Impact of viral testing on duration of antibiotic treatment and hospitalisation of febrile infants.

AIM: To assess the duration of antimicrobial treatment; hospital length of stay; and invasive bacterial infections rates in hospitalised infants following the adoption of a management guideline. METHODS: Faculty agreed to a standard of 24 h of antibiotic treatment for well-appearing febrile infants with proven viral infection and no growth on bacterial cultures. The outcomes were the duration of hospitalisation and antibiotic treatment of febrile infants less than 8 weeks of age who have enterovirus, parechovirus, respiratory viruses detected. We monitored re-admissions and missed invasive infections. RESULTS: Of the total 1696 infants studied, the median antibiotic treatment duration decreased from 31.5 to 24.8 h in virus-infected infants ≤21 days of age (p = 0.02) and from 26 to 19.7 h in infants 22-56 days of age (p < 0.001). The decrease was less in infants not infected with a virus. No patient had an invasive infection identified after discharge. CONCLUSION: The implementation of our care standard resulted in reduction in antibiotic treatment duration without known delayed diagnosis of bacterial infections. Infants without a proven viral aetiology may need further study to inform management decisions.

A growth type pathway for improving the folding of BPTI.

The in vitro oxidative folding of the protein bovine pancreatic trypsin inhibitor (BPTI) with oxidized dithiothreitol or glutathione has served as a paradigm for protein folding but could take weeks at physiological pH because of the need to escape from kinetic traps via a rearrangement type pathway. The two major kinetic traps are called N' and N* and contain two of the three native disulfide bonds, which occur between residues 5 and 55, 30 and 51, and 14 and 38. N' is missing the disulfide bond between residues 5 and 55 while N* is missing the disulfide bond between residues 30 and 51. By determining rate constant for the reactions of the kinetic traps N* and N' and their mixed disulfides with glutathione and glutathione disulfide, many for the first time, we demonstrate that growth type pathways are feasible and could even be more efficient than rearrangement type pathways. Thus, formally unproductive pathways became productive. Interestingly, under physiological redox conditions both rearrangement and growth type pathways are important highlighting the redundancy of oxidative protein folding. With the new set of rate constants, modeling indicated that in vitro oxidative protein folding of BPTI via a growth type pathway using an oxidation, reduction and oxidation cycle would significantly improve protein folding efficiency, albeit under non-physiological redox conditions. With these changing conditions 91 ± 2% of native BPTI was achieved in 12 h compared to 83% native protein in 24 h using our previous best conditions of 5 mM GSSG and 5 mM GSH. Therefore, changing redox conditions via an oxidation, reduction and oxidation cycle may become an additional methodology for enhancing in vitro protein folding in aqueous solution.

Risk Factors for Deterioration Events in the Pediatric Acute Care Setting.

OBJECTIVES: Rapid response system (RRS) activations resulting in emergency transfers (ETs) and codes outside the ICU are associated with increased mortality and length of stay. We aimed to evaluate the patient and care team characteristics of RRS activations resulting in ETs and codes outside the ICU (together classified as "deterioration events") versus those that did not result in a deterioration event. METHODS: For each RRS activation at our institution from 2019 to 2021, data were gathered on patient demographics and medical diagnoses, care team and treatment factors, and ICU transfer. Descriptive statistics, bivariate analyses, and multivariable logistic regression using a backward elimination model selection method were performed to assess potential risk factors for deterioration events. RESULTS: Over the 3-year period, 1765 RRS activations were identified. Fifty-three (3%) activations were deemed acute care codes, 64 (4%) were noncode ETs, 921 (52%) resulted in nonemergent transfers to an ICU, and 727 (41%) patients remained in an acute care unit. In a multivariable model, any complex chronic condition (adjusted odds ratio, 6.26; 95% confidence interval, 2.83-16.60) and hematology/oncology service (adjusted odds ratio, 2.19; 95% confidence interval, 1.28-3.74) were independent risk factors for a deterioration event. CONCLUSIONS: Patients with medical complexity and patients on the hematology/oncology service had a higher risk of deterioration events than other patients with RRS activations. Further analyzing how our hospital evaluates and treats these specific patient populations is critical as we develop targeted interventions to reduce deterioration events.

