuals at high risk who might benefit from secondary fracture prevention. We sought to standardise VF reporting and to signpost fracture prevention services. Our aim was to improve rates of VF detection and access to our fracture liaison service (FLS). METHODS: We introduced a standardised reporting tool within the radiology department to flag VFs with signposting for referral for bone densitometry (DXA) and osteoporosis assessment in line with Royal Osteoporosis Society guidelines. We monitored uptake of VF reporting during a quality improvement phase and case identification within the FLS service. RESULTS: Recruitment of individuals with VF to the FLS service increased from a baseline of 63 cases in 2017 (6%) to 95 (8%) in 2018 and 157 (8%) in 2019 and to 102 (12%) in the first 6 months of 2020 (p = 0.001). One hundred fifty-three patients with VFs were identified during the QI period (56 males; 97 females). Use of the terminology 'fracture' increased to 100% (mean age 70 years; SD 13) in computed tomography (n = 110), plain X-ray (n = 37) or magnetic resonance imaging (n = 6) reports within the cohort. Signposting to DXA and osteoporosis assessment was included in all reports (100%). DXA was arranged for 103/153; 12 failed to attend. Diagnostic categories were osteoporosis (31%), osteopenia (36%) or normal bone density (33%). A new prescription for bone protection therapy was issued in 63/153. Twelve of the series died during follow-up. CONCLUSIONS: Standardisation of radiology reporting systems facilitates reporting of prevalent vertebral fractures and supports secondary fracture prevention strategies.

A service evaluation of e-triage in the osteoporosis outpatient clinic-an effective tool to improve patient access?

We introduced an electronic triage system into our osteoporosis service to actively manage referral demand in a busy outpatient service. Our study demonstrated the effectiveness of e-triage in supporting alternative management pathways, through use of virtual advice and direct to investigation services, to improve patient access. PURPOSE: Osteoporosis referrals are increasing with awareness of the potential for prevention of fragility fracture and with complex decision making around management with long-term bisphosphonate therapy. We examined whether active triage of referrals might improve referral management processes and patient access to osteoporosis services. METHODS: We implemented electronic triage (e-triage) of referrals to our osteoporosis service using the Northern Ireland electronic health care record. This included the option of 'advice only', direct to investigation with DXA or face-to-face appointments at the consultant-led complex osteoporosis service. We anticipated that there was scope to manage patient flow direct to investigation, or to provide referring clinicians with clinical advice without the need for a face-to-face assessment, at the consultant-led specialist service. RESULTS: We reviewed e-triage outcomes of 809 referrals (692 F; 117 M) to osteoporosis specialist services (mean age 65 ± 16.5 years) over a 12-month period. There was a high degree of agreement for the triage category between the referring clinician and specialist services (741/809). 73.3% attended a face-to-face appointment at the consultant-led clinic, while active triage enabled direct to investigation (18.4%) or discharge (8.3%) in the remainder. The mean time between receipt of an electronic referral and e-triage was 3 days over the 12-month period as compared with 2.1 days (median 1.1 days) when annual leave periods were excluded. CONCLUSION: E-triage supports effective referral management in a busy osteoporosis service. Efficiency is limited by reliance on a sole clinician and 5 day working at present. There is scope to further improve systems access through multidisciplinary team working, virtual clinics and future information technology developments.

Systemic Lupus Erythematosus Presenting with Ischemic Proctitis and Abdominal Compartment Syndrome.

Ischemic colitis and proctitis is a rare manifestation of systemic lupus erythematosus (SLE) and results from mesenteric vasculitis. Owing to diverse blood supply and presence of multiple collaterals, rectum is the least effected site in SLE enteritis. Ischemic proctocolitis as the presenting feature of SLE is exceedingly rare, with only three cases reported in the published scientific literature. We present the first case of SLE presenting as ischemic proctitis, leading to intraperitoneal hemorrhage and abdominal compartment syndrome. A young lady presented with ischemic proctitis and a hematoma masquerading as a pelvic mass, with subsequent development of massive intraperitoneal hemorrhage, shock, and rectal perforation. The patient required urgent surgery and was initiated on high-dose steroids.

Using a Reconciliation Module Leads to Large Gains in Evolution Acceptance.

Too many students reject the theory of evolution because they view it as incompatible with their religious beliefs. Some have argued that abandoning religious belief is the only way to help religious individuals accept evolution. Conversely, our data support that highlighting faith/evolution compatibility is an effective means to increase student acceptance. We surveyed students enrolled in entry-level biology courses at four religiously affiliated institutions. At each university, teachers gave students a presentation that demonstrated potential compatibility between evolution and faith within the teachings of each university's respective religious affiliation. Students were asked to evaluate their own beliefs about evolution both before and after this instruction. After instruction at each university, students showed significant gains in evolution acceptance without abandoning their religious beliefs. These results demonstrate that giving religious students the opportunity to reconcile their religious beliefs with the theory of evolution under the influence of intentional instruction on the compatibility of belief and evolution can lead to increased evolution acceptance among religious students.

GCC Consolidated Feedback to ICH on the 2019 ICH M10 Bioanalytical Method Validation Draft Guideline.

The 13th GCC Closed Forum for Bioanalysis was held in New Orleans, Louisiana, USA on April 5th, 2019. This GCC meeting was organized to discuss the contents of the 2019 ICH M10 Bioanalytical Method Validation Draft Guideline published in February 2019 and consolidate the feedback of the GCC members. In attendance were 63 senior-level participants from eight countries representing 44 bioanalytical CRO companies/sites. This event represented a unique opportunity for CRO bioanalytical experts to share their opinions and concerns regarding the ICH M10 Bioanalytical Method Validation Draft Guideline and to build unified comments to be provided to the ICH.

Remotely Monitored Therapy and Nitric Oxide Suppression Identifies Nonadherence in Severe Asthma.

RATIONALE: Poor adherence is common in difficult-to-control asthma. Distinguishing patients with difficult-to-control asthma who respond to inhaled corticosteroids (ICS) from refractory asthma is an important clinical challenge. OBJECTIVES: Suppression of fractional exhaled nitric oxide (FeNO) with directly observed ICS therapy over 7 days can identify nonadherence to ICS treatment in difficult-to-control asthma. We examined the feasibility and utility of FeNO suppression testing in routine clinical care within UK severe asthma centers using remote monitoring technologies. METHODS: A web-based interface with integrated remote monitoring technology was developed to deliver FeNO suppression testing. We examined the utility of FeNO suppression testing to demonstrate ICS responsiveness and clinical benefit on electronically monitored treatment with standard high-dose ICS and long-acting ß2-agonist treatment. MEASUREMENTS AND MAIN RESULTS: Clinical response was assessed using the Asthma Control Questionnaire-5, spirometry, and biomarker measurements (FeNO and peripheral blood eosinophil count). Of 250 subjects, 201 completed the test with 130 positive suppression tests. Compared with a negative suppression test, a positive test identified a FeNO-low population when adherent with ICS/long-acting ß2-agonist (median, 26 ppb [interquartile range, 16-36 ppb] vs. 43 ppb [interquartile range, 38-73 ppb]) with significantly greater FEV1% (mean, 88.2 ± 16.4 vs. 74.1 ± 20.9; P < 0.01). Asthma Control Questionnaire-5 improved significantly in both groups (positive test: mean difference, -1.2; 95% confidence interval, -0.9 to -1.5; negative test: mean difference, -0.9; 95% confidence interval, -0.4 to -1.3). CONCLUSIONS: Remote FeNO suppression testing is an effective means of identifying nonadherence to ICS in subjects with difficult-to-control asthma and the substantial population of subjects who derive important clinical benefits from optimized ICS/long-acting ß2-agonist treatment.

Diabetes distress, illness perceptions and glycaemic control in adults with type 2 diabetes.

The emotional distress associated with adjusting to and living with diabetes has been termed diabetes distress. Diabetes distress is associated with glycaemic control but interventions to reduce diabetes distress have failed to consistently improve diabetes control. Various illness perceptions have previously been linked with both diabetes distress and glycaemic control but interrelationships between these features have not been previously investigated. We hypothesised that illness perceptions mediate the relationship between diabetes distress and glycaemia. Participants with type 2 diabetes attending diabetes outpatient clinics (n = 84) provided demographic and clinical information and completed the Diabetes Distress Scale-17 and the Brief Illness Perceptions Questionnaire. Using regression analysis we demonstrated that the illness perceptions of personal control, regimen-related distress, socioeconomic status and insulin use were significant contributors in the final model predicting HbA1c. Higher levels of personal control were associated with better glycaemic control. Conversely, regimen-related distress was associated with hyperglycaemia. Mediation analyses showed that the relationship between regimen-related distress and HbA1c was mediated by personal control. Our work suggests that psychological interventions designed to reduce diabetes distress may be more efficacious in improving glycaemic control if they address an individual's perception of personal control.

The Peroxiredoxin Family: An Unfolding Story.

Peroxiredoxins (Prxs) are a large and conserved family of peroxidases that are considered to be the primary cellular guardians against oxidative stress in all living organisms. Prxs share a thioredoxin fold and contain a highly-reactive peroxidatic cysteine in a specialised active-site environment that is able to reduce their peroxide substrates. The minimal functional unit for Prxs are either monomers or dimers, but many dimers assemble into decameric rings. Ring structures can further form a variety of high molecular weight complexes. Many eukaryotic Prxs contain a conserved GGLG and C-terminal YF motif that confer sensitivity to elevated levels of peroxide, leading to hyperoxidation and inactivation. Inactive forms of Prxs can be re-reduced by the enzyme sulfiredoxin, in an ATP-dependent reaction. Cycles of hyperoxidation and reactivation are considered to play an integral role in a variety of H2O2-mediated cell signalling pathways in both stress and non-stress conditions. Prxs are also considered to exhibit chaperone-like properties when cells are under oxidative or thermal stress. The roles of various types of covalent modifications, e.g. acetylation and phosphorylation are also discussed. The ability of Prxs to assemble into ordered arrays such as nanotubes is currently being exploited in nanotechnology.

