Service user satisfaction with telemedicine in an occupational healthcare setting.

BACKGROUND: Telemedicine has existed pre-pandemic and has been used in some healthcare settings with high patient satisfaction. The COVID-19 pandemic increased the use of telemedicine to help minimize transmission while maintaining service provision. AIMS: To assess service user satisfaction with telephone assessment and to assess distance/time saved by telephone assessment as services users did not have to travel to their appointment. METHODS: Prospective review of service users attending one occupational health clinic over a 1-month period. Service users were asked two questions regarding method of travel, and satisfaction with telephone review. All data captured were anonymous, and distances and times for travel were calculated for driving using Google Maps. RESULTS: Seventy-three service users were recruited to the review. Ninety per cent were reviewed by telephone and 10% reviewed in person. Eighty-eight per cent of service users were satisfied with telephone review. Seventy-eight per cent of service users planned to drive to Dr Steevens' Hospital. In total, 4058.4 km (77 h 6 min) of commuting was saved with phone reviews, and 2753.2 km (54 h 16 min) driving was saved. CONCLUSIONS: Service user satisfaction with telephone review was found to be high, and telephone review resulted in saving of both commuting time for the healthcare worker, reduced time away from the workplace, as well as having a positive environmental impact.

Resigning oneself to a life of wound-related odour - A thematic analysis of patient experiences.

AIMS: To determine how patients with chronic wounds describe wound odour, identify what strategies they use to manage it and how effective these are. MATERIALS AND METHODS: Using a qualitative descriptive approach, semi-structured interviews were conducted between July and August 2021 with seven patients living with an odorous chronic wound at home. Data were analysed using Braun and Clarke's thematic analysis framework. RESULTS: The results were organised into two main themes: 1) becoming resigned to living with wound-related odour 2) strategies used to manage wound-related odour. Participants were sad, embarrassed and felt isolated but became resigned to living with this odour and accepting of it as a consequence of having a wound. Frequent dressing changes, household cleaning along with the use of sprays were the most frequently used tactics to manage odour none of which were deemed to be very effective. CONCLUSION: This study highlights the problem of odour management in clinical practice and how individuals develop strategies to overcome odour. Sadly, patients were resigned to living with wound odour and were accepting of it as part of daily life. This highlights the importance for healthcare professionals to recognise, assess for and ensure a better understanding of how people experience wound odour, the impact it can have on them personally. Frequent dressing changes can help manage wound odour from the patient's perspective.

Systematic review of topical interventions for the management of odour in patients with chronic or malignant fungating wounds.

Chronic wounds adversely affect the quality of life of individuals and odour is a well-recognised associated factor. Odour can affect sleep, well-being, social interactions, diet and potentially wound healing. This systematic review aims to examine the effectiveness of topical interventions in the management of odour associated with chronic and malignant fungating wounds. A systematic review guided by PRISMA recommendations of randomised controlled trials where odour intensity/odour is the primary outcome was undertaken. Inclusion criteria were adults (18 years and over) with chronic venous, arterial, diabetic or pressure ulcers or with malignant fungating wounds where odour has been managed through topical application of pharmacological/non-pharmacological agents. Searches were conducted in CENTRAL, CINAHL, EMBASE, MEDLINE, Scopus, and Web of Science. Eligibility screening, risk of bias assessment and data extraction was completed by authors working independently. Searches retrieved 171 titles and abstracts (157 post de-duplication). Thirteen studies were retained for full text review of which five (n = 137 individuals) examining the following treatments remained: metronidazole (n = 4), silver (n = 1). Meta-analysis was not possible but individual studies suggest improved outcomes (i.e., reduced odour) using metronidazole. Treatment options to manage wound odour are limited and hampered by lack of clinical trials, small sample sizes, and absence of standardised outcomes and consistent measurement. Whereas metronidazole and silver may have a role in controlling wound odour, robust and well-designed interventions with rigorous procedures and standardised odour outcomes are necessary to evaluate their contribution.

Lifestyle factors and risk of sporadic colorectal cancer by microsatellite instability status: a systematic review and meta-analyses.

