A proposed method of grading malaria chemoprevention efficacy.

The efficacy and effectiveness of antimalarial drugs are threatened by increasing levels of resistance and therefore require continuous monitoring. