This paper describes a rural immersive attachment program for allied health students at an Australian University Department of Rural Health and its workforce outcomes. A mixed methods longitudinal ...cohort study, with data collected via end-of-placement and post-graduation surveys. Over 13 years, 311 allied health ‘year-long’ immersive rural attachments, as well as short-term placements, were supported. Pre- and post-placement rural practice intention ratings were paired (from 572 end of placement surveys) for 553 (96.7%) students. Students from metropolitan (49.4%, n = 273, p < 0.001), and rural origin (50.6%, n = 280, p < 0.001) showed a significant increase in rural practice intention. At 1 year post-graduation, 40.3% (n = 145) of graduates had worked in a rural or remote location in Australia, 39.9% at 3 years (n = 87) and 36.5% (n = 42) at 5 years. Longer-term rural attachments were found to be associated with rural practice location, independent of rural background. Those who had undertaken a longer rural attachment (≥18-weeks) were twice as likely to be working in a rural or remote area than those <18 weeks at 1 year (OR 2.018 95% CI 1.204–3.382) and 2.7 times as likely at 3 years (OR 2.727, 95% CI (1.325–5.614). Supporting students to undertake rural immersive attachments appears to be associated with greater rural practice intention and later rural practice.
Impaired awareness of hypoglycemia (IAH) and defective counterregulation significantly increase severe hypoglycemia risk in type 1 diabetes (T1D). We evaluated restoration of IAH/defective ...counterregulation by a treatment strategy targeted at hypoglycemia avoidance in adults with T1D with IAH (Gold score ≥4) participating in the U.K.-based multicenter HypoCOMPaSS randomized controlled trial.
Eighteen subjects with T1D and IAH (mean ± SD age 50 ± 9 years, T1D duration 35 ± 10 years, HbA1c 8.1 ± 1.0% 65 ± 10.9 mmol/mol) underwent stepped hyperinsulinemic-hypoglycemic clamp studies before and after a 6-month intervention. The intervention comprised the HypoCOMPaSS education tool in all and randomized allocation, in a 2 × 2 factorial study design, to multiple daily insulin analog injections or continuous subcutaneous insulin infusion therapy and conventional glucose monitoring or real-time continuous glucose monitoring. Symptoms, cognitive function, and counterregulatory hormones were measured at each glucose plateau (5.0, 3.8, 3.4, 2.8, and 2.4 mmol/L), with each step lasting 40 min with subjects kept blinded to their actual glucose value throughout clamp studies.
After intervention, glucose concentrations at which subjects first felt hypoglycemic increased (mean ± SE from 2.6 ± 0.1 to 3.1 ± 0.2 mmol/L, P = 0.02), and symptom and plasma metanephrine responses to hypoglycemia were higher (median area under curve for symptoms, 580 interquartile range {IQR} 420-780 vs. 710 460-1,260, P = 0.02; metanephrine, 2,412 -3,026 to 7,279 vs. 5,180 -771 to 11,513, P = 0.01). Glycemic threshold for deterioration of cognitive function measured by four-choice reaction time was unchanged, while the color-word Stroop test showed a degree of adaptation.
Even in long-standing T1D, IAH and defective counterregulation may be improved by a clinical strategy aimed at hypoglycemia avoidance.
Abstract Purpose Up to 50% of urinary tract infections (UTIs) in young children are missed in primary care. Urine culture is essential for diagnosis, but urine collection is often difficult. Our aim ...was to derive and internally validate a 2-step clinical rule using (1) symptoms and signs to select children for urine collection; and (2) symptoms, signs, and dipstick testing to guide antibiotic treatment. Methods We recruited acutely unwell children aged under 5 years from 233 primary care sites across England and Wales. Index tests were parent-reported symptoms, clinician-reported signs, urine dipstick results, and clinician opinion of UTI likelihood (clinical diagnosis before dipstick and culture). The reference standard was microbiologically confirmed UTI cultured from a clean-catch urine sample. We calculated sensitivity, specificity, and area under the receiver operator characteristic (AUROC) curve of coefficient-based (graded severity) and points-based (dichotomized) symptom/sign logistic regression models, and we then internally validated the AUROC using bootstrapping. Results Three thousand thirty-six children provided urine samples, and culture results were available for 2,740 (90%). Of these results, 60 (2.2%) were positive: the clinical diagnosis was 46.6% sensitive, with an AUROC of 0.77. Previous UTI, increasing pain/crying on passing urine, increasingly smelly urine, absence of severe cough, increasing clinician impression of severe illness, abdominal tenderness on examination, and normal findings on ear examination were associated with UTI. The validated coefficient- and points-based model AUROCs were 0.87 and 0.86, respectively, increasing to 0.90 and 0.90, respectively, by adding dipstick nitrites, leukocytes, and blood. Conclusions A clinical rule based on symptoms and signs is superior to clinician diagnosis and performs well for identifying young children for noninvasive urine sampling. Dipstick results add further diagnostic value for empiric antibiotic treatment.