Benchmarking non-attendance patterns in paediatric medical imaging: A retrospective cohort study spotlighting First Nations children.

INTRODUCTION: Non-attendance at Medical Imaging (MI) appointments can result in inefficiencies in healthcare resource allocation, increased financial burdens, and lead to potential barriers to effective healthcare delivery. We evaluated factors associated with non-attendance of MI appointments for children including variables: gender; age groups; residential postcodes; Indigenous status; appointment dates; appointment reminders and socio-economic status. METHOD: Retrospective cohort study of children with scheduled MI appointments at a Tertiary paediatric hospital in Australia, between January and December 2022. Data were extracted from the Radiology Information System and integrated with socio-economic census data through linking with postcode. Chi-squared, and logistic regression analysis were performed to identify significant predictors of non-attendance. RESULTS: Out of 17,962 scheduled outpatient appointments, 6.2 % did not attend. Males were less likely to attend than females (7.3 % vs. 5.8 %; p < 0.001). Older children had the highest frequency of non-attendance (p < 0.001). First Nations identified children had a higher likelihood of non-attendance at 14.5 % compared to non-First Nations at 5.8 %, and the odds ratio (OR) of First Nation children not attending was 2.54 (CI 2.13-3.03; p < 0.001) higher than non-First Nations children. Children from areas of disadvantage were less likely to attend (p < 0.001). Bone mineral densitometry had the highest odds of non-attendance (19.4 % of bookings) compared to other imaging modalities (p < 0.001). CONCLUSION: The following characteristics were associated with non-attendance: older male gender, residing in areas of socio-economic disadvantage, or identifying as First Nations Australians. By reviewing these findings with the cultural and professional experience of our Indigenous co-author, we have identified some strategies for improving attendance amongst First Nations children. IMPLICATIONS FOR PRACTICE: Factors associated with non-attendance, or "missed opportunities for care", provide opportunities for intervention to improve attendance for vulnerable groups of children who require medical imaging.

Histopathology and levels of proteins in plasma associate with survival after colorectal cancer diagnosis.

BACKGROUND: The TNM system is used to assess prognosis after colorectal cancer (CRC) diagnosis. Other prognostic factors reported include histopathological assessments of the tumour, tumour mutations and proteins in the blood. As some of these factors are strongly correlated, it is important to evaluate the independent effects they may have on survival. METHODS: Tumour samples from 2162 CRC patients were visually assessed for amount of tumour stroma, severity of lymphocytic infiltrate at the tumour margins and the presence of lymphoid follicles. Somatic mutations in the tumour were assessed for 2134 individuals. Pre-surgical levels of 4963 plasma proteins were measured in 128 individuals. The associations between these features and prognosis were inspected by a Cox Proportional Hazards Model (CPH). RESULTS: Levels of stroma, lymphocytic infiltration and presence of lymphoid follicles all associate with prognosis, along with high tumour mutation burden, high microsatellite instability and TP53 and BRAF mutations. The somatic mutations are correlated with the histopathology and none of the somatic mutations associate with survival in a multivariate analysis. Amount of stroma and lymphocytic infiltration associate with local invasion of tumours. Elevated levels of two plasma proteins, CA-125 and PPP1R1A, associate with a worse prognosis. CONCLUSIONS: Tumour stroma and lymphocytic infiltration variables are strongly associated with prognosis of CRC and capture the prognostic effects of tumour mutation status. CA-125 and PPP1R1A may be useful prognostic biomarkers in CRC.

Management of aseptic nonunions and severe bone defects: let us get this thing healed!

Effective nonunion and bone defect management requires consideration of multiple potential contributing factors including biomechanics, biology, metabolic, and patient factors. This article reviews these factors as well as several potential nonunion or bone defect treatments including bone grafts, bone graft substitutes, the induced membrane technique, and distraction osteogenesis. A summary of these concepts and guidelines for an overall approach to management are also provided.

A randomised controlled trial of compression therapies for the treatment of venous leg ulcers (VenUS 6): study protocol for a pragmatic, multicentre, parallel-group, three-arm randomised controlled trial.

