The gut microbiota in adults with cystic fibrosis compared to colorectal cancer.

BACKGROUND: Gut dysbiosis is implicated in colorectal cancer (CRC) pathogenesis. Cystic fibrosis (CF) is associated with both gut dysbiosis and increased CRC risk. We therefore compared the faecal microbiota from individuals with CF to CRC and screening samples. We also assessed changes in CRC-associated taxa before and after triple CF transmembrane conductance regulator (CFTR) modulator therapy. METHODS: Bacterial DNA amplification comprising V4 16S rRNA analysis was conducted on 84 baseline and 53 matched follow-up stool samples from adults with CF. These data were compared to an existing cohort of 430 CRC and 491 control gFOBT samples from the NHS Bowel Cancer Screening Programme. Data were also compared to 26 previously identified CRC-associated taxa from a published meta-analysis. RESULTS: Faecal CF samples had a lower alpha diversity and clustered distinctly from both CRC and control samples, with no clear clinical variables explaining the variation. Compared to controls, CF samples had an increased relative abundance in 6 of the 20 enriched CRC-associated taxa and depletion of 2 of the 6 taxa which have been reported as reduced in CRC. Commencing triple modulator therapy had subtle influence on the relative abundance of CRC-associated microbiota (n = 23 paired CF samples). CONCLUSIONS: CF stool samples were clearly dysbiotic, clustering distinctly from both CRC and control samples. Several bacterial shifts in CF samples resembled those observed in CRC. Studies assessing the impact of dietary or other interventions and the longer-term use of CFTR modulators on reducing this potentially pro-oncogenic milieu are needed.

Reflections of maternity service users and midwives' on the co-creation of interventions to support midwives addressing alcohol during antenatal care.

BACKGROUND: There are divergent perspectives between midwives and pregnant women on how alcohol consumption during pregnancy could be addressed. Co-creation is an approach where lay people and professionals work together as equal partners, offering the opportunity to bridge the gap. OBJECTIVES: Our aim was to evaluate how well we carried out authentic co-creation of an intervention to support midwives have a dialogue about alcohol consumption with pregnant women. PATIENT INVOLVEMENT: Recent maternity service users including women with experience of harm due to alcohol during pregnancy provided feedback on the design, conduct and dissemination of the study. METHODS: An iterative co-creation approach rooted in participatory research methods was used. Five online workshops were carried out with thirteen midwives and six maternity service users via Zoom July-August 2021. Data were analysed using the core values of co-create as a framework: equality, inclusivity, holistic, resource, positivity, transparency, iterative, and sustainability. RESULTS: The co-creation process was productive and rewarding to midwives and maternity service users. There were positive experiences across the co-creation framework with some unintended positive consequences for maternity-service users. DISCUSSION: This evaluation provides new knowledge on how well the co-creation process worked in relation to research involving a sensitive topic that can invite stigma. Co-creation projects require generous time and financial resources to ensure a high-quality process and robust outcome for all. PRACTICAL VALUE: Co-creation of strategies involving both service providers and service users have potential to facilitate evidence-based practice. FUNDING: This research is funded by the National Institute for Health Research (Reference: NIHR201128).

Effectiveness of interventions to support the early detection of skin cancer through skin self-examination: a systematic review and meta-analysis.