Introduction: The association of lifestyle factors with molecular pathological subtypes of colorectal cancer (CRC), such as microsatellite instability (MSI), could provide further knowledge about the colorectal carcinogenic process. The aim of this review was to evaluate possible associations between lifestyle factors and risk of sporadic CRC by MSI status. Methods: PubMed and Web of Science were searched for studies investigating the association between alcohol, body mass index, dietary fiber, hormone replacement therapy (HRT), non-steroidal anti-inflammatory drugs, physical activity, red meat, smoking, or statin use, with MSI-high (MSI-H) and microsatellite stable (MSS) CRC. Meta-analyses were carried out to calculate summary relative risks (sRR). Results: Overall, 31 studies reporting on the association between lifestyle factors and CRC according to MSI status were included in this review. Ever smoking was associated with MSI-H (sRR = 1.62; 95% CI: 1.40-1.88) and MSS/MSI-low CRC (sRR = 1.10; 95% CI: 1.01-1.20), but the association was significantly stronger for MSI-H CRC. The use of HRT was associated with a 20% decrease (sRR = 0.80; 95% CI: 0.73-0.89) in the risk of MSS CRC, but was not associated with MSI-H CRC. An increase in body mass index per 5 kg/m2 was equally associated with MSS and MSI-H CRC (sRR = 1.22, in both cases), but was statistically significant for MSS CRC only (95% CI: 1.11-1.34 and 0.94-1.58, respectively). Limited evidence for associations between other lifestyle factors and CRC by MSI status exists. Conclusions: Lifestyle factors, such as HRT and smoking are differentially associated with the risk of MSI-H and MSS CRC. Further research on associations of lifestyle factors and CRC subtypes is necessary to provide a better understanding of the CRC disease pathway.

Widespread prevalence of a CREBRF variant amongst Maori and Pacific children is associated with weight and height in early childhood.

OBJECTIVE: Investigating a large and ethnically diverse cohort from the Pacific region, we aimed to replicate and extend the recently reported findings that a CREBRF genetic variant is strongly associated with body mass index in Samoans. METHODS: A birth cohort of more than six thousand children was utilised. In this study, genotyping of two markers (rs12513649 and rs373863828) was undertaken in Maori, Pacific, European and Asian individuals in the cohort. RESULTS: We report that these CREBRF genetic variants are not confined to Samoans but are prevalent in all other Pacific populations sampled, including Maori. We found that the rs373863828 variant was significantly associated with growth at 4 years of age. On average, we observed allele-specific increases in weight (P=0·004, +455 g, s.e. 0.158), height (P=0·007, +0·70 cm, s.e. 0.26) and waist circumference (P=0·004, +0·70 cm, s.e. 0.24) at 4 years of age. The rs373863828 variant was not associated with birth weight (P=0·129). CONCLUSIONS: We replicated the finding that a CREBRF variant is associated with increased body mass. We then built on the original findings by demonstrating the prevalence of the rs12513649 and rs373863828 variants in multiple Pacific population groups and by demonstrating that the rs373863828 variant is associated with growth in early childhood. Pacific population groups experience a disproportionately high burden of obesity, starting in early childhood. This new knowledge offers potential for evidence-based interventions aimed at establishing healthy growth trajectories from the earliest possible age.

Vascular access device type for systemic anti-cancer therapies in cancer patients: A scoping review.

BACKGROUND: Patients with cancer can expect to receive numerous invasive vascular access procedures for intravenous therapy and clinical diagnostics. Due to the increased incidence and prevalence of cancer globally there will be significantly more people who require first-line intravenous chemotherapy over the next ten years. METHODS: Our objective was to determine the types of evidence that exist for the vascular access device (VAD) type for the delivery of systemic anti-cancer therapy (SACT) in cancer patients. We used JBI scoping review methodology to identify the types of VADs used for SACT and with a specific search strategy included articles from 2012-2022 published in the English language. We identify (i) type of VADs used for SACT delivery (ii) the type of insertion and post-insertion complications (iii) the geographical location and clinical environment (iv) and whether VAD choice impacts on quality of life (QOL). Findings were presented using the PAGER framework. MAIN FINDINGS: Our search strategy identified 10,390 titles, of these, 5318 duplicates were removed. The remaining 5072 sources were screened for eligibility, 240 articles met the inclusion criteria. The most common design include retrospective study designs (n = 91) followed by prospective study designs (n = 31). We found 28 interventional studies with 21 registered in a clinical trial registry and identified no core outcome sets papers specific to VAD for SACT. The most prevalent publications were those that featured two or more VAD types (n = 70), followed by tunnelled intravenous VADs (n = 67). Of 38 unique complications identified, the most frequent catheter related complication was catheter related thrombosis (n = 178, 74%), followed by infection (n = 170, 71%). The county where the most publications originated from was China (n = 62) with one randomized controlled multicenter study from a comprehensive cancer centre. Of the thirty three studies that included QOL we found 4 which reported on body image. No QOL measurement tools specific to the process of SACT administration via VAD are available INTERPRETATION: Our findings suggest a systematic review and meta-analysis of VAD use for intravenous SACT can be considered. However, the development of a core outcome set for SACT should be prioritised. Funding for high quality programs of research for VAD in cancer are needed. Comprehensive cancer centres should lead this research agenda.