BACKGROUND: Venous leg ulcer(s) are common, recurring, open wounds on the lower leg, resulting from diseased or damaged leg veins impairing blood flow. Wound healing is the primary treatment aim for venous leg ulceration, alongside the management of pain, wound exudate and infection. Full (high) compression therapy delivering 40 mmHg of pressure at the ankle is the recommended first-line treatment for venous leg ulcers. There are several different forms of compression therapy available including wraps, two-layer hosiery, and two-layer or four-layer bandages. There is good evidence for the clinical and cost-effectiveness of four-layer bandage and two-layer hosiery but more limited evidence for other treatments (two-layer bandage and compression wraps). Robust evidence is required to compare clinical and cost-effectiveness of these and to investigate which is the best compression treatment for reducing time to healing of venous leg ulcers whilst offering value for money. VenUS 6 will therefore investigate the clinical and cost-effectiveness of evidence-based compression, two-layer bandage and compression wraps for time to healing of venous leg ulcers. METHODS: VenUS 6 is a pragmatic, multi-centre, three-arm, parallel-group, randomised controlled trial. Adult patients with a venous leg ulcer will be randomised to receive (1) compression wraps, (2) two-layer bandage or (3) evidence-based compression (two-layer hosiery or four-layer bandage). Participants will be followed up for between 4 and 12 months. The primary outcome will be time to healing (full epithelial cover in the absence of a scab) in days since randomisation. Secondary outcomes will include key clinical events (e.g. healing of the reference leg, ulcer recurrence, ulcer/skin deterioration, amputation, admission/discharge, surgery to close/remove incompetent superficial veins, infection or death), treatment changes, adherence and ease of use, ulcer related pain, health-related quality of life and resource use. DISCUSSION: VenUS 6 will provide robust evidence on the clinical and cost-effectiveness of the different forms of compression therapies for venous leg ulceration. VenUS 6 opened to recruitment in January 2021 and is currently recruiting across 30 participating centres. TRIAL REGISTRATION: ISRCTN67321719 . Prospectively registered on 14 September 2020.

Exploring views of members of the public and policymakers on the acceptability of population level dietary and active-travel policies: a qualitative study.

BACKGROUND: There is limited evidence on what shapes the acceptability of population level dietary and active-travel policies in England. This information would be useful in the decision-making process about which policies should be implemented and how to increase their effectiveness and sustainability. To fill this gap, we explored public and policymakers' views about factors that influence public acceptability of dietary and active-travel policies and how to increase public acceptability for these policies. METHODS: We conducted online, semi-structured interviews with 20 members of the public and 20 policymakers in England. A purposive sampling frame was used to recruit members of the public via a recruitment agency, based on age, sex, socioeconomic status and ethnicity. Policymakers were recruited from existing contacts within our research collaborations and via snowball sampling. We explored different dietary and active-travel policies that varied in their scope and focus. Interviews were transcribed verbatim and analysed using thematic reflexive analysis with both inductive and deductive coding. RESULTS: We identified four themes that informed public acceptability of dietary and active-travel policies: (1) perceived policy effectiveness, i.e., policies that included believable mechanisms of action, addressed valued co-benefits and barriers to engage in the behaviour; (2) perceived policy fairness, i.e., policies that provided everyone with an opportunity to benefit (mentioned only by the public), equally considered the needs of various population subgroups and rewarded 'healthy' behaviours rather than only penalising 'unhealthy' behaviours; (3) communication of policies, i.e., policies that were visible and had consistent and positive messages from the media (mentioned only by policymakers) and (4) how to improve policy support, with the main suggestion being an integrated strategy addressing multiple aspects of these behaviours, inclusive policies that consider everyone's needs and use of appropriate channels and messages in policy communication. CONCLUSIONS: Our findings highlight that members' of the public and policymakers' support for dietary and active-travel policies can be shaped by the perceived effectiveness, fairness and communication of policies and provide suggestions on how to improve policy support. This information can inform the design of acceptable policies but can also be used to help communicate existing and future policies to maximise their adoption and sustainability.

Spatiotemporal characteristics of ozone and the formation sensitivity over the Fenwei Plain.

