Paediatric quality-of-life following adenotonsillectomy: an evaluation of T14 paediatric throat disorder quality-of-life outcomes according to operative indication.

INTRODUCTION: Adenotonsillectomy is the most common surgical intervention for obstructive sleep apnoea (OSA) or recurrent tonsillitis. The Paediatric Throat Disorder Quality of Life Outcome (T14) questionnaire is a validated tool completed by parents to compare the outcome of surgery by measuring the pre- and postoperative scores. This study was undertaken to evaluate the quality-of-life outcome in children undergoing surgical intervention for recurrent tonsillitis and/or OSA. METHODS: This was a prospective, uncontrolled study of 117 children who underwent adenotonsillectomy and tonsillectomy at a single tertiary ear, nose and throat department. An analysis of pre- and postoperative T14 paediatric throat disorder quality-of-life outcomes was undertaken at 12 months. RESULTS: Of the 117 children, 105 were included in the study sample; 75 with recurrent tonsillitis, 8 with OSA and 22 with both tonsillitis and OSA. All children had an improved T14 score postoperatively. The greatest change in pre- and postoperative T14 score was observed in the tonsillitis and OSA combined group (mean change -29.36, p<0.001). However, an improvement in T14 score was also noted in the tonsilitis (-24.453, p<0.001) and OSA groups (-14.25, p<0.001). CONCLUSIONS: This study found a statistically significant improvement in the T14 quality-of-life score at 12 months postoperatively in children undergoing adenotonsillectomy. This demonstrates improved parental perception of their child's symptoms for all operative indications of adenotonsillectomy.

Symptoms in first-degree relatives of patients with rheumatoid arthritis: evaluation of cross-sectional data from the symptoms in persons at risk of rheumatoid arthritis (SPARRA) questionnaire in the PRe-clinical EValuation of Novel Targets in RA (PREVeNT-RA) Cohort.

BACKGROUND: First-degree relatives (FDRs) of people with rheumatoid arthritis (RA) have a fourfold increased risk of developing RA. The Symptoms in Persons At Risk of Rheumatoid Arthritis (SPARRA) questionnaire was developed to document symptoms in persons at risk of RA. The aims of this study were (1) to describe symptoms in a cohort of FDRs of patients with RA overall and stratified by seropositivity and elevated CRP and (2) to determine if patient characteristics were associated with symptoms suggestive of RA. METHODS: A cross-sectional study of FDRs of patients with RA, in the PREVeNT-RA study, who completed a study questionnaire, provided a blood sample measured for rheumatoid factor, anti-CCP and CRP and completed the SPARRA questionnaire. Moderate/severe symptoms and symmetrical, small and large joint pain were identified and described. Symptoms associated with both seropositivity and elevated CRP were considered suggestive of RA. Logistic regression was used to determine if symptoms suggestive of RA were associated with patient characteristics. RESULTS: Eight hundred seventy participants provided all data, 43 (5%) were seropositive and 122 (14%) had elevated CRP. The most frequently reported symptoms were sleep disturbances (20.3%) and joint pain (17.9%). Symmetrical and small joint pain were 11.3% and 12.8% higher, respectively, in those who were seropositive and 11.5% and 10.7% higher in those with elevated CRP. In the logistic regression model, seropositivity, older age and feeling depressed were associated with increased odds of small and symmetrical joint pain. CONCLUSIONS: This is the first time the SPARRA questionnaire has been applied in FDRs of patients with RA and has demonstrated that the presence of symmetrical and small joint pain in this group may be useful in identifying people at higher risk of developing RA.

'Everything was just getting worse and worse': deteriorating job quality as a driver of doctor emigration from Ireland.