Haplotype tagging for the identification of common disease genes.

Genome-wide linkage disequilibrium (LD) mapping of common disease genes could be more powerful than linkage analysis if the appropriate density of polymorphic markers were known and if the genotyping effort and cost of producing such an LD map could be reduced. Although different metrics that measure the extent of LD have been evaluated, even the most recent studies have not placed significant emphasis on the most informative and cost-effective method of LD mapping-that based on haplotypes. We have scanned 135 kb of DNA from nine genes, genotyped 122 single-nucleotide polymorphisms (SNPs; approximately 184,000 genotypes) and determined the common haplotypes in a minimum of 384 European individuals for each gene. Here we show how knowledge of the common haplotypes and the SNPs that tag them can be used to (i) explain the often complex patterns of LD between adjacent markers, (ii) reduce genotyping significantly (in this case from 122 to 34 SNPs), (iii) scan the common variation of a gene sensitively and comprehensively and (iv) provide key fine-mapping data within regions of strong LD. Our results also indicate that, at least for the genes studied here, the current version of dbSNP would have been of limited utility for LD mapping because many common haplotypes could not be defined. A directed re-sequencing effort of the approximately 10% of the genome in or near genes in the major ethnic groups would aid the systematic evaluation of the common variant model of common disease.

Conformational sampling, catalysis, and evolution of the bacterial phosphotriesterase.

To efficiently catalyze a chemical reaction, enzymes are required to maintain fast rates for formation of the Michaelis complex, the chemical reaction and product release. These distinct demands could be satisfied via fluctuation between different conformational substates (CSs) with unique configurations and catalytic properties. However, there is debate as to how these rapid conformational changes, or dynamics, exactly affect catalysis. As a model system, we have studied bacterial phosphotriesterase (PTE), which catalyzes the hydrolysis of the pesticide paraoxon at rates limited by a physical barrier-either substrate diffusion or conformational change. The mechanism of paraoxon hydrolysis is understood in detail and is based on a single, dominant, enzyme conformation. However, the other aspects of substrate turnover (substrate binding and product release), although possibly rate-limiting, have received relatively little attention. This work identifies "open" and "closed" CSs in PTE and dominant structural transition in the enzyme that links them. The closed state is optimally preorganized for paraoxon hydrolysis, but seems to block access to/from the active site. In contrast, the open CS enables access to the active site but is poorly organized for hydrolysis. Analysis of the structural and kinetic effects of mutations distant from the active site suggests that remote mutations affect the turnover rate by altering the conformational landscape.

Crystal structure of the N-terminal domain of the TyrR transcription factor responsible for gene regulation of aromatic amino acid biosynthesis and transport in Escherichia coli K12.

The X-ray structure of the N-terminal domain of TyrR has been solved to a resolution of 2.3 A. It reveals a modular protein containing an ACT domain, a connecting helix, a PAS domain and a C-terminal helix. Two dimers are present in the asymmetric unit with one monomer of each pair exhibiting a large rigid-body movement that results in a hinging around residue 74 of approximately 50 degrees . The structure of the dimer is discussed with reference to other transcription regulator proteins. Putative binding sites are identified for the aromatic amino acid cofactors.

An improved resolution structure of the human beta common receptor involved in IL-3, IL-5 and GM-CSF signalling which gives better definition of the high-affinity binding epitope.