High surface ozone (O3) levels affect human and environmental health. The Fenwei Plain (FWP), one of the critical regions for China's "Blue Sky Protection Campaign", has reported severe O3 pollution. This study investigates the spatiotemporal properties and the causes of O3 pollution over the FWP using high-resolution data from the TROPOspheric Monitoring Instrument (TROPOMI) from 2019 to 2021. This study characterizes spatial and temporal variations in O3 concentration by linking O3 columns and surface monitoring using a trained deep forest machine learning model. O3 concentrations in summer were 2-3 times higher than those found in winter due to higher temperatures and greater solar irradiation. The spatial distributions of O3 correlate with the solar radiation showing decreased trends from the northeastern to the southwestern FWP, with the highest O3 values in Shanxi Province and the lowest in Shaanxi Province. For urban areas, croplands and grasslands, the O3 photochemistry in summer is NOx-limited or in the transitional regime, while it is VOC-limited in winter and other seasons. Reducing NOx emissions would be effective for decreasing O3 levels in summer, while VOC reductions are necessary for winter. The annual cycle in vegetated areas included both NOx-limited and transitional regimes, indicating the importance of NOx controls to protect ecosystems. The O3 response to limiting precursors shown here is of importance for optimizing control strategies and is illustrated by emission changes during the 2020 COVID-19 outbreak.

Phagocytosis increases an oxidative metabolic and immune suppressive signature in tumor macrophages.

Phagocytosis is a key macrophage function, but how phagocytosis shapes tumor-associated macrophage (TAM) phenotypes and heterogeneity in solid tumors remains unclear. Here, we utilized both syngeneic and novel autochthonous lung tumor models in which neoplastic cells express the fluorophore tdTomato (tdTom) to identify TAMs that have phagocytosed neoplastic cells in vivo. Phagocytic tdTompos TAMs upregulated antigen presentation and anti-inflammatory proteins, but downregulated classic proinflammatory effectors compared to tdTomneg TAMs. Single-cell transcriptomic profiling identified TAM subset-specific and common gene expression changes associated with phagocytosis. We uncover a phagocytic signature that is predominated by oxidative phosphorylation (OXPHOS), ribosomal, and metabolic genes, and this signature correlates with worse clinical outcome in human lung cancer. Expression of OXPHOS proteins, mitochondrial content, and functional utilization of OXPHOS were increased in tdTompos TAMs. tdTompos tumor dendritic cells also display similar metabolic changes. Our identification of phagocytic TAMs as a distinct myeloid cell state links phagocytosis of neoplastic cells in vivo with OXPHOS and tumor-promoting phenotypes.

Evaluation of vascular repair by tissue-engineered human acellular vessels or expanded polytetrafluoroethylene grafts in a porcine model of limb ischemia and reperfusion.

BACKGROUND: This study evaluated performance of a tissue-engineered human acellular vessel (HAV) in a porcine model of acute vascular injury and ischemia. The HAV is an engineered blood vessel consisted of human vascular extracellular matrix proteins. Limb reperfusion and vascular outcomes of the HAV were compared with those from synthetic expanded polytetrafluoroethylene (ePTFE) grafts. METHODS: Thirty-six pigs were randomly assigned to four treatment groups, receiving either the HAV or a PTFE graft following a hind limb ischemia period of either 0 or 6 hours. All grafts were 3-cm-long interposition 6-mm diameter grafts implanted within the right iliac artery. Animals were not immunosuppressed and followed for up to 28 days after surgery. Assessments performed preoperatively and postoperatively included evaluation of graft patency, hind limb function, and biochemical markers of tissue ischemia or reperfusion injury. Histological analysis was performed on explants to assess host cell responses. RESULTS: Postoperative gait assessment and biochemical analysis confirmed that ischemia and reperfusion injury were caused by 6-hour ischemia, regardless of vascular graft type. Hind limb function and tissue damage biomarkers improved in all groups postoperatively. Final patency rates at postoperative day 28 were higher for HAV than for ePTFE graft in both the 0-hour (HAV, 85.7%; ePTFE, 66.7%) and 6-hour (HAV, 100%; ePTFE, 75%) ischemia groups, but these differences were not statistically significant. Histological analyses identified some intimal hyperplasia and host reactivity to the xenogeneic HAV and also to the synthetic ePTFE graft. Positive host integration and vascular cell infiltration were identified in HAV but not ePTFE explants. CONCLUSION: Based on the functional performance and the histologic profile of explanted HAVs, this study supports further investigation to evaluate long-term performance of the HAV when used to repair traumatic vascular injuries.