BACKGROUND: Medicine is a high-status, high-skill occupation which has traditionally provided access to good quality jobs and relatively high salaries. In Ireland, historic underfunding combined with austerity-related cutbacks has negatively impacted job quality to the extent that hospital medical jobs have begun to resemble extreme jobs. Extreme jobs combine components of a good quality job-high pay, high job control, challenging demands, with those of a low-quality job-long working hours, heavy workloads. Deteriorating job quality and the normalisation of extreme working is driving doctor emigration from Ireland and deterring return. METHODS: Semi-structured qualitative interviews were conducted with 40 Irish emigrant doctors in Australia who had emigrated from Ireland since 2008. Interviews were held in July-August 2018. RESULTS: Respondents reflected on their experiences of working in the Irish health system, describing hospital workplaces that were understaffed, overstretched and within which extreme working had become normalised, particularly in relation to long working hours, fast working pace, doing more with less and fighting a climate of negativity. Drawing on Hirschman's work on exit, voice and loyalty (1970), the authors consider doctor emigration as exit and present respondent experiences of voice prior to emigration. Only 14/40 respondent emigrant doctors intend to return to work in Ireland. DISCUSSION: The deterioration in medical job quality and the normalisation of extreme working is a key driver of doctor emigration from Ireland, and deterring return. Irish trained hospital doctors emigrate to access good quality jobs in Australia and are increasingly likely to remain abroad once they have secured them. To improve doctor retention, health systems and employers must mitigate a gainst the emergence of extreme work in healthcare. Employee voice (about working conditions, about patient safety, etc.) should be encouraged and used to inform health system improvement and to mitigate exit.

The impact of change of renal replacement therapy modality on sleep quality in patients with end-stage renal disease: a systematic review and meta-analysis.

BACKGROUND: Sleep disorders are common and multi-factorial in patients with advanced chronic kidney disease and end-stage renal disease (ESRD). Sleep disorders and disturbance have a negative impact on wellbeing and quality of life. OBJECTIVE: To assess the impact of a change in renal replacement therapy (RRT) modality on sleep quality and sleep disturbance in patients with ESRD. DATA SOURCES: Multiple electronic databases were searched without publication type/period restrictions. The reference lists of all included articles were manually searched for additional citations. Non-published data was identified by hand searching key conference abstracts. STUDY ELIGIBILITY CRITERIA: Participants of interest were adult patients with ESRD requiring RRT [conventional haemodialysis (HD), short daily HD, nocturnal HD, continuous ambulatory peritoneal dialysis (CAPD), continuous cycler-assisted peritoneal dialysis (CCPD) or transplantation]. The exposure or intervention of interest was switch of RRT modality. STUDY APPRAISAL: Two reviewers independently assessed all studies for inclusion and extracted relevant data. RESULTS: Sixteen studies with a combined total of 670 patients and 191 controls were included for review and described in detail. Looking specifically at restless leg syndrome, symptoms resolved in over 60% of affected patients with a switch to increased intensity RRT (either intensive HD, CCPD or transplant). Meta-analysis of the nine studies that looked specifically at sleep apnoea parameters again favoured intensive RRT over standard/conventional RRT (conventional HD or CAPD) with statistical significance [Risk ratio 0.66 (95% CI 0.51-0.84)]. Meta-analysis of all studies favoured a switch to increased intensity RRT in terms of overall sleep quality, with statistical significance [Risk ratio 0.58 (95% CI 0.40-8.83)]. LIMITATIONS: Restriction to the English language may have introduced selection bias. Funnel plot analysis suggested there was also an element of publication bias. Studies were heterogeneous in terms of patient selection, means of sleep quality assessment and modality switch. CONCLUSIONS AND IMPLICATIONS OF KEY FINDINGS: Sleep disturbance, sleep apnoea and restless legs syndrome all tend to improve when a switch is made to intensive dialysis or transplant. This is important information for patients struggling with disturbed sleep and marked fatigue. This hypothesis-generating review highlights the need for more high quality prospective research in the area.

Hospital Resource Utilisation by Patients with Community-Acquired Pneumonia.

