Filling in the Gaps. Making Sense of Living with Temporomandibular Disorders: A Reflexive Thematic Analysis.

INTRODUCTION: Persistent, painful temporomandibular disorders (TMDs) are challenging to manage and usually require the active engagement of patients. To achieve this, it is necessary to understand the complex and multifactorial nature of persistent pain. Many dental professionals have little education about persistent pain and may prefer to offer structural management and advice. This research aims to explore how people understand their persistent TMD and how this understanding has been influenced by their treatment providers. METHODS: Twenty-one people were recruited to represent a diversity of experience with persistent TMD. Interviews followed a semistructured topic guide. Themes were constructed through reflexive thematic analysis to represent how people made sense of their symptoms and the messages that they had picked up through their treatment journey. RESULTS: Participants described examples of conflicting opinions and inconsistent management recommendations. They rarely recalled collaborative discussions about the nature and complexity of their symptoms and different options for treatment. This experience is represented by a single theme, "a medical merry-go-round." Subthemes of "a medical journey to nowhere-participants' frustrated attempts to find medical management that will end their pain" and "is it me?-participants' questioning their role in persisting pain" kept participants on the merry-go-round, while symptom resolution and participants' emerging development of a holistic understanding of their TMD pain provided exit points. Understanding pain holistically tended to be helpful and typically occurred despite rather than because of the advice given in routine treatment settings. CONCLUSION: Participants in this study had not typically found their pain management within dental and medical settings to have helped them to construct meaning and understand their experiences of painful TMD. However, understanding symptoms holistically was experienced as beneficial. This study suggests that improved communication and signposting within services for persistent TMD may be beneficial to patients with TMD pain. KNOWLEDGE TRANSFER STATEMENT: Results of this study confirm that being offered a series of anatomically based, singular-cause explanations for persisting pain symptoms had been experienced as unhelpful by the participants who had sought help for their TMD. Participants highlighted the importance of accurate and collaborative communication and of dental professionals explicitly adopting and communicating a biopsychosocial understanding of pain to their patients who have TMD. Results highlight that some people can struggle to manage persisting pain with minimal support. Signposting patients to appropriate services and resources may help them to understand more about the nature of persistent pain and methods of managing it.

Parental Perceptions Regarding the Impact of Housing on Child Health.

Introduction Childhood poverty has life-long adverse impacts. We aimed to assess perceptions of parents of a cohort of children attending a paediatric emergency department regarding the impact of their housing on their child and family Methods From 01/11/2020 - 08/01/2021 a cross-sectional study was performed in a paediatric emergency department in Dublin Results Of 312 parents who completed a questionnaire, 4.5% (n = 14) reported themselves to be homeless. Homeless children were less likely to be registered with general practitioners (78.6% vs. 97.5%, p = .009) or be fully vaccinated (71.4% vs. 92.4%, p = .024). Homeless parents were more likely to feel unsafe at home (35.7% vs. 3.4%, p <.001), and to report that their housing negatively impacted their child's education (58.3% vs 10.7%, p <.001), physical health (45.5% vs 11.7, p = .007), and mental health (61.5% vs 12.6%, p <.001). Ten percent of non-homeless parents were concerned about losing their home. A lack of landlord permission to install child safety measures in the home was reported by 28% of all parents. Conclusion Homeless parents were more likely to report that their living situation negatively impacted their child's play, development, education, safety, and health.

Implementation of a Low-Field Portable MRI Scanner in a Resource-Constrained Environment: Our Experience in Malawi.

Low-field, portable MR imaging may expedite patient management in the setting of critical illness. We successfully implemented low-field MR imaging at the Queen Elizabeth Central Hospital in Malawi; a low-resource setting. We present our experience of low-field, portable MR imaging start-up and use in Malawi; the first of its kind in Sub-Saharan Africa, together with complementary troubleshooting mechanisms that may be used especially in similar resource-constrained contexts.

Implementation of initiatives designed to improve healthcare worker health and wellbeing during the COVID-19 pandemic: comparative case studies from 13 healthcare provider organisations globally.