BACKGROUND: As skin cancer incidence rises, there is a need to evaluate early detection interventions by the public using skin self-examination (SSE); however, the literature focuses on primary prevention. No systematic reviews have evaluated the effectiveness of such SSE interventions. OBJECTIVES: To systematically examine, map, appraise and synthesize, qualitatively and quantitatively, studies evaluating the early detection of skin cancer, using SSE interventions. METHODS: This is a systematic review (narrative synthesis and meta-analysis) examining randomized controlled trials (RCTs) and quasiexperimental, observational and qualitative studies, published in English, using PRISMA and National Institute for Health and Care Excellence guidance. The MEDLINE, Embase and PsycINFO databases were searched through to April 2015 (updated in April 2018 using MEDLINE). Risk-of-bias assessment was conducted. RESULTS: Included studies (n = 18), totalling 6836 participants, were derived from 22 papers; these included 12 RCTs and five quasiexperiments and one complex-intervention development. More studies (n = 10) focused on targeting high-risk groups (surveillance) than those at no higher risk (screening) (n = 8). Ten (45%) study interventions were theoretically underpinned. All of the study outcomes were self-reported, behaviour related and nonclinical in nature. Meta-analysis demonstrated the impact of the intervention on the degree of SSE activity from five studies, especially in the short term (up to 4 months) (odds ratio 2·31, 95% confidence interval 1·90-2·82), but with small effect sizes. Risk-of-bias assessment indicated that 61% of the studies (n = 11) were of weak quality. CONCLUSIONS: Four RCTs and a quasiexperimental study indicate that some interventions can enhance SSE activity and so are more likely to aid early detection of skin cancer. However, the actual clinical impact remains unclear, and this is based on overall weak study (evidence) quality.

A compartmentalized phosphoinositide signaling axis at cilia is regulated by INPP5E to maintain cilia and promote Sonic Hedgehog medulloblastoma.

Sonic Hedgehog (SHH) signaling at primary cilia drives the proliferation and progression of a subset of medulloblastomas, the most common malignant paediatric brain tumor. Severe side effects associated with conventional treatments and resistance to targeted therapies has led to the need for new strategies. SHH signaling is dependent on primary cilia for signal transduction suggesting the potential for cilia destabilizing mechanisms as a therapeutic target. INPP5E is an inositol polyphosphate 5-phosphatase that hydrolyses PtdIns(4,5)P2 and more potently, the phosphoinositide (PI) 3-kinase product PtdIns(3,4,5)P3. INPP5E promotes SHH signaling during embryonic development via PtdIns(4,5)P2 hydrolysis at cilia, that in turn regulates the cilia recruitment of the SHH suppressor GPR161. However, the role INPP5E plays in cancer is unknown and the contribution of PI3-kinase signaling to cilia function is little characterized. Here, we reveal INPP5E promotes SHH signaling in SHH medulloblastoma by negatively regulating a cilia-compartmentalized PI3-kinase signaling axis that maintains primary cilia on tumor cells. Conditional deletion of Inpp5e in a murine model of constitutively active Smoothened-driven medulloblastoma slowed tumor progression, suppressed cell proliferation, reduced SHH signaling and promoted tumor cell cilia loss. PtdIns(3,4,5)P3, its effector pAKT and the target pGSK3ß, which when non-phosphorylated promotes cilia assembly/stability, localized to tumor cell cilia. The number of PtdIns(3,4,5)P3/pAKT/pGSK3ß-positive cilia was increased in cultured Inpp5e-null tumor cells relative to controls. PI3-kinase inhibition or expression of wild-type, but not catalytically inactive HA-INPP5E partially rescued cilia loss in Inpp5e-null tumor cells in vitro. INPP5E mRNA and copy number were reduced in human SHH medulloblastoma compared to other molecular subtypes and consistent with the murine model, reduced INPP5E was associated with improved overall survival. Therefore our study identifies a compartmentalized PtdIns(3,4,5)P3/AKT/GSK3ß signaling axis at cilia in SHH-dependent medulloblastoma that is regulated by INPP5E to maintain tumor cell cilia, promote SHH signaling and thereby medulloblastoma progression.

The inter-relationship of symptom severity and quality of life in 2055 patients with primary biliary cholangitis.