Little data is available on the resource utilisation of patients admitted with Community-Acquired Pneumonia (CAP) in Ireland. A retrospective review of 50 randomly-selected patients admitted to Beaumont Hospital with CAP was undertaken. The mean length of stay of patients with CAP was 12 days (+/- 16 days). All patients were emergency admissions, all had a chest x-ray, a C-reactive protein blood test, and occupied a public bed at some point during admission. Common antimicrobial therapies were intravenous (IV) amoxicillin/clavulanic acid and oral clarithromycin; 60% received physiotherapy. The estimated mean cost of CAP per patient was €14,802.17. Costs arising from admission to hospital with CAP are substantial, but efforts can be undertaken to ensure that resources are used efficiently to improve patient care such as discharge planning and fewer in-hospital ward transfers.

Prevalence of myeloma precursor state monoclonal gammopathy of undetermined significance in 12372 individuals 10-49 years old: a population-based study from the National Health and Nutrition Examination Survey.

We studied the prevalence of monoclonal gammopathy of undetermined significance (MGUS) in younger individuals, age 10-49 years, using samples from the National Health and Nutritional Examination Survey (NHANES) III. NHANES prevalence rates were standardized to the 2000 US total population. Among 12 372 individuals (4073 blacks, 4146 Mexican-Americans, 3595 whites, and 558 others), MGUS was identified in 63 persons (0.34%, 95% CI 0.23-0.50). The prevalence of MGUS was significantly higher in blacks (0.88%, 95% CI 0.62-1.26) compared with whites (0.22%, 95% CI 0.11-0.45), P=0.001. The prevalence of MGUS in Mexican-Americans was at an intermediate level (0.41%, 95% CI 0.23-0.73). The disparity in prevalence of MGUS between blacks and whites was most striking in the 40-49 age-group; 3.26% (95% CI 2.04-5.18) versus 0.53% (95% CI 0.20-1.37), P=0.0013. There was a trend to earlier age of onset of MGUS in blacks compared with whites. MGUS was seen in only two persons in the 10-19 age-group (both Mexican-American), and in three persons in the 20-29-year age-group (all of whom were black). In persons less than 50 years of age, MGUS is significantly more prevalent, with up to 10 years earlier age of onset, in blacks compared with whites.

ALDH1A3 is epigenetically regulated during melanocyte transformation and is a target for melanoma treatment.

Despite the promising targeted and immune-based interventions in melanoma treatment, long-lasting responses are limited. Melanoma cells present an aberrant redox state that leads to the production of toxic aldehydes that must be converted into less reactive molecules. Targeting the detoxification machinery constitutes a novel therapeutic avenue for melanoma. Here, using 56 cell lines representing nine different tumor types, we demonstrate that melanoma cells exhibit a strong correlation between reactive oxygen species amounts and aldehyde dehydrogenase 1 (ALDH1) activity. We found that ALDH1A3 is upregulated by epigenetic mechanisms in melanoma cells compared with normal melanocytes. Furthermore, it is highly expressed in a large percentage of human nevi and melanomas during melanocyte transformation, which is consistent with the data from the TCGA, CCLE and protein atlas databases. Melanoma treatment with the novel irreversible isoform-specific ALDH1 inhibitor [4-dimethylamino-4-methyl-pent-2-ynthioic acid-S methylester] di-methyl-ampal-thio-ester (DIMATE) or depletion of ALDH1A1 and/or ALDH1A3, promoted the accumulation of apoptogenic aldehydes leading to apoptosis and tumor growth inhibition in immunocompetent, immunosuppressed and patient-derived xenograft mouse models. Interestingly, DIMATE also targeted the slow cycling label-retaining tumor cell population containing the tumorigenic and chemoresistant cells. Our findings suggest that aldehyde detoxification is relevant metabolic mechanism in melanoma cells, which can be used as a novel approach for melanoma treatment.

Multivariate genetic architecture of the Anolis dewlap reveals both shared and sex-specific features of a sexually dimorphic ornament.