BACKGROUND: Healthcare workers are at a disproportionate risk of contracting COVID-19. The physical and mental repercussions of such risk have an impact on the wellbeing of healthcare workers around the world. Healthcare workers are the foundation of all well-functioning health systems capable of responding to the ongoing pandemic; initiatives to address and reduce such risk are critical. Since the onset of the pandemic healthcare organizations have embarked on the implementation of a range of initiatives designed to improve healthcare worker health and wellbeing. METHODS: Through a qualitative collective case study approach where participants responded to a longform survey, the facilitators, and barriers to implementing such initiatives were explored, offering global insights into the challenges faced at the organizational level. 13 healthcare organizations were surveyed across 13 countries. Of these 13 participants, 5 subsequently provided missing information through longform interviews or written clarifications. RESULTS: 13 case studies were received from healthcare provider organizations. Mental health initiatives were the most commonly described health and wellbeing initiatives among respondents. Physical health and health and safety focused initiatives, such as the adaption of workspaces, were also described. Strong institutional level direction, including engaged leadership, and the input, feedback, and engagement of frontline staff were the two main facilitators in implementing initiatives. The most common barrier was HCWs' fear of contracting COVID-19 / fear of passing COVID-19 to family members. In organizations who discussed infection prevention and control initiatives, inadequate personal protective equipment and supply chain disruption were highlighted by respondents. CONCLUSIONS: Common themes emerge globally in exploring the enablers and barriers to implementing initiatives to improve healthcare workers health and wellbeing through the COVID-19 pandemic. Consideration of the themes outlined in the paper by healthcare organizations could help influence the design and deployment of future initiatives ahead of implementation.

The effect of mental fatigue on the performance of Australian football specific skills amongst amateur athletes.

OBJECTIVES: This study investigated the effects of induced mental fatigue on the performance of Australian football (AF) specific skills amongst amateur AF players. DESIGN: Randomised cross over trial. METHODS: Twenty-five amateur AF players performed a series of standardised tests from the Australian Football League (AFL) Draft Combine after completing a 30-min Stroop test (mental fatigue condition) or 30-min control condition. The AFL Draft Combine tests included the standing vertical jump test, running vertical jump test, agility test, 20m sprint, Matthew Lloyd clean hands test, Brad Johnson goal kicking test and a Yo-Yo Intermittent Recovery Level 1 (Yo-Yo IR1) test. RESULTS: The Stroop test score decreased during the Stroop test (first five trials: mean=84.7, SD=3.5; last five trials: mean=82.2, SD=5.0, p=0.03). The Yo-Yo IR1 test (mental fatigue: median=920m, IQR=400; control: median=1040m, IQR=760; p=0.03) and Brad Johnson goalkicking test (mental fatigue: median=19.0, IQR=5.0; control: median=25.0, IQR=10.0, p=0.048) were negatively affected by mental fatigue. No other Draft Combine tests demonstrated a negative affect from mental fatigue. CONCLUSIONS: Mental fatigue had a detrimental influence on the performance of AF specific skills. The findings may have implications for AF players who are required to sustain attention and concentration for prolonged periods before and during matches.

Rare variant analysis in multiply affected families, association studies and functional analysis suggest a role for the ITGΒ4 gene in schizophrenia and bipolar disorder.

Recent results imply that rare variants contribute to the risk of schizophrenia. Exome sequence data from the UK10K project was used to identify three rare, amino acid changing variants in the ITGB4 gene which segregated with schizophrenia in two families: rs750367954, rs147480547 and rs145976111. Association analysis was carried out in the exome-sequenced Swedish schizophrenia study and in UCL schizophrenia and bipolar cases and controls genotyped for these variants. A gene-wise weighted burden test was performed on a trio sample of schizophrenia cases and their parents. rs750367954 was seen in two Swedish cases and in no controls. The other two variants were commoner in cases than controls in both Swedish and UCL cohort samples and an overall burden test was significant at p=0.0000031. The variants were not observed in the trio sample but ITGB4 was most highly ranked out of 14,960 autosomal genes in a gene-wise weighted burden test. The effect of rs147480547 and rs145976111 was studied in human neuroblastoma SH-SY5Y cells. Cells transfected with both variants had increased proliferation at both 24 and 48h (p=0.013 and p=0.05 respectively) compared to those with wild-type ITGB4. Taken together, these results suggest that rare variants in ITGB4 which affect function may contribute to the aetiology of schizophrenia and bipolar disorder.