Longitudinal Lung Function Assessment of Patients Hospitalized With COVID-19 Using 1H and 129Xe Lung MRI.

BACKGROUND: Microvascular abnormalities and impaired gas transfer have been observed in patients with COVID-19. The progression of pulmonary changes in these patients remains unclear. RESEARCH QUESTION: Do patients hospitalized with COVID-19 without evidence of architectural distortion on structural imaging exhibit longitudinal improvements in lung function measured by using 1H and 129Xe MRI between 6 and 52 weeks following hospitalization? STUDY DESIGN AND METHODS: Patients who were hospitalized with COVID-19 pneumonia underwent a pulmonary 1H and 129Xe MRI protocol at 6, 12, 25, and 51 weeks following hospital admission in a prospective cohort study between November 2020 and February 2022. The imaging protocol was as follows: 1H ultra-short echo time, contrast-enhanced lung perfusion, 129Xe ventilation, 129Xe diffusion-weighted, and 129Xe spectroscopic imaging of gas exchange. RESULTS: Nine patients were recruited (age 57 ± 14 [median ± interquartile range] years; six of nine patients were male). Patients underwent MRI at 6 (n = 9), 12 (n = 9), 25 (n = 6), and 51 (n = 8) weeks following hospital admission. Patients with signs of interstitial lung damage were excluded. At 6 weeks, patients exhibited impaired 129Xe gas transfer (RBC to membrane fraction), but lung microstructure was not increased (apparent diffusion coefficient and mean acinar airway dimensions). Minor ventilation abnormalities present in four patients were largely resolved in the 6- to 25-week period. At 12 weeks, all patients with lung perfusion data (n = 6) showed an increase in both pulmonary blood volume and flow compared with 6 weeks, although this was not statistically significant. At 12 weeks, significant improvements in 129Xe gas transfer were observed compared with 6-week examinations; however, 129Xe gas transfer remained abnormally low at weeks 12, 25, and 51. INTERPRETATION: 129Xe gas transfer was impaired up to 1 year following hospitalization in patients who were hospitalized with COVID-19 pneumonia, without evidence of architectural distortion on structural imaging, whereas lung ventilation was normal at 52 weeks.

Study of dielectric breakdown in liquid xenon with XeBrA: The xenon breakdown apparatus.

Maintaining the electric fields necessary for the current generation of noble liquid time projection chambers (TPCs), with drift lengths exceeding 1 m, requires a large negative voltage applied to their cathode. Delivering such high voltage is associated with an elevated risk of electrostatic discharge and electroluminescence, which would be detrimental to the performance of the experiment. The Xenon Breakdown Apparatus (XeBrA) is a 5-l, high voltage test chamber built to investigate the contributing factors to electrical breakdown in noble liquids. In this work, we present the main findings after conducting scans over stressed electrode areas, surface finish, pressure, and high voltage ramp speed in the medium of liquid xenon. Area scaling and surface finish were observed to be the dominant factors affecting breakdown, whereas no significant changes were observed with varying pressure or ramp speed. A general rise in both the anode current and photon rate was observed in the last 30 s, leading up to a breakdown, with a marked increase in the last couple of seconds. In addition, the position of breakdowns was reconstructed with a system of high-speed cameras and a moderate correlation with the Fowler-Nordheim field emission model was found. Tentative evidence for bubble nucleation being the originating mechanism of breakdown in the liquid was also observed. We deem the results presented in this work to be of particular interest for the design of future, large TPCs, and practical recommendations are provided.

Hybrid screw fixation for femoral neck fractures: Does it prevent mechanical failure?