Abstract
DNAAF1 (LRRC50) is a cytoplasmic protein required for dynein heavy chain assembly and cilia motility, and DNAAF1 mutations cause primary ciliary dyskinesia (PCD; MIM 613193). We describe ...four families with DNAAF1 mutations and complex congenital heart disease (CHD). In three families, all affected individuals have typical PCD phenotypes. However, an additional family demonstrates isolated CHD (heterotaxy) in two affected siblings, but no clinical evidence of PCD. We identified a homozygous DNAAF1 missense mutation, p.Leu191Phe, as causative for heterotaxy in this family. Genetic complementation in dnaaf1-null zebrafish embryos demonstrated the rescue of normal heart looping with wild-type human DNAAF1, but not the p.Leu191Phe variant, supporting the conserved pathogenicity of this DNAAF1 missense mutation. This observation points to a phenotypic continuum between CHD and PCD, providing new insights into the pathogenesis of isolated CHD. In further investigations of the function of DNAAF1 in dynein arm assembly, we identified interactions with members of a putative dynein arm assembly complex. These include the ciliary intraflagellar transport protein IFT88 and the AAA+ (ATPases Associated with various cellular Activities) family proteins RUVBL1 (Pontin) and RUVBL2 (Reptin). Co-localization studies support these findings, with the loss of RUVBL1 perturbing the co-localization of DNAAF1 with IFT88. We show that RUVBL1 orthologues have an asymmetric left-sided distribution at both the mouse embryonic node and the Kupffer's vesicle in zebrafish embryos, with the latter asymmetry dependent on DNAAF1. These results suggest that DNAAF1-RUVBL1 biochemical and genetic interactions have a novel functional role in symmetry breaking and cardiac development.
Associations between single nucleotide polymorphisms (SNPs) at 5p15 and multiple cancer types have been reported. We have previously shown evidence for a strong association between prostate cancer ...(PrCa) risk and rs2242652 at 5p15, intronic in the telomerase reverse transcriptase (TERT) gene that encodes TERT. To comprehensively evaluate the association between genetic variation across this region and PrCa, we performed a fine-mapping analysis by genotyping 134 SNPs using a custom Illumina iSelect array or Sequenom MassArray iPlex, followed by imputation of 1094 SNPs in 22 301 PrCa cases and 22 320 controls in The PRACTICAL consortium. Multiple stepwise logistic regression analysis identified four signals in the promoter or intronic regions of TERT that independently associated with PrCa risk. Gene expression analysis of normal prostate tissue showed evidence that SNPs within one of these regions also associated with TERT expression, providing a potential mechanism for predisposition to disease.
In the HypoCOMPaSS trial, adults with long-standing type 1 diabetes and problematic hypoglycemia were randomized to compare insulin pump (continuous subcutaneous insulin infusion; CSII) with multiple ...daily injections (MDI) and real-time continuous glucose monitoring (RT-CGM) with conventional self-monitoring of blood glucose (SMBG). Our aim was to investigate participants' satisfaction with these technologies at 6-month randomized, controlled trial (RCT) endpoint and at 2-year follow-up.
Participants completed the Insulin Treatment Satisfaction Questionnaire subscales "device delivery" and "hypoglycemia control"; and Glucose Monitoring Experience Questionnaire, assessing "convenience", "effectiveness", "intrusiveness", and "total satisfaction." We assessed change over time and between-group differences by insulin and monitoring modalities.