Whole-exome sequencing of individuals from an isolated population implicates rare risk variants in bipolar disorder.

Bipolar disorder affects about 1% of the world's population, and its estimated heritability is about 75%. Only few whole genome or whole-exome sequencing studies in bipolar disorder have been reported, and no rare coding variants have yet been robustly identified. The use of isolated populations might help finding variants with a recent origin, more likely to have drifted to higher frequency by chance. Following this approach, we investigated 28 bipolar cases and 214 controls from the Faroe Islands by whole exome sequencing, and the results were followed-up in a British sample of 2025 cases and 1358 controls. Seventeen variants in 16 genes in the single-variant analysis, and 3 genes in the gene-based statistics surpassed exome-wide significance in the discovery phase. The discovery findings were supported by enrichment analysis of common variants from genome-wide association studies (GWAS) data and interrogation of protein-protein interaction networks. The replication in the British sample confirmed the association with NOS1 (missense variant rs79487279) and NCL (gene-based test). A number of variants from the discovery set were not present in the replication sample, including a novel PITPNM2 missense variant, which is located in a highly significant schizophrenia GWAS locus. Likewise, PIK3C2A identified in the gene-based analysis is located in a combined bipolar and schizophrenia GWAS locus. Our results show support both for existing findings in the literature, as well as for new risk genes, and identify rare variants that might provide additional information on the underlying biology of bipolar disorder.

A novel strategy to reduce very late HIV diagnosis in high-prevalence areas in South-West England: serious incident audit.

Background: Very late diagnosis of HIV is a serious public health issue. We used serious incident reporting (SIR) to identify and address reasons for late diagnoses across the patient pathway. Methods: Cases of very late HIV diagnosis were reported via SIR in two 6-month batches between 2011 and 2012 in Bournemouth, Poole and Bristol. Case notes were reviewed for missed opportunities for earlier diagnosis using a root-cause analysis tool. Results: A total of 33 patients (aged 30-67 years, 66% male) were diagnosed very late. Although the majority were white British (n = 17), Black African (n = 9) and Eastern European (n = 4) ethnicities were over-represented. Twenty-four (73%) patients had clinical indicator conditions for HIV, 30 (91%) had a risk factor for HIV acquisition, with 13 (39%) having 2 or more (men-who-have-sex-with-men (n = 11), partner HIV positive (n = 11), from high-prevalence area (n = 12)). Actions resulting from SIR included increasing awareness of indicator conditions, HIV education days within primary care, and initiatives to increase testing within hospital specialities. Conclusions: SIR allowed identification of reasons for very late HIV diagnosis and provided an impetus for initiatives to address them. SIR may be part of an effective strategy to prevent late diagnosis of HIV which would have important benefits for individual and population health.

CACNA1C hypermethylation is associated with bipolar disorder.

The CACNA1C gene, encoding a subunit of the L-type voltage-gated calcium channel is one of the best-supported susceptibility genes for bipolar disorder (BD). Genome-wide association studies have identified a cluster of non-coding single-nucleotide polymorphisms (SNPs) in intron 3 to be highly associated with BD and schizophrenia. The mechanism by which these SNPs confer risk of BD appears to be through an altered regulation of CACNA1C expression. The role of CACNA1C DNA methylation in BD has not yet been addressed. The aim of this study was to investigate if CACNA1C DNA methylation is altered in BD. First, the methylation status of five CpG islands (CGIs) across CACNA1C in blood from BD subjects (n=40) and healthy controls (n=38) was determined. Four islands were almost completely methylated or completely unmethylated, while one island (CGI 3) in intron 3 displayed intermediate methylation levels. In the main analysis, the methylation status of CGI 3 was analyzed in a larger sample of BD subjects (n=582) and control individuals (n=319). Out of six CpG sites that were investigated, five sites showed significant hypermethylation in cases (lowest P=1.16 × 10(-7) for CpG35). Nearby SNPs were found to influence the methylation level, and we identified rs2238056 in intron 3 as the strongest methylation quantitative trait locus (P=2.6 × 10(-7)) for CpG35. In addition, we found an increased methylation in females, and no difference between bipolar I and II. In conclusion, we find that CACNA1C methylation is associated with BD and suggest that the regulatory effect of the non-coding risk variants involves a shift in DNA methylation.