X-ray diffraction has been used to produce and refine a model of the extracellular domains of the beta common cytokine receptor. A minor improvement in resolution has resulted in improved electron-density maps, which have given a clearer indication of the position and stabilization of the key residues Tyr15, Phe79, Tyr347, His349, Ile350 and Tyr403 in the elbow region between domain 1 and domain 4 of the dimer-related molecule.

The complex nature of constitutional de novo apparently balanced translocations in patients presenting with abnormal phenotypes.

OBJECTIVE: To describe the systematic analysis of constitutional de novo apparently balanced translocations in patients presenting with abnormal phenotypes, characterise the structural chromosome rearrangements, map the translocation breakpoints, and report detectable genomic imbalances. METHODS: DNA microarrays were used with a resolution of 1 Mb for the detailed genome-wide analysis of the patients. Array CGH was used to screen for genomic imbalance and array painting to map chromosome breakpoints rapidly. These two methods facilitate rapid analysis of translocation breakpoints and screening for cryptic chromosome imbalance. Breakpoints of rearrangements were further refined (to the level of spanning clones) using fluorescence in situ hybridisation where appropriate. RESULTS: Unexpected additional complexity or genome imbalance was found in six of 10 patients studied. The patients could be grouped according to the general nature of the karyotype rearrangement as follows: (A) three cases with complex multiple rearrangements including deletions, inversions, and insertions at or near one or both breakpoints; (B) three cases in which, while the translocations appeared to be balanced, microarray analysis identified previously unrecognised imbalance on chromosomes unrelated to the translocation; (C) four cases in which the translocation breakpoints appeared simple and balanced at the resolution used. CONCLUSIONS: This high level of unexpected rearrangement complexity, if generally confirmed in the study of further patients, will have an impact on current diagnostic investigations of this type and provides an argument for the more widespread adoption of microarray analysis or other high resolution genome-wide screens for chromosome imbalance and rearrangement.

Backbone dynamics of homologous fibronectin type III cell adhesion domains from fibronectin and tenascin.

BACKGROUND: Fibronectin type III domains are found as autonomously-folded domains in a large variety of multidomain proteins, including extracellular matrix proteins. A subset of these domains employ an Arg-Gly-Asp (RGD) tripeptide motif to mediate contact with cell-surface receptors (integrins). This motif mediates protein-protein interactions in a diverse range of biological processes, such as in tissue development, would healing and metastasis. The molecular basis for affinity and specificity of cell adhesion via type III domains has not been clearly established. The tenth type III domain from fibronectin (FNfn10) and the third type III domain from tenascin-C (TNfn3) have 27% sequence identity and share the same overall protein fold, but present the RGD motifs in different structural contexts. The dynamical properties of the RGD motifs may affect the specificity and affinity of the FNfn10 and TNfn3 domains. Structure-dynamics correlations for these structurally homologous proteins may reveal common molecular features which are important to the dynamical properties of proteins. RESULTS: The intramolecular dynamics of the protein backbones of FNfn10 and TNfn3 have been studied by 15N nuclear spin relaxation. The FG loop in FNfn10, which contains the RGD motif, exhibits extensive flexibility on picosecond to nanosecond timescales, but motions on microsecond to millisecond timescales are not observed. The equivalent region in TNfn3 is as rigid as regular elements of secondary structure. The CC' loop also is more flexible on picosecond-nanosecond timescales in FNfn10 than in TNfn3. Conformational exchange, reflecting flexibility on microsecond-millisecond timescales, is observed in beta strands A and B of both FNfn10 and TNfn3. CONCLUSIONS: Comparison of the structures of the FNfn10 and TNfn3 reveals several features related to their different dynamical properties. The larger amplitude motions of loops in FNfn10 are consistent with the hypothesis that flexibility of these regions facilitates induced-fit recognition of fibronectin by multiple receptors. Similarly, the more rigid loops of TNfn3 may reflect greater specificity for particular integrins. The correlations observed between structural features and dynamical properties of the homologous type III domains indicate the influence of hydrogen bonding and hydrophobic packing on dynamical fluctuations in proteins.

Chloroplast NADP-malate dehydrogenase: structural basis of light-dependent regulation of activity by thiol oxidation and reduction.

