Health-related quality of life in people with different diabetes-related foot ulcer health states: A cross-sectional study of healed, non-infected, infected, hospitalised and amputated ulcer states.

AIMS: Diabetes-related foot ulcers (DFU) are a leading cause of infection, hospitalisation and amputation. However, to our knowledge no studies have compared the health-related quality of life (HRQoL) of people with DFU that were infected, hospitalised or amputated. This study aimed to investigate and compare the HRQoL of different groups of people with healed, non-infected, infected, hospitalised, or amputated DFU. METHODS: This was a multi-centre cross-sectional study measuring the HRQoL of patients, attending one of 18 Diabetic Foot Services across Queensland, Australia, with one of five DFU health states: healed, non-infected, infected, hospitalised, amputated. HRQoL was measured using the EQ-5D-5L to estimate age-sex adjusted utility values. RESULTS: Of 376 included patients (mean age 63 (12) years, 75% male), age-sex adjusted HRQoL utility estimates (95% CIs) were: healed DFU 0.57 (0.51-0.64), non-infected DFU 0.55 (0.49-0.62), infected DFU 0.45 (0.36-0.55), hospitalised DFU 0.53 (0.42-0.64), and amputated DFU 0.55 (0.46-0.63). CONCLUSION: People in any DFU health state have considerably reduced HRQoL, with greatest reductions in those with infected DFU. These findings provide valuable HRQoL estimates and comparisons for several different important DFU health states, adding to our understanding of the impact of DFU on HRQoL and facilitating future economic evaluations.

Telephone cognitive screening with older Aboriginal Australians: A preliminary study.

OBJECTIVES: Cognitive screening via telehealth is increasingly employed, particularly during the COVID-19 pandemic. Telephone adaptations of existing cognitive screening tests must be validated across diverse populations. The present study sought to evaluate an existing 26-point telephone adaptation of the Mini-Mental State Examination (tMMSE) in a sample of older Aboriginal Australians. Additionally, we aimed to evaluate a telephone adaptation of the urban version of the Kimberley Indigenous Cognitive Assessment short-form (tKICA screen). METHODS: A sub-sample (n = 20) of participants (aged 55-69 years; 11 women) who had completed an in-person cognitive assessment (MMSE and KICA screen) within the past 6 months as part of the Koori Growing Old Well Study completed telephone-based cognitive testing without an assistant. RESULTS: There was moderate correlation and reasonable agreement between MMSE versions (rs  = 0.33; p = 0.2), although the limits of agreement were unacceptably wide (-4.1 and 4.8 points difference). Poorer performance was seen on the tMMSE for Season (p = 0.02) and Phrase (p = 0.02) items, and better performance for three-word Recall (p = 0.03). KICA-screen versions were poorly correlated (rs  = 0.20; p = 0.4) with telephone scoring a mean of 2.17 points below the face-to-face score, greater bias observed at the lower end of the performance and worse scores for Season (p = 0.02) and Recall (p = 0.001) items. Age and education were not associated with telephone screening performance. Hearing impairment was associated with poorer performance on the tKICA screen (p = 0.04) but not the tMMSE (p = 0.6). CONCLUSIONS: Results indicate that telephone administration of the MMSE and/or KICA screen is not equivalent to in-person testing for older Aboriginal people, and further revision and evaluation are required.

Randomized clinical trial of DTaP5-HB-IPV-Hib vaccine administered concomitantly with meningococcal serogroup C conjugate vaccines during the primary infant series.