Targeting ErbB-2 nuclear localization and function inhibits breast cancer growth and overcomes trastuzumab resistance.

Membrane overexpression of ErbB-2/HER2 receptor tyrosine kinase (membrane ErbB-2 (MErbB-2)) has a critical role in breast cancer (BC). We and others have also shown the role of nuclear ErbB-2 (NErbB-2) in BC, whose presence we identified as a poor prognostic factor in MErbB-2-positive tumors. Current anti-ErbB-2 therapies, as with the antibody trastuzumab (Ttzm), target only MErbB-2. Here, we found that blockade of NErbB-2 action abrogates growth of BC cells, sensitive and resistant to Ttzm, in a scenario in which ErbB-2, ErbB-3 and Akt are phosphorylated, and ErbB-2/ErbB-3 dimers are formed. Also, inhibition of NErbB-2 presence suppresses growth of a preclinical BC model resistant to Ttzm. We showed that at the cyclin D1 promoter, ErbB-2 assembles a transcriptional complex with Stat3 (signal transducer and activator of transcription 3) and ErbB-3, another member of the ErbB family, which reveals the first nuclear function of ErbB-2/ErbB-3 dimer. We identified NErbB-2 as the major proliferation driver in Ttzm-resistant BC, and demonstrated that Ttzm inability to disrupt the Stat3/ErbB-2/ErbB-3 complex underlies its failure to inhibit growth. Furthermore, our results in the clinic revealed that nuclear interaction between ErbB-2 and Stat3 correlates with poor overall survival in primary breast tumors. Our findings challenge the paradigm of anti-ErbB-2 drug design and highlight NErbB-2 as a novel target to overcome Ttzm resistance.

Is the NHS best practice tariff for type 1 diabetes applicable in the Irish context?

The National Health Service in the UK has identified thirteen key standards of paediatric diabetes care. Funding depends on services meeting these standards. The aim of this study was to determine if these standards are applicable in an Irish setting. All patients attending the diabetes service during 2012 were included. Patient charts, electronic appointments, nursing notes and computerised results were used to ascertain relevant information for comparison with the NHS standards. Patients attended a mean 2.97 (SD 0.7) medical and 2.2 (SD 2.9) nursing appointments per year, with a median additional contacts of 8 nurse phone calls (range 0 - 125). Most standards were met by this service. In comparing our service to the NHS standard, we have identified a number of areas for improving our service provision. Limited resources and staff shortages make a number of these standards unachievable, namely annual dietetic review and three monthly outpatient appointments.

Antioxidant capacity of flaxseed products: the effect of in vitro digestion.

This study evaluated the effect of in vitro digestion of flaxseed products on Folin-Ciocalteu reagent reducing substances (FCRRS), its antioxidant capacity and prevention of oxidative DNA damage in human monocyte cell line U937. Flaxseed protein isolate was obtained from defatted flaxseed meal and the protein hydrolysate with high antioxidant capacity was obtained from hydrolysis of the protein isolate with Alcalase in a two factor central composite rotatable design (pH 8.5 and enzyme: substrate 1:90, w/w). The FCRRS content and antioxidant capacity measured by FRAP and ORAC in aqueous and 70 % methanol extracts were the highest in protein hydrolysate, followed by protein isolate, while the defatted meal showed the lowest values. After in vitro gastrointestinal digestion, the FCRRS content of protein isolate and hydrolysate reached similar values, however the hydrolysate had the highest antioxidant capacity, measured by FRAP while the isolate had the highest ORAC values. The defatted meal showed the lowest capacity in all assays (p < 0.05). The hydrolysate did not protect against DNA damage induced by H2O2 in U937 cells under the conditions of the present study. The results suggest that flaxseed protein isolate and hydrolysate are potential functional food ingredients with antioxidant capacity.