The Pyruvate Dehydrogenase Complex and Related Assemblies in Health and Disease.

The family of 2-oxoacid dehydrogenase complexes (2-OADC), typified by the pyruvate dehydrogenase multi-enzyme complex (PDC) as its most prominent member, are massive molecular machines (Mr, 4-10 million) controlling key steps in glucose homeostasis (PDC), citric acid cycle flux (OGDC, 2-oxoglutarate dehydrogenase) and the metabolism of the branched-chain amino acids, leucine, isoleucine and valine (BCOADC, branched-chain 2-OADC). These highly organised mitochondrial arrays, composed of multiple copies of three separate enzymes, have been widely studied as paradigms for the analysis of enzyme cooperativity, substrate channelling, protein-protein interactions and the regulation of activity by phosphorylation . This chapter will highlight recent advances in our understanding of the structure-function relationships, the overall organisation and the transport and assembly of PDC in particular, focussing on both native and recombinant forms of the complex and their individual components or constituent domains. Biophysical approaches, including X-ray crystallography (MX), nuclear magnetic resonance spectroscopy (NMR), cryo-EM imaging, analytical ultracentrifugation (AUC) and small angle X-ray and neutron scattering (SAXS and SANS), have all contributed significant new information on PDC subunit organisation, stoichiometry, regulatory mechanisms and mode of assembly. Moreover, the recognition of specific genetic defects linked to PDC deficiency, in combination with the ability to analyse recombinant PDCs housing both novel naturally-occurring and engineered mutations, have all stimulated renewed interest in these classical metabolic assemblies. In addition, the role played by PDC, and its constituent proteins, in certain disease states will be briefly reviewed, focussing on the development of new and exciting areas of medical and immunological research.

Diabetes distress: understanding the hidden struggles of living with diabetes and exploring intervention strategies.

Diabetes distress is a rational emotional response to the threat of a life-changing illness. Distinct from depression, it is conceptually rooted in the demands of diabetes management and is a product of emotional adjustment. Diabetes distress has been found to be significantly associated with glycated haemoglobin (HbA1c) level and the likelihood of an individual adopting self-care behaviours. The lack of perceived support from family, friends and healthcare professionals significantly contributes to elevated diabetes distress, and this issue tends to be overlooked when designing interventions. Pioneering large-scale research, DAWN2, gives voices to the families of those with diabetes and reaffirms the need to consider psychosocial factors in routine diabetes care. Structured diabetes education programmes are the most widely used in helping individuals cope with diabetes, but they tend not to include the psychological or interpersonal aspects of diabetes management in their curricula. The need for health practitioners, irrespective of background, to demonstrate an understanding of diabetes distress and to actively engage in discussion with individuals struggling to cope with diabetes is emphasised.

High-throughput bioanalysis of bile acids and their conjugates using UHPLC coupled to HRMS.

BACKGROUND: Quantitative assessment of bile acids in biological matrixes is of growing interest, primarily due to hepatic toxicity resulting from drug interactions with the bile salt export pump. Nevertheless, many bile acids demonstrate poor fragmentation in MS, making conventional MS/MS not a good match for their selective quantitation in biological matrices. RESULTS: The current study was designed to evaluate the feasibility of simultaneous quantitation of 19 bile acids using HRMS coupled to UHPLC separation with minimal instrument optimization. An effective chromatography was developed using an Agilent Zorbax(®) Eclipse XDB-C18 column (1.8 µm, 50 x 2.1 mm internal diameter), achieving separation of 19 compounds in 10 min. Excellent assay reproducibility was demonstrated, with two sets of standard curves, run 42 days apart. CONCLUSIONS: The results show that LC-HRMS is a viable platform for high throughput bioanalysis of bile acids especially in a drug-discovery setting.

Non-adherence in difficult asthma and advances in detection.

Non-adherence to anti-inflammatory therapies is common in patients referred for specialist assessment at difficult-to-treat asthma services. In the difficult asthma setting, non-adherence to treatment is associated with poor baseline asthma control, increased frequency of exacerbations and asthma-related hospitalizations, as well as increased risk of death. Here, we present a review of the current literature surrounding the prevalence and risks of non-adherence in difficult asthma and we report on current methods of measuring treatment adherence and advances in the detection of non-adherence. We will also explore methods by which non-adherence in difficult asthma can be addressed.