BACKGROUND: Concomitant administration of vaccines simplifies delivery. DTaP5-HB-IPV-Hib is a fully liquid, combination vaccine against 6 diseases. This study evaluated the compatibility of DTaP5-HB-IPV-Hib with 2 different meningococcus group C conjugate (MCC) vaccines in infants. METHODS: In a phase 3, open-label study, 284 healthy infants from 11 UK centres received DTaP5-HB-IPV-Hib at age 2, 3, and 4 months; 13-valent pneumococcal conjugate vaccine (PCV13) at 2 and 4 months; a Haemophilus influenzae type b (Hib)-MCC vaccine and a measles/mumps/rubella vaccine at 12 months. Participants were randomised 1:1 to receive either an MCC-detoxified tetanus toxin vaccine (MCC-TT; n = 141) or an MCC-Corynebacterium diphtheriae CRM197 protein vaccine (MCC-CRM; n = 143) at 3 and 4 months. The primary outcome was seroprotection rate (SPR) to MCC (percent with rabbit complement serum bactericidal antibody titer ≥8). RESULTS: Per protocol analysis, MCC SPRs were 100 and 96.4 one month after the first dose, 100 and 99.1 after the second dose, and 100 and 97.3 after the third (booster) dose of MCC in the MCC-TT and MCC-CRM groups, respectively. One month after all 3 doses of DTaP5-HB-IPV-Hib, immunoglobulin G anti-polyribosylribitol phosphate SPRs (% ≥0.15 µg/mL) were 97.8 in the MCC-TT group and 100 in the MCC-CRM group; anti-hepatitis B antigen SPRs (% ≥10 mIU/mL) were 96.8 and 96.3 in the MCC-TT and MCC-CRM groups, respectively. All participants were seroprotected against diphtheria and tetanus (≥0.01 IU/mL) and poliovirus types 1, 2, and 3 (≥8 dilution), and seroresponse rates to all pertussis antigens were ≥90.4%. Two vaccine-related serious adverse events (transient severe abdominal pain and crying) occurred concomitantly in 1 participant in the MCC-CRM group. Adverse event rates were similar to other studies of DTaP5-HB-IPV-Hib, with pyrexia ≥38 °C in 10.9% of participants following any dose. CONCLUSIONS: DTaP5-HB-IPV-Hib can be effectively used in a 2-, 3-, and 4-month infant priming schedule when given with 2 doses of MCC.

VEGF/VEGFR2 signaling regulates hippocampal axon branching during development.

Axon branching is crucial for proper formation of neuronal networks. Although originally identified as an angiogenic factor, VEGF also signals directly to neurons to regulate their development and function. Here we show that VEGF and its receptor VEGFR2 (also known as KDR or FLK1) are expressed in mouse hippocampal neurons during development, with VEGFR2 locally expressed in the CA3 region. Activation of VEGF/VEGFR2 signaling in isolated hippocampal neurons results in increased axon branching. Remarkably, inactivation of VEGFR2 also results in increased axon branching in vitro and in vivo. The increased CA3 axon branching is not productive as these axons are less mature and form less functional synapses with CA1 neurons. Mechanistically, while VEGF promotes the growth of formed branches without affecting filopodia formation, loss of VEGFR2 increases the number of filopodia and enhances the growth rate of new branches. Thus, a controlled VEGF/VEGFR2 signaling is required for proper CA3 hippocampal axon branching during mouse hippocampus development.

Panniculitis in a 3-year-old child with Fanconi anemia-associated bone marrow hypoplasia heralds transformation to acute myeloid leukemia.

Fanconi anemia is a rare, autosomal recessive genomic instability disorder characterized by congenital limb anomalies, panmyelopathy and a high risk of malignancy, principally acute myeloid leukemia. Hematologic malignancy presenting with acute febrile neutrophilic dermatosis (Sweet syndrome), both deep and superficial forms, is well described in Fanconi anemia patients but is a rare phenomenon in otherwise healthy children. We present a case of panniculitis (presumptive subcutaneous Sweet syndrome) heralding transformation to acute myeloid leukemia in a 3-year-old boy with a severe Fanconi anemia phenotype.

Adopting innovation in gynaecology: The introduction of e-consult.

OBJECTIVE: To describe the development of an e-consultation service as part of the triaging and grading process of referrals and to report on the efficacy and safety of such a service. METHODS: All gynaecology e-consults in the study period June 2015 to March 2016 were retrospectively reviewed. The outcomes of interest were the initial reduction in first face-to-face hospital visits, and the rate of re-referrals. Acute admission for the same reason, a subsequent diagnosis of underlying (pre)-malignancy, or patient death from the condition related to the index referral were selected as measures for patient safety. RESULTS: Seven thousand and forty-two (7042) referrals were made to the gynaecology service in the 10 month study period. After exclusion of referrals to colposcopy and the early pregnancy clinic, 4738 e-referrals remained. Of these, 1013 referrals (21.4%) were triaged for an e-consult. One hundred and forty-seven patients (14.5%) with an initial e-consult were re-referred within 6 months for the same condition. The reduction in face-to-face contacts was 18.2% (866/4738). No death and/or acute admission for the same reason as stated in the initial referral occurred among the patients with e-consultation and none were later diagnosed with an underlying (pre)-malignancy. CONCLUSION: E-consultation was effective at reducing the number of first outpatient face-to-face contacts without notable compromise of the quality of care or patient safety. E-consultation allows specialists to provide expert clinical guidance, management and support to the referring provider when appropriate. Topics for further study include patient benefits and satisfaction, and further assessment of the social, economic and financial impacts on all parties involved.