Assessment of the ability of seaweed extracts to protect against hydrogen peroxide and tert-butyl hydroperoxide induced cellular damage in Caco-2 cells.

The ability of brown seaweed extracts, Ascophyllum nodosum, Laminaria hyperborea, Pelvetia canaliculata, Fucus vesiculosus and Fucus serratus to protect against tert-butyl hydroperoxide (tert-BOOH) induced stress in Caco-2 cells was investigated. Oxidative stress was determined by measuring alteration in the enzymatic activity of catalase (CAT) and superoxide dismutases (SOD) and cellular levels of glutathione (GSH). L. hyperborea, P. canaliculata and F. serratus significantly protected against tert-BOOH induced SOD reduction but did not protect against the reduction in CAT activity or the increased cellular levels of GSH. The ability of F. serratus and F. vesiculosus to protect against H(2)O(2) and tert-BOOH induced DNA damage was also assessed. The DNA protective effects of the two seaweed extracts was compared to those of three metal chelators; deferoxamine mesylate (DFO), 1,10-phenanthroline (o-phen) and 1,2-Bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid tetrakis (BAPTA-AM). F. serratus and F. vesiculosus significantly protected (P<0.05) against H(2)O(2) (50 µM) induced DNA damage but not tert-BOOH induced damage.

Endovascular approaches to acute aortic type A dissection: a CT-based feasibility study.

BACKGROUND: Open graft replacement of the ascending aorta is the current treatment of choice for Stanford acute type A dissections. However, approximately 20% of patients are deemed unfit for open surgery. To determine if an endovascular option exists for this latter group of patients, we performed a computed tomography (CT)-based feasibility study. METHODS: A cohort of consecutive patients presenting to the cardiovascular care unit (CVCU) for an acute Stanford type A aortic dissection between 2006 and 2009 was retrospectively analysed. Inclusion criterion was a high-quality preoperative angio-CT scan that could be analysed on a three-dimensional (3D) workstation. Numerous anatomical parameters of the dissection were studied, including the location and the length of the primary proximal entry tear. Finally, we determined which of the patients would have been potential candidates for an endovascular repair (stentgraft implantation). RESULTS: A total of 102 patients were included in our study. The median distance of the primary entry tear to the closest coronary artery was 23 mm (range 0-128). The median true lumen and true + false lumen (total) diameters at the level of the entry tear was 38 mm (range 22-78) and 46 mm (range 28-93), respectively. The median length of the ascending aorta was 84 mm (range 40-130). An endovascular repair with a tubular stentgraft was deemed feasible in 37 patients. An additional eight patients were also candidates for a tubular endovascular repair but would have required a carotidecarotid cross over bypass. Finally, an arch-branched stentgraft could have been used in 13 patients to exclude an entry tear located in the arch. CONCLUSION: Open repair of acute type A dissection is and remains the 'gold standard' of care. Our study demonstrates that approximately half the patients undergoing an open repair could potentially benefit from an endovascular repair. This new treatment option has not been evaluated to date.

Hyperlactataemia in HIV-infected subjects initiating antiretroviral therapy in a large randomized study (a substudy of the INITIO trial).