BACKGROUND: Age at presentation with primary biliary cholangitis (PBC) is associated with differential response to ursodeoxycholic acid (UDCA) therapy. Younger-presenting patients are less likely to respond to treatment and more likely to need transplant or die from the disease. PBC has a complex impact on quality of life (QoL), with systemic symptoms often having significant impact. AIM: To explain the impact of age at presentation on perceived QoL and the inter-related symptoms which impact upon it. METHODS: Using the UK-PBC cohort, symptoms were assessed using the PBC-40 and other validated tools. Data were available on 2055 patients. RESULTS: Of the 1990 patients reporting a global PBC-QoL score, 66% reported good/neutral scores and 34% reported poor scores. Each 10-year increase in age at presentation was associated with a 14% decrease in risk of poor perceived QoL (OR = 0.86, 95% CI: 0.75-0.98, P < 0.05). All symptom domains were similarly age-associated (P < 0.01). Social dysfunction was the symptom factor with the greatest impact on QoL. Median (interquartile range) PBC-40 social scores for patients with good perceived QoL were 18 (14-23) compared with 34 (29-39) for those with poor QoL. CONCLUSION: The majority of patients with primary biliary cholangitis do not feel their QoL is impaired, although impairment is reported by a sizeable minority. Age at presentation is associated with impact on perceived QoL and the symptoms impairing it, with younger patients being more affected. Social dysfunction makes the greatest contribution to QoL impairment, and it should be targeted in trials aimed at improving life quality.

Implementation of a 'care bundle' improves the management of patients admitted to hospital with decompensated cirrhosis.

BACKGROUND: Since 1970, there has been a 400% increase in liver-related deaths due to the increasing prevalence of chronic liver disease in the United Kingdom (UK). The 2013 UK National Confidential Enquiry into Patient Outcome and Death report found that only 47% of patients who died from alcohol-related liver disease received 'good care' during their hospital stay. AIM: To develop a 'care bundle' for patients with decompensated cirrhosis, aiming to ensure that evidence-based treatments are delivered within the first 24 h of hospital admission. METHODS: This work gives practical advice about how to implement the bundle and examines its effects on patient care at three National Health Service Hospital Trusts in the UK by collecting data on patient care before and after introduction of the bundle. RESULTS: Data were collected on 228 patients across three centres (59% male, median age 53 years). Alcohol-related liver disease was the aetiology of chronic liver disease in 85% of patients. The overall mortality rate during hospital admission was 15%. The audits demonstrated improvements in patient care for patients with a completed care bundle who were significantly more likely to have a diagnostic ascitic performed within the first 24 h (P = 0.020), have an accurate alcohol history documented (P < 0.0001) and be given antibiotics as prophylaxis against infection following a variceal haemorrhage (P = 0.0096). In Newcastle, the bundle completion rate increased from 25% to 90% during the review periods. CONCLUSIONS: The introduction of a care bundle was associated with increased rates of diagnostic paracentesis and antibiotic prophylaxis with variceal haemorrhage in patients with decompensated cirrhosis.

Early primary biliary cholangitis is characterised by brain abnormalities on cerebral magnetic resonance imaging.

BACKGROUND: Brain change can occur in primary biliary cholangitis (PBC), potentially as a result of cholestatic and/or inflammatory processes. This change is linked to systemic symptoms of fatigue and cognitive impairment. AIM: To identify whether brain change occurs early in PBC. If the change develops early and is progressive, it may explain the difficulty in treating these symptoms. METHODS: Early disease brain change was explored in 13 patients with newly diagnosed biopsy-proven precirrhotic PBC using magnetisation transfer, diffusion-weighted imaging and 1 H magnetic resonance spectroscopy. Results were compared to 17 healthy volunteers. RESULTS: Cerebral magnetisation transfer ratios were reduced in early PBC, compared to healthy volunteers, in the thalamus, putamen and head of caudate with no greater reduction in patients with greater symptom severity. Mean apparent diffusion coefficients were increased in the thalamus only. No 1 H magnetic resonance spectroscopy abnormalities were seen. Serum manganese levels were elevated in all PBC patients, but no relationship was seen with imaging or symptom parameters. There were no correlations between neuroimaging data, laboratory data, symptom severity scores or age. CONCLUSIONS: This is the first study to be performed in this precirrhotic patient population, and we have highlighted that neuroimaging changes are present at a much earlier stage than previously demonstrated. The neuroimaging abnormalities suggest that the brain changes seen in PBC occur early in the pathological process, even before significant liver damage has occurred. If such changes are linked to symptom pathogenesis, this could have important implications for the timing of second-line-therapy use.