Aminoacyl-tRNA quality control is required for efficient activation of the TOR pathway regulator Gln3p.

The aminoacylation status of the cellular tRNA pool regulates both general amino acid control (GAAC) and target of rapamycin (TOR) stress response pathways in yeast. Consequently, fidelity of translation at the level of aminoacyl-tRNA synthesis plays a central role in determining accuracy and sensitivity of stress responses. To investigate effects of translational quality control (QC) on cell physiology under stress conditions, phenotypic microarray analyses were used to identify changes in QC deficient cells. Nitrogen source growth assays showed QC deficient yeast grew differently compared to WT. The QC deficient strain was more tolerant to caffeine treatment than wild type through altered interactions with the TOR and GAAC pathways. Increased caffeine tolerance of the QC deficient strain was consistent with the observation that the activity of Gln3p, a transcription factor controlled by the TOR pathway, is decreased in the QC deficient strain compared to WT. GCN4 translation, which is typically repressed in the absence of nutritional stress, was enhanced in the QC deficient strain through TOR inhibition. QC did not impact cell cycle regulation; however, the chronological lifespan of QC deficient yeast strains decreased compared to wild type, likely due to translational errors and alteration of the TOR-associated regulon. These findings support the idea that changes in translational fidelity provide a mechanism of cellular adaptation by modulating TOR activity. This, in turn, supports a central role for aminoacyl-tRNA synthesis QC in the integrated stress response by maintaining the proper aa-tRNA pools necessary to coordinate the GAAC and TOR.

Editing of misaminoacylated tRNA controls the sensitivity of amino acid stress responses in Saccharomyces cerevisiae.

Amino acid starvation activates the protein kinase Gcn2p, leading to changes in gene expression and translation. Gcn2p is activated by deacylated tRNA, which accumulates when tRNA aminoacylation is limited by lack of substrates or inhibition of synthesis. Pairing of amino acids and deacylated tRNAs is catalyzed by aminoacyl-tRNA synthetases, which use quality control pathways to maintain substrate specificity. Phenylalanyl-tRNA synthetase (PheRS) maintains specificity via an editing pathway that targets non-cognate Tyr-tRNAPhe. While the primary role of aaRS editing is to prevent misaminoacylation, we demonstrate editing of misaminoacylated tRNA is also required for detection of amino acid starvation by Gcn2p. Ablation of PheRS editing caused accumulation of Tyr-tRNAPhe (5%), but not deacylated tRNAPhe during amino acid starvation, limiting Gcn2p kinase activity and suppressing Gcn4p-dependent gene expression. While the PheRS-editing ablated strain grew 50% slower and displayed a 27-fold increase in the rate of mistranslation of Phe codons as Tyr compared to wild type, the increase in mistranslation was insufficient to activate an unfolded protein stress response. These findings show that during amino acid starvation a primary role of aaRS quality control is to help the cell mount an effective stress response, independent of the role of editing in maintaining translational accuracy.

From paperwork to parenting: experiences of professional staff in student support.

CONTEXT: For academic staff, responding to student concerns is an important responsibility. Professional staff, or non-academic staff who do administrative work in medical schools, are often the first to be approached by students, yet there is little research on how they manage student issues. Informed by the conceptual framework of emotional labour, we examined the experiences of professional staff, aiming to identify theoretical and practical insights for improving the provision of student support. We examined the scope of support provided, the impact of providing this support on staff and how these impacts can be managed. METHODS: Professional staff at two medical schools were invited to participate in semi-structured qualitative interviews. Interviews were transcribed and independently analysed for emergent themes. Data analysis continued with purposive sampling for maximum variation until thematic saturation was reached. Findings were returned to participants in writing and via oral presentations for member checking and refinement. RESULTS: Twenty-two female staff from clinical, teaching and commercial backgrounds at nine urban and rural teaching sites were interviewed. Participants described providing support for diverse concerns, from routine requests to life-threatening emergencies. Four major themes emerged: firstly, all described roles consistent with emotional labour. Secondly, student support was regarded as informal work, and not well recognised or defined. Consequently, many drew upon their personal orientation to provide support. Finally, we identified both positive and negative personal impacts, including ongoing distress after critical events. CONCLUSIONS: Professional staff perform a range of student support work, leading to emotional, personal and work impacts. In turn, they need support, recognition and training in this essential but under-recognised role. Emotional labour offers a conceptual framework for understanding the gendered nature and impact of this work and how it may be managed. We suggest practical strategies for promoting positive and preventing negative effects on staff from supporting medical students.