OBJECTIVE: The aim of the study was to evaluate the predictive value of clinical and molecular risk factors, including peripheral blood mononuclear cell (PBMC) mitochondrial DNA (mtDNA) and mitochondrial RNA (mtRNA), for the development of lactic acidosis (LA) and symptomatic hyperlactataemia (SHL). METHODS: In a substudy of a large multicentre, randomized trial of three antiretroviral regimens, all containing didanosine (ddI) and stavudine (d4T), in antiretroviralnaïve, HIV-1-infected patients, patients with LA/SHL ('cases') were compared with those without LA/SHL in a univariate analysis, with significant parameters analysed in a multivariate model. In a molecular substudy, PBMC mtDNA and mtRNA from cases and matched controls at baseline and time of event were examined. RESULTS: In 911 subjects followed for a median of 192 weeks, 24 cases were identified (14 SHL and 10 LA). In univariate analysis, cases were more likely to be female (P=0.05) and to have a high body mass index (BMI) (P=0.02). In multivariate analyses, only BMI remained an independent predictor of the development of LA/SHL (P=0.03). Between cases and controls there was no significant difference in mtDNA copy number at baseline (389 vs. 411 copies/cell, respectively; P=0.60) or at time of event (329 vs. 474 copies/cell, respectively; P=0.21), in the change in mtDNA copy number from baseline to event (-65 vs. +113 copies/cell, respectively; P=0.12), in mtRNA expression at baseline or time of event, or in the change in mtRNA expression from baseline to event. CONCLUSION: The development of LA/SHL was associated with increased BMI, but PBMC mtDNA and mtRNA did not predict LA/SHL. This demonstrates the ineffectiveness of routine measurement of PBMC mtDNA in patients on ddI and d4T as a means of predicting development of LA/SHL.

A multi-centre randomised phase III trial of Dexamethasone vs Dexamethasone and diethylstilbestrol in castration-resistant prostate cancer: immediate vs deferred Diethylstilbestrol.

BACKGROUND: The role of further hormone therapy in castration-resistant prostate cancer (CRPC) remains unclear. We performed a multi-centre randomised phase III study comparing the use of Dexamethasone, Aspirin, and immediate addition of Diethylstilbestrol (DAiS) vs Dexamethasone, Aspirin, and deferred (until disease progression) addition of Diethylstilbestrol (DAdS). METHODS: From 2001 to 2008, 270 men with chemotherapy-naive CRPC were randomly assigned, in a 1 : 1 ratio, to receive either DAiS or DAdS. They were stratified for performance status, presence of bone metastases, and previous normalisation of prostate-specific antigen (PSA) to androgen deprivation. The study end points were the proportion of patients achieving a 50% PSA response, progression-free survival (PFS), overall survival, and quality of life. Intention-to-treat analysis was carried out. The effect of treatment was studied first by Kaplan-Meier curves and log-rank test, and finally through multivariable stratified Cox's proportional hazards model adjusting for the effects of possible baseline prognostic factors. Quality of life was analysed using multivariate analysis of variance. RESULTS: At study entry, the median age was 76 years (inter-quartile range: 70-80 years), the median PSA was 79 ng ml(-1), and 76% of the cohort had metastatic disease. The response rates for DAiS (68%) and DAdS (64%) were not significantly different (P=0.49). Similar to the response rate, neither the PFS (median=8.1 months for both arms) nor the overall survival (19.4 vs 18.8 months) differed significantly between the DAiS and DAdS groups (P>0.20). However, the response rate for the DAiS (68%) was significantly higher than the response rate of DA (before adding Diethylstilbestrol) (50%) (P=0.002). Similarly, the median time to progression for DAiS (8.6 months) was significantly longer than that of DA (4.5 months) (P<0.001). Multivariable analysis showed that patients with previous haemoglobin ≥11 g dl(-1) decreased the risk of death significantly (hazard ratio: 0.44, 95% CI: 0.25-0.77). Patients treated with previous anti-androgens alone had more than 5 times more risk of death compared with patients treated with gonadorelin analogues throughout their castration-sensitive phase. Treatment sequencing did not affect the quality of life but pre-treatment performance status did. The incidence of veno-thromboembolic events was 22% (n=28) in DAiS and 11% (n=14) in the DA arm (P=0.02). Painful gynaecomastia occurred in only 1% on DA, whereas in 40% on DAiS (P=0.001). CONCLUSION: Dexamethasone and immediate Diethylstilbestrol resulted in neither higher PSA response rate nor higher PFS compared with Dexamethasone with deferred Diethylstilbestrol. There was no suggestion of significantly improved overall survival or quality of life. Given the significantly higher toxicity of Diethylstilbestrol, deferring Diethylstilbestrol until failure of Dexamethasone is the preferred strategy when using these agents in CRPC.