Participants (
= 96) were 64% women, aged 49 ± 12 years, with a diabetes duration of 29 ± 12 years. At 6 months, participants reported improvements compared with baseline (all
< 0.001) in satisfaction with insulin "delivery device" (
0.39) and "hypoglycemia control" (
= 0.52), and trends toward significance in perceived "effectiveness" (
0.42) and "intrusiveness" (
= 0.27) of monitoring device (but not "convenience",
= 0.139). All improvements were sustained at 2 years. At 6 months, the only difference between arms was that greater satisfaction with insulin "delivery device" was reported in the CSII group compared with MDI (
< 0.001,
= 0.40). No between-group differences were observed at 2 years.
Overall, significant improvements in participant satisfaction with diabetes technologies were observed over the 6-month RCT, in all domains except "convenience," and maintained at 2 years. Although HypoCOMPaSS demonstrated noninferiority of SMBG versus CGM, and MDI versus CSII in terms of biomedical outcomes, detailed assessments confirm that participants' satisfaction with delivery device was greater in those allocated to CSII than MDI.
The neuronal perturbations in Alzheimer's disease are attributed to the formation of extracellular amyloid-β (Aβ) neuritic plaques, composed predominantly of the neurotoxic Aβ42 isoform. Although the ...plaques have demonstrated a role in synaptic dysfunction, neuronal cytotoxicity has been attributed to soluble Aβ42 oligomers. The 37kDa/67kDa laminin receptor has been implicated in Aβ42 shedding and Aβ42-induced neuronal cytotoxicity, as well as internalization of this neurotoxic peptide. As the cellular prion protein binds to both LRP/LR and Aβ42, the mechanism underlying this cytotoxicity may be indirectly due to the PrPc-Aβ42 interaction with LRP/LR. The effects of this interaction were investigated by 3-4,5-dimethylthiazol-2-yl-2,5 diphenyl tetrazolium bromide assays. PrPc overexpression significantly enhanced Aβ42 cytotoxicity in vitro, while PrP-/- cells were more resistant to the cytotoxic effects of Aβ42 and exhibited significantly less cell death than PrPc expressing N2a cells. Although anti-LRP/LR specific antibody IgG1-iS18 significantly enhanced cell viability in both pSFV1-huPrP1-253 transfected and non-transfected cells treated with exogenous Aβ42, it failed to have any cell rescuing effect in PrP-/- HpL3-4 cells. These results suggest that LRP/LR plays a significant role in Aβ42-PrPc mediated cytotoxicity and that anti-LRP/LR specific antibodies may serve as potential therapeutic tools for Alzheimer's disease.
Evaluates the effect of energy-dense vs routine enteral nutrition on day-90 mortality by ethnic group in critically ill adults. Tests the hypothesis that for day-90 mortality there would be a ...statistically significant interaction between ethnicity and treatment allocation. Reports the mortality of enrolled participants by ethnic group adjusted for treatment allocation and important baseline covariates. Source: National Library of New Zealand Te Puna Matauranga o Aotearoa, licensed by the Department of Internal Affairs for re-use under the Creative Commons Attribution 3.0 New Zealand Licence.
Hope is the subjective probability of a good outcome for ourselves or someone close to us. During mortal extreme experience, observers and participants in the experience hope for life over death. In ...cancer, the illness/treatment experience is similar to the experience of dying, but with the redeeming element of hope for cure, for life over death. If cure is not obtained, hope for the participant moves to a ‘good death’.
If the outcome is cure, however, the hope for life has been realised for both participant and observer. Hope, which is always for the future, may now diverge between participant and observer. Observers hope for a return to normality, and use a discourse of normality which emphasises such things as ‘getting over it’, ‘moving on’ and ‘getting back to normal’.
Survivors may not find the realisation of hope for life to be as comfortable as might be expected. After the euphoria of being declared free of disease, about 30% of survivors develop post-cancer distress with
death salience. They recognise, whether they want to or not, that they have confronted their own annihilation, and that they will at some stage have to do so again. We all know that we will die, but there is a greater vividness and proximity in that knowledge for someone who has been through mortal extreme experience.
Death salience provokes a confrontation with meaning in a person's life. Thus survivors turn inward to their deep selves in order to establish an understanding of what their life projects might become. Observers, on the other hand, find death salience hard to live with, and may turn away from the distressed survivor.
The hopes and discourses of survivors and those close to them may have different structures and different objects. These differences may help to explain the frequency with which stress and disruption affect close relationships after cancer and other life-threatening experiences.
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