INTRODUCTION: Traditionally, femoral neck fracture fixation has been performed using three partially threaded cancellous screws. However, fracture collapse with femoral neck shortening, and varus deformation frequently occurs due to posterior medial comminution and lack of calcar support. We hypothesize replacing the inferior neck/calcar screw with a fully threaded, length stable, screw will provide improved biomechanical stability, decrease femoral neck shortening and varus collapse. METHODS: Ten matched cadaveric pairs (20 femurs) were randomly assigned to two screw fixation groups. Group 1 (Hybrid) utilized one fully threaded calcar screw & two partially threaded superior screws. Group 2 (PT) utilized all partially threaded screws. Specimens underwent standardized femoral neck osteotomies, 45° from the horizontal, with 5 mm posteromedial wedge removed to simulate posteromedial comminution. Screws were placed using fluoroscopic guidance. Specimens were biomechanically tested using two loading sequences: 1) Axial load applied up to 700 N, followed by cyclic loading at 2 Hz with loads of 700 to 1,400 N for 10,000 cycles. 2) All surviving constructs were cyclically loaded to failure in stepwise incremental manner with max load of 4,000 N. Paired t-tests used to compare stiffness, cycles to failure, and max load to failure (defined as 15 mm load actuator displacement). RESULTS: Construct stiffness was 2848 ± 344 N/mm in PT vs. 2767 ± 665 for Hybrid (P = 0.628). Load to failure demonstrated, hybrid superiority with max cycles to failure (3797 ± 400 cycles) vs. (2981 ± 856 cycles in PT) (p = 0.010), and max load prior to failure (3290 ± 196 N) vs. (2891 ± 421 N in PT) (p = 0.010). No significant difference in bone mineral density was noted in any of the specimens. CONCLUSIONS: Our study is the first to assess the biomechanical effects of hybrid fixation for femoral neck fractures. Hybrid screw configuration resulted in significantly stronger constructs, with higher axial load and increased cycles prior to failure. The advantageous mechanical properties demonstrated using a fully threaded inferior calcar screw provides a length stable construct which may prevent the common complication of excessive femoral neck shortening, varus collapse and poor functional outcome.

The impact of malaria-protective red blood cell polymorphisms on parasite biomass in children with severe Plasmodium falciparum malaria.

Severe falciparum malaria is a major cause of preventable child mortality in sub-Saharan Africa. Plasma concentrations of P. falciparum Histidine-Rich Protein 2 (PfHRP2) have diagnostic and prognostic value in severe malaria. We investigate the potential use of plasma PfHRP2 and the sequestration index (the ratio of PfHRP2 to parasite density) as quantitative traits for case-only genetic association studies of severe malaria. Data from 2198 Kenyan children diagnosed with severe malaria, genotyped for 14 major candidate genes, show that polymorphisms in four major red cell genes that lead to hemoglobin S, O blood group, α-thalassemia, and the Dantu blood group, are associated with substantially lower admission plasma PfHRP2 concentrations, consistent with protective effects against extensive parasitized erythrocyte sequestration. In contrast the known protective ATP2B4 polymorphism is associated with higher plasma PfHRP2 concentrations, lower parasite densities and a higher sequestration index. We provide testable hypotheses for the mechanism of protection of ATP2B4.

Augmentation of Fracture Repair: Is Anything Ready for Prime Time?

There continues to be a significant burden of disease associated with the delayed healing of common fractures. Despite a number of trials focused on the augmentation of fracture repair, management remains controversial and evidence regarding cost-effectiveness is lacking. The recent evidence that has challenged traditional thinking regarding management of fracture healing problems will be evaluated.

Technical considerations for the management of segmental osseous defects with an internal bone transport nail.

INTRODUCTION: Traditionally, distraction osteogenesis has been accomplished with an external fixator. All internal transport utilizing magnetic intramedullary nails is a newer technique for bone reconstruction. The Precice Bone Transport Nail is a new implant that allows for noninvasive transport via a magnetically driven motor. AREAS COVERED: This report describes the function of the Bone Transport Nail along with the technical considerations on how to successfully manage bone defects with this new technology. Appropriate use of the nail, preoperative planning, intraoperative considerations, and postoperative management are discussed in detail. EXPERT OPINION: The Precice Bone Transport Nail utilizes the technology of the original Precice nail to provide an all-internal option for reconstruction of intercalary defects. This obviates the need for an additional plate with a standard Precice nail when performing bone transport and allows for a less invasive option that decreases operating room time. It provides a more cosmetic result than external fixation and avoids the risks of pin tract infection. Preoperative planning is essential to appropriate execution of the operative procedure and to perform a successful transport. A thorough understanding of the nail design and limitations are a prerequisite as this implant is significantly different from a standard intramedullary nail.