Darwin viewed the ornamentation of females as an indirect consequence of sexual selection on males and the transmission of male phenotypes to females via the 'laws of inheritance'. Although a number of studies have supported this view by demonstrating substantial between-sex genetic covariance for ornament expression, the majority of this work has focused on avian plumage. Moreover, few studies have considered the genetic basis of ornaments from a multivariate perspective, which may be crucial for understanding the evolution of sex differences in general, and of complex ornaments in particular. Here, we provide a multivariate, quantitative-genetic analysis of a sexually dimorphic ornament that has figured prominently in studies of sexual selection: the brightly coloured dewlap of Anolis lizards. Using data from a paternal half-sibling breeding experiment in brown anoles (Anolis sagrei), we show that multiple aspects of dewlap size and colour exhibit significant heritability and a genetic variance-covariance structure (G) that is broadly similar in males (Gm ) and females (Gf ). Whereas sexually monomorphic aspects of the dewlap, such as hue, exhibit significant between-sex genetic correlations (rmf ), sexually dimorphic features, such as area and brightness, exhibit reduced rmf values that do not differ from zero. Using a modified random skewers analysis, we show that the between-sex genetic variance-covariance matrix (B) should not strongly constrain the independent responses of males and females to sexually antagonistic selection. Our microevolutionary analysis is in broad agreement with macroevolutionary perspectives indicating considerable scope for the independent evolution of coloration and ornamentation in males and females.

Lingual tonsil: clinically applicable macroscopic anatomical classification system.

OBJECTIVE: To classify the adult lingual tonsil according to the macroscopic appearance. STUDY DESIGN: Prospective study. LEVEL OF EVIDENCE: Four. METHODS: Lingual tonsils were classified according to their appearance and relationship to surrounding structures. This was possible following serial views of lingual tonsils. The classification was named 'Swansea classification for lingual tonsil', representing the place of origin. The classification was then discussed with fellow clinicians. Independent professional observers graded lingual tonsil pictures. Intra-observer agreements were measured to validate the classification. RESULTS: A total of 22 professional observers went through a set of six pictures of three different grades of lingual tonsil. The pictures were then graded for validation. The intra-observer agreement was 0.81, confirming good agreement. CONCLUSION: Swansea classification for lingual tonsil is reliable and reproducible. This classification should be routinely used during ENT examination, enabling accurate documentation and providing opportunities for future research and audit of practice.

Peripheral blood stem cells collection on spectra optia apheresis system using the continuous mononuclear cell collection protocol: A single center report of 39 procedures.

BACKGROUND: The aim of the study was to assess the performance of the new Continuous Mononuclear Cell Collection (CMNC) protocol on the Spectra Optia Apheresis System for collecting autologous Peripheral Blood Stem Cells (PBSC) in adult patients with respect to collection variables, CD34+ cells harvest prediction and engraftment data. In this retrospective study, 39 CMNC procedures on 23 mobilized patients with multiple myeloma and lymphoma were analyzed. CD34+ cells and blood cells yields, collection efficiencies (CE1 and CE2), cell losses were calculated. Engraftment data of 17 autologous transplantations were collected. RESULTS: Apheresis duration was 239 min for a product volume of 220 mL. Cell product haematocrit, MNC and platelets counts were acceptable (respectively 2.4%, 65%, 834 x 109/L). Median platelet loss was 27.3%. Median CD34+ CE1 and CE2 were 64.6% and 48.5% respectively. We harvested 2.92 × 106 CD34+ cells/kg, with a CD34 dose ≥ 2 × 106 /kg for 67% of the procedures. Linear correlation between preapheresis CD34 count and the CP CD34 dose/kg allowed a prediction model with a decrease trend for high WBC precount. Procedures were well tolerated. For 17 autologous transplantations, median time to neutrophils and platelets reconstitutions were 12 and 13 days respectively. CONCLUSIONS: Spectra Optia CMNC protocol successfully collected CD34+ cells with yields permitting the harvest of sufficient enriched grafts for autologous transplantation. The CD34+ cell yield prediction was excellent. PBSC collection with CMNC protocol had advantages of high processing rate, low product volume, and acceptable contamination by platelets. J. Clin. Apheresis 32:182-190, 2017. © 2016 Wiley Periodicals, Inc.

Aldehyde dehydrogenases inhibition eradicates leukemia stem cells while sparing normal progenitors.