Isoacceptor specific characterization of tRNA aminoacylation and misacylation in vivo.

Amino acid misincorporation during protein synthesis occurs due to misacylation of tRNAs or defects in decoding at the ribosome. While misincorporation of amino acids has been observed in a variety of contexts, less work has been done to directly assess the extent to which specific tRNAs are misacylated in vivo, and the identity of the misacylated amino acid moiety. Here we describe tRNA isoacceptor specific aminoacylation profiling (ISAP), a method to identify and quantify the amino acids attached to a tRNA species in vivo. ISAP allows compilation of aminoacylation profiles for specific isoacceptors tRNAs. To demonstrate the efficacy and broad applicability of ISAP, tRNAPhe and tRNATyr species were isolated from total aminoacyl-tRNA extracted from both yeast and Escherichia coli. Isolated aminoacyl-tRNAs were washed until free of detectable unbound amino acid and subsequently deacylated. Free amino acids from the deacylated fraction were then identified and quantified by mass spectrometry. Using ISAP allowed quantification of the effects of quality control on the accumulation of misacylated tRNA species under different growth conditions.

Mucocutaneous manifestations in a UK national cohort of juvenile-onset systemic lupus erythematosus patients.

OBJECTIVE: To determine whether mucocutaneous manifestations are associated with major organ involvement in a UK national cohort of juvenile-onset SLE (JSLE) patients. METHODS: JSLE patients (n = 241) from 15 different centres whose diagnosis fulfilled four or more of the ACR criteria were divided into two groups: those with at least one ACR mucocutaneous criterion (ACR skin feature positive) and those without (ACR skin feature negative) at diagnosis. The relative frequency of skin involvement was described by the paediatric adaptation of the 2004 British Isles Lupus Assessment Group (pBILAG-2004) index. RESULTS: One hundred and seventy-nine patients (74%) had ACR-defined skin involvement with no significant demographic differences compared with those without. ACR skin feature negative patients showed greater haematological (84% vs 67%), renal (43% vs 26%) (P < 0.05) and neurological (16% vs 4%) involvement (P = 0.001). Forty-two per cent of ACR skin feature negative patients had skin involvement using pBILAG-2004, which included maculopapular rash (17%), non-scaring alopecia (15%), cutaneous vasculitis (12%) and RP (12%). ACR skin feature negative patients with moderate to severe skin involvement by pBILAG-2004 showed greater renal and haematological involvement at diagnosis and over the follow-up period (P < 0.05). Higher immunosuppressive drug use in the skin feature negative group was demonstrated. CONCLUSION: Patients who fulfil the ACR criteria but without any of the mucocutaneous criteria at diagnosis have an increased risk of major organ involvement. The pBILAG-2004 index has shown that other skin lesions may go undetected using the ACR criteria alone, and these lesions show a strong correlation with disease severity and major organ involvement.

Atypical fibroxanthoma--a retrospective immunohistochemical study of 42 cases.

PURPOSE: Atypical fibroxanthoma is a cutaneous dermal malignancy that presents on the sun-damaged skin of elderly people. It requires a definitive diagnosis, from a high-grade sarcoma to a nonmesenchymal neoplasm. The recommended treatment protocol differs from similar histologically related tumors; thus, a diagnosis of atypical fibroxanthoma should fulfill strict histologic and immunohistochemical stain criteria. The use of these standards will exclude other skin malignancies, including malignant fibrous histiocytoma, angiosarcoma, malignant melanoma, and squamous cell carcinoma. This study was performed with the aim of identifying key immunostains to develop diagnostic criteria. MATERIALS AND METHODS: Forty-two cases were studied retrospectively over a 10-year period using a panel of immunostains. RESULTS: The average age at presentation was 78 years, with a male predominance. The scalp was found to be the most common site of occurrence, although other investigators have found the forehead, cheeks, nose, and ears as the prevailing sites of presentation. CONCLUSIONS: An extensive panel of immunohistochemical stains can be used to prove a diagnosis of atypical fibroxanthoma.