BACKGROUND: NADP-dependent malate dehydrogenase (EC 1.1.1.82) is a light-activated chloroplast enzyme that functions in the C4 pathway of photosynthesis. The light regulation is believed to be mediated in vivo by thioredoxin-catalyzed reduction and re-oxidation of cystine residues. The rates of reversible activation and inactivation of the enzyme are strongly influenced by the coenzyme substrates that seem to ultimately determine the steady-state extent of activation in vivo. RESULTS: The X-ray structure of the inactive, oxidized enzyme was determined at 2.8 A resolution. The core structure is homologous to AND-dependent malate dehydrogenases. Two surface-exposed and thioredoxin-accessible disulfide bonds are present, one in the N-terminal extension and the other in the C-terminal extension. The C-terminal peptide of the inactive, oxidized enzyme is constrained by its disulfide bond to fold into the active site over NADP+, hydrogen bonding to the catalytic His225 as well as obstructing access of the C4 acid substrate. Two loops flanking the active site, termed the Arg2 and Trp loops, that contain the C4 acid substrate binding residues are prevented from closing by the C-terminal extension. CONCLUSIONS: The structure explains the role of the C-terminal extension in inhibiting activity. The negative C terminus will interact more strongly with the positively charged nicotinamide of NADP+ than NADPH, explaining why the coenzyme-binding affinities of the enzyme differ so markedly from those of all other homologous alpha-hydroxy acid dehydrogenases. NADP+ may also slow dissociation of the C terminus upon reduction, providing a mechanism for the inhibition of activation by NADP+ but not NADPH.

Structure of the Escherichia coli signal transducing protein PII.

BACKGROUND: In Gram-negative proteobacteria, the nitrogen level in the cell is reflected by the uridylylation status of a key signal transducing protein, PII. PII modulates the activity of glutamine synthetase (GS) through its interaction with adenylyl transferase and it represses the expression of GS by acting in concert with nitrogen regulatory protein II. RESULTS: The three-dimensional structure of the Escherichia coli PII trimer has been determined at 2.7 A resolution. PII shows a low level of structural similarity to a broad family of alpha/beta proteins and contains a double beta alpha beta motif. The PII trimer contains three beta-sheets, each of which is composed of strands from each of the three monomers. These are surrounded by six alpha-helices. CONCLUSIONS: The structure of PII suggests potential regions of interaction with other proteins and serves as an initial step in understanding its signal transducing role in nitrogen regulation.

Nocardia infections in cats: a retrospective multi-institutional study of 17 cases.

OBJECTIVE: To record 17 cases of nocardiosis in cats from eastern Australia and to compare this series with cases previously reported. DESIGN: Retrospective/prospective study. RESULTS: Nocardia spp infections were diagnosed in 17 cats over 14 years from the three eastern states of Australia. There were no isolates from dogs during this period, but one isolate from a koala and two from dairy cows. The majority of cats presented with spreading lesions of the subcutis and skin associated with draining sinus tract(s). Early cutaneous lesions consisted of circumscribed abscesses. Infections spread at a variable rate, generally by extension to adjacent tissues. Lesions were generally located in regions subjected to cat bite or scratch injuries, including limbs, body wall, inguinal panniculus and nasal bridge. In some other cases, lesions were situated on distal extremities. The clinical course was variable, from chronic, indolent, initially localised infections to acute fulminating disease. Of the 17 cats, 14 were domestic crossbreds and three were purebreds. There was a preponderance of male cats (12 castrated, 1 entire young adult, 1 entire kitten). Nine of 17 cats were 10 years or older. Interestingly, the majority of infections were attributable to N nova. Immediate and/or predisposing causes could be identified in all cases, and included: renal transplantation [one cat]; chronic corticosteroid administration [three cats]; catabolic state following chylothorax surgery [one cat]; fight injuries [seven cats]; FIV infections [three of seven cats tested]. Of the 17 cats, three were apparently cured. Four were thought to be cured, but infection recurred after several months. Three cats responded partially but were euthanased, while another was improving when it died of unrelated complications. Two died despite treatment and two were euthanased without an attempt at therapy. For two cats there were either insufficient records or the patient was lost to follow up. CONCLUSION: Nocardiosis is a rare, serious disease. Currently it is more common in cats than dogs. Nocardial panniculitis may be clinically indistinguishable from the syndrome caused by rapidly growing mycobacteria. Although the prognosis is guarded, patients with localised infections caused by N nova often respond to appropriate therapy. If definitive treatment is delayed because of misdiagnosis, the disease tends to become chronic, extensive and refractory. Insufficient duration of therapy leads to disease recurrence.