The vast majority of patients with acute myeloid leukemia (AML) achieve complete remission (CR) after standard induction chemotherapy. However, the majority subsequently relapse and die of the disease. A leukemia stem cell (LSC) paradigm has been invoked to explain this failure of CR to reliably translate into cure. Indeed, LSCs are highly enriched in CD34+CD38- leukemic cells that exhibit positive aldehyde dehydrogenase activity (ALDH+) on flow cytometry, these LSCs are resistant to currently existing treatments in AML such as cytarabine and anthracycline that, at the cost of great toxicity on normal cells, are highly active against the leukemic bulk, but spare the LSCs responsible for relapse. To try to combat the LSC population selectively, a well-characterized ALDH inhibitor by the trivial name of dimethyl ampal thiolester (DIMATE) was assessed on sorted CD34+CD38- subpopulations from AML patients and healthy patients. ALDH activity and cell viability were monitored by flow cytometry. From enzyme kinetic studies DIMATE is an active enzyme-dependent, competitive, irreversible inhibitor of ALDH1. On cells in culture, DIMATE is a powerful inhibitor of ALDHs 1 and 3, has a major cytotoxic activity on human AML cell lines. Moreover, DIMATE is highly active against leukemic populations enriched in LSCs, but, unlike conventional chemotherapy, DIMATE is not toxic for healthy hematopoietic stem cells which retained, after treatment, their self-renewing and multi-lineage differentiation capacity in immunodeficient mice, xenografted with human leukemic cells. DIMATE eradicates specifically human AML cells and spares healthy mouse hematologic cells.

Natural killer cells in acute myeloid leukemia patients: from phenotype to transcriptomic analysis.

Chemotherapies allow complete remission in more than 50 % of patients with acute myeloid leukemia (AML), however, with frequent relapse. This suggests that residual leukemic cells may escape to chemotherapy and immune system. Natural killer (NK) cells from AML patients (AML-NK) have a weaker natural cytotoxicity-activating receptors (NCRs) expression than NK cells from healthy donors (HD-NK). Coding genes for NCR1/NKp46, NCR2/NKp44 and NCR3/NKp30 are located at different loci on two different chromosomes; however, their expression is tightly coordinated. Most NK cells express either high (NCRbright) or low levels (NCRdull) of all three NCRs. This suggests the existence of negative/positive regulation factor(s) common to the three receptors. In order to find transcription factor(s) or pathway(s) involved in NCRs co-regulation, this study compared the transcriptomic signature of HD-NK and AML-NK cells, before and after in vitro NK cells culture. Microarrays analysis revealed a specific NK cells transcriptomic signature in patients with AML. However, in vitro NK cells expansion erased this signature and up-regulated expression of central molecules of NK functions, such as NCR, NKG2D and also ETS-1, regardless of their origin, i.e., AML-NK vs HD-NK. ETS-1 transcription factor was shown to bind to a specific and common region in the NCRs promoters, thus appearing as a good candidate to explain the coordinated regulation of three NCRs. Such results are encouraging regarding in vitro AML-NK cytotoxicity restoration and provide a new conceptual support for innovative cellular therapy based on in vitro NK cells expansion before their reinfusion in AML patients.

Micafungin as primary antifungal prophylaxis in patients presenting with acute myeloid leukemia.

OBJECTIVE: To study the efficacy and safety of micafungin for prophylaxis of invasive fungal infections in patients undergoing induction chemotherapy for acute myeloid leukemia. PATIENTS AND METHODS: A prospective observational single-center study of 41 patients from the hematology department between May 2012 and April 2015. Micafungin was administered once daily from the first day of induction chemotherapy to the end of the neutropenic phase. RESULTS: Neither Candida nor Aspergillus infection was documented in our 41 patients from the first day of micafungin infusion to the end of the neutropenic phase. Patients were followed for three months after discontinuation of micafungin and none of them contracted an invasive fungal infection. Only one patient presented with grade III-IV hepatic and ionic toxicities. CONCLUSION: Micafungin is associated with a good safety profile and is an interesting option for preventing invasive fungal infections in the high-risk population of patients presenting with hematological disorders.