Republished: Non-alcoholic fatty liver disease: a practical approach to treatment.

Non-alcoholic fatty liver disease (NAFLD) affects up to a third of the population in many developed countries. Between 10% and 30% of patients with NAFLD have non-alcoholic steatohepatitis (NASH) that can progress to cirrhosis. There are metabolic risk factors common to both NAFLD and cardiovascular disease, so patients with NASH have an increased risk of liver-related and cardiovascular death. Management of patients with NAFLD depends largely on the stage of disease, emphasising the importance of careful risk stratification. There are four main areas to focus on when thinking about management strategies in NAFLD: lifestyle modification, targeting the components of the metabolic syndrome, liver-directed pharmacotherapy for high risk patients and managing the complications of cirrhosis.

Non-alcoholic fatty liver disease: a practical approach to treatment.

Non-alcoholic fatty liver disease (NAFLD) affects up to a third of the population in many developed countries. Between 10% and 30% of patients with NAFLD have non-alcoholic steatohepatitis (NASH) that can progress to cirrhosis. There are metabolic risk factors common to both NAFLD and cardiovascular disease, so patients with NASH have an increased risk of liver-related and cardiovascular death. Management of patients with NAFLD depends largely on the stage of disease, emphasising the importance of careful risk stratification. There are four main areas to focus on when thinking about management strategies in NAFLD: lifestyle modification, targeting the components of the metabolic syndrome, liver-directed pharmacotherapy for high risk patients and managing the complications of cirrhosis.

Republished: Non-alcoholic fatty liver disease: non-invasive investigation and risk stratification.

Non-alcoholic fatty liver disease (NAFLD) encompasses a histological spectrum of liver disease, from simple steatosis through to cirrhosis. As the worldwide rates of obesity have increased, NAFLD has become the commonest cause of liver disease in many developed countries, affecting up to a third of the population. The majority of patients have simple steatosis that carries a relatively benign prognosis. However, a significant minority have non-alcoholic steatohepatitis, and have increased liver related and cardiovascular mortality. Identifying those at risk of progressive disease is crucial. Liver biopsy remains the gold standard investigation for assessing stage of disease but its invasive nature makes it impractical for widespread use as a prognostic tool. Non-invasive tools for diagnosis and disease staging are required, reserving liver biopsy for those patients where it offers clinically relevant additional information. This review discusses the non-invasive modalities available for assessing steatosis, steatohepatitis and fibrosis. We propose a pragmatic approach for the assessment of patients with NAFLD to identify those at high risk of progressive disease who require referral to specialist services.

The effects of hoarding disorder on families: an integrative review.

Compulsive hoarding affects approximately 2-5% of the adult population. Increasing recognition has led to its inclusion as a distinct condition in forthcoming revisions to the Diagnostic and Statistical Manual V. Hoarding behaviour can have a detrimental effect on the health and well-being of family members. A rigorous review of available evidence using a novel three-stage literature search was undertaken: (1) an extensive scoping review; (2) a traditional search of databases including Cumulative Index to Nursing and Allied Health Literature, Medical Literature Analysis and Retrieval System Online, and psycINFO using combinations of keywords; and (3) review of cited references and hand-searching of selected journals. Evidence was selected using predefined inclusion criteria. Papers included two surveys, one qualitative study and one case study. An integrative review methodology was used to synthesize the evidence presented. Analysis revealed three overriding themes: quality of life, shattered families and rallying around. These illuminated the experiences of family members. These papers revealed families under strain and often at breaking point but with the resolve to pull together if the right support is available. This review concludes that further research is needed to investigate the effects of hoarding on family members and how these may best be met.

Failure analysis of the ball bearings of dental air turbine handpieces.

BACKGROUND: The aim of this study was to identify the nature and causes of deterioration and failure in dental handpiece ball bearings and thus provide guidance for clinical handling for service longevity. METHODS: The bearings of 36 turbine assemblies were dismantled for visual inspection, documented using a digital camera, and examined using scanning electron microscopy, as appropriate. RESULTS: For the metal parts of the ball bearing assembly, defects observed were mainly wear arising from the running load and corrosion. This was in the form of scratches and discoloured circumferential bands on the balls, and dull or worn surfaces extending around the circumference of the raceways. Cage damage including cracking, fracture, surface rubbing and distortion occurred, in varying degrees, in every failed turbine. CONCLUSIONS: Dental ball bearing failure modes have been identified. Cumulative effects of damage from corrosion and mechanical factors lead to handpiece deterioration. The cage was found to be very vulnerable to damage, and this may be the key limitation on bearing lifetime. Autoclaving may contribute to that, as it does to corrosion in the absence of adequate lubrication, but this seems to be minor in comparison to the effects of abuse. There is no justification for failing to observe usage and sterilization instructions.

Non-alcoholic fatty liver disease: non-invasive investigation and risk stratification.

Non-alcoholic fatty liver disease (NAFLD) encompasses a histological spectrum of liver disease, from simple steatosis through to cirrhosis. As the worldwide rates of obesity have increased, NAFLD has become the commonest cause of liver disease in many developed countries, affecting up to a third of the population. The majority of patients have simple steatosis that carries a relatively benign prognosis. However, a significant minority have non-alcoholic steatohepatitis, and have increased liver related and cardiovascular mortality. Identifying those at risk of progressive disease is crucial. Liver biopsy remains the gold standard investigation for assessing stage of disease but its invasive nature makes it impractical for widespread use as a prognostic tool. Non-invasive tools for diagnosis and disease staging are required, reserving liver biopsy for those patients where it offers clinically relevant additional information. This review discusses the non-invasive modalities available for assessing steatosis, steatohepatitis and fibrosis. We propose a pragmatic approach for the assessment of patients with NAFLD to identify those at high risk of progressive disease who require referral to specialist services.

Effect of different advancement positions on the maximum retrusive force of the mandible.

INTRODUCTION: Functional appliances lead, in different degrees, to loss of anchorage in the lower arch. By anchoring them to the mandibular bone, any dental side effects may be avoided and the skeletal effect enhanced. Stability of bone-borne fixation would be affected by forces created by the pull of the masticatory muscles. We aimed to identify mean maximum forces produced by mandibular retrusive muscles, at different degrees of advancement. SUBJECTS AND METHODS: Eighteen healthy adult volunteers participated in the study. Maximum retrusive force was measured using a splint/load cell system. Readings of the maximum forces of retrusion were taken from five mandibular positions: unstrained retruded position, and 4, 5, 6, and 7 mm anterior to the unstrained position. Data were presented as means ± SD and anova was performed to examine statistical significant differences between means of the maximum retrusion force. RESULTS: Mean maximum retrusion force ranged between 63.3 and 198.2 newtons at the unstrained and 7 mm positions, respectively. It increased as the distance of advancement increased, being statistically significantly (p < 0.05) less at unstrained position compared with all advancement distances, 4 mm of advancement than 6 and 7 mm advancement, 5 mm of advancement than at 7 mm advancement. CONCLUSION: Magnitude of the forces exerted by muscles during voluntary maximum retrusion movement from different advancement positions increased proportionately as the retrusion distance increased up to 7 mm. Such range of high forces might be important to consider when designing a bone-borne functional appliance.

Self-perceived preparedness for dental practice amongst graduates of The University of Hong Kong's integrated PBL dental curriculum.

OBJECTIVES: To determine how prepared for dental practice graduates from the integrated problem-based learning (PBL) dental undergraduate curriculum at The University of Hong Kong (HKU) perceive themselves to be and to identify factors associated with self-perceived preparedness. MATERIALS AND METHODS: A postal questionnaire was sent to five cohorts of dentists who had graduated from HKU's integrated PBL curriculum between 2004 and 2008. Using a 4-point Likert scale, the questionnaire assessed the self-perceived level of preparedness in 59 competencies grouped in nine domains. Responses were dichotomised into 'poorly prepared' and 'well prepared'. RESULTS: The response rate was 66% (159/241). The mean proportion (±standard deviation) of respondents indicating well-preparedness was 72.0±15.1% overall, and for each domain was as follows: general patient management, 93.1±12.1%; practice management, 81.0±22.2%; periodontology and dental public health, 73.5±19.3%; conservative dentistry, 92.5±13.1%; oral rehabilitation, 62.8±24.0%; orthodontics, 23.0±32.9%; managing children and special-needs patients, 64.8±28.9%; oral and maxillofacial surgery, 52.2±25.2%; and drug and emergency management, 84.7±22.6%. The odds of self-perceived well-preparedness were increased for cohorts graduating in 2004 and 2005 and graduates working in a non-solo dental practice. CONCLUSIONS: Dental graduates of HKU's integrated PBL curriculum felt well prepared for the most fundamental aspects of dental practice. However, apparent deficiencies of training in orthodontics and oral and maxillofacial surgery will need to be addressed by continuing education, postgraduate training and planning for the new 6-year undergraduate curriculum in 2012.

A randomized trial on root caries prevention in elders.

Root caries is common in institutionalized elders, and effective prevention methods are needed. This clinical trial compared the effectiveness of four methods in preventing new root caries. From 21 residential homes, 306 generally healthy elders having at least 5 teeth with exposed sound root surfaces were randomly allocated into one of four groups: (1) individualized oral hygiene instruction (OHI); (2) OHI and applications of 1% chlorhexidine varnish every 3 months; (3) OHI and applications of 5% sodium fluoride varnish every 3 months; and (4) OHI and annual applications of 38% silver diamine fluoride (SDF) solution. Two-thirds (203/306) of the elders were followed for 3 years. Mean numbers of new root caries surfaces in the four groups were 2.5, 1.1, 0.9, and 0.7, respectively (ANOVA, p < 0.001). SDF solution, sodium fluoride varnish, and chlorhexidine varnish were more effective in preventing new root caries than giving OHI alone.

ART and conventional root restorations in elders after 12 months.

Successful use of atraumatic restorative treatment (ART) in children has been reported, but little information is available regarding its use in older adults. The hypothesis of this study was that survival rates of root restorations placed by both ART and the conventional technique were similar. Root-surface caries lesions in 103 institutionalized elders in Hong Kong were treated randomly by either: (1) the conventional approach-caries removed by dental burs, and the cavity filled with light-cured resin-modified glass ionomer; or (2) the ART approach-caries removed by hand instruments, and the cavity filled with chemically cured high-strength glass ionomer. In total, 84 conventional and 78 ART restorations were placed. After 12 months, 63 conventional and 59 ART restorations were reviewed, and the respective 12-month survival rates were 91.7% and 87.0% (p > 0.05). It is concluded that the survival rates of both types of root restorations were high and similar.

Discharge of lubricant from air turbine handpieces.

OBJECTIVE: To demonstrate and quantify the discharge of lubricating oil from high-speed air turbine handpieces whilst running. MATERIALS AND METHODS: Dye-marked oil (Kavospray, KaVo) was used to lubricate four handpieces (Quiet-Air, Midwest) and the air discharged from around the lower bearing was directed at the moving chart paper on a recorder whilst running for 40 minutes. Secondly, seven new handpieces (Quiet-Air, 300SE, Midwest; Topair 796, Topair 795, W+H; VIP-Sigma, Pana-air, NSK; Lares, Lares Research) were cleaned, weighed and then lubricated with unmarked oil (Kavospray, KaVo). Oil discharge was determined gravimetrically over runs of 240 minutes. Data were fitted to the logistic dose response function. RESULT: The dye-marked oil tests showed that oil was discharged for at least 40 minutes in the direction of the bur. The gravimetric tests showed that oil continued to be discharged up to at least 240 minutes, and that the usual practice of removing excess lubricant by running for 1-2 minutes was ineffective in preventing cut-surface contamination. SIGNIFICANCE: Bonding procedures in dentistry may be jeopardised by oil contamination from handpiece lubricants. Decontamination with a detergent is suggested as a means of ensuring effective adhesive dentistry.