Temperature dependence of intramolecular dynamics of the basic leucine zipper of GCN4: implications for the entropy of association with DNA.

The basic leucine zipper domain of the yeast transcription factor GCN4 consists of a C-terminal leucine zipper and an N-terminal basic DNA-binding region that achieves a stable structure only after association with DNA. Backbone dynamics of a peptide encompassing the basic and leucine zipper bZip domain (residues 226-281) are described using NMR spectroscopy. The 15N longitudinal relaxation rates, 15N transverse relaxation rates, and {1H}-15N nuclear Overhauser effects were measured for the backbone amide nitrogen atoms at 290 K, 300 K, and 310 K. The relaxation data were interpreted using reduced spectral density mapping to determine values of the spectral density function, J(omega), at the frequencies 0, omegaN, and 0.87omegaH to characterize overall and intramolecular motions on picosecond-nanosecond timescales. To account for the temperature dependence of overall rotational diffusion, the J(0) values were normalized using Stoke's Law. At 310 K, the 13Calpha and 13CO chemical shifts in conjunction with the spectral density values indicate that the leucine zipper sequence forms a highly ordered alpha-helix, while the basic region populates an ensemble of highly dynamic transient structures with substantial helical character. The normalized values of J(0) and the values of J(0.87omegaH) for residues in the leucine zipper dimerization domain are independent of temperature. In contrast, residues in the basic region exhibit pronounced increases in the normalized J(0) and decreases in J(0.87omegaH) as temperature is decreased. A strong correlation exists between the temperature dependence of 13CO chemical shifts and of J(0.87omegaH). These results suggest that, for the basic region, lowering the temperature increases the population of transient helical conformations, and concomitantly reduces the amplitude or timescale of conformational fluctuations on picosecond-nanosecond timescales. Changes in the conformational dynamics of the peptide backbone of the basic region that accompany DNA binding contribute to the overall thermodynamics of complex formation. The change in backbone conformational entropy derived from NMR spin-relaxation data agrees well with the result calculated from calorimetric measurements. Restriction of the conformational space accessible to the basic region may significantly reduce the entropic cost associated with formation of the basic region helices consequent to DNA binding.

The crystal structure of bikunin from the inter-alpha-inhibitor complex: a serine protease inhibitor with two Kunitz domains.

Bikunin is a serine protease inhibitor found in the blood serum and urine of humans and other animals. Its sequence shows internal repetition, suggesting that it contains two domains that resemble bovine pancreatic trypsin inhibitor (BPTI). A fragment of bikunin has been crystallised, its structure solved and subsequently refined against 2.5 A data. The two BPTI-like domains pack closely together and are related by an approximate 60 degrees rotation combined with a translation. These domains are very similar to each other and other proteins with this fold. The largest variations occur in the loops responsible for protease recognition. The loops of the first domain are unobstructed by the remaining protein. However, the loops of the second domain are close to the first domain and it is possible that protease binding may be affected or, in some cases, abolished by the presence of the first domain. Thus, cleavage of the two domains could alter the substrate specificity of domain II. Bikunin has a hydrophobic patch close to the N terminus of domain I, which is the most likely site for cell-surface receptor binding. In addition, there is a basic patch at one end of domain II that may be responsible for the inhibition of calcium oxalate crystallization in urine.

Crystallization and low temperature diffraction studies of the DNA binding domain of the single-stranded DNA binding protein from Escherichia coli.

The DNA binding domain of the single-stranded DNA binding protein from Escherichia coli has been overproduced, purified and crystallized in a form suitable for X-ray diffraction studies. Crystals were produced by dialysis against low ionic strength buffer at high pH. The crystals belong to space group I222 or I2(1)2(1)2(1) with a = 82.47 A, b = 65.27 A and c = 46.50 A. Data were collected at several temperatures and a significant improvement in data quality was observed with a decrease in temperature. On occasion, with the decrease in temperature, a transformation to a primitive space group was observed and temperature appears to play a key role in this transformation. A complete native data set has been collected to 2.57 A at -15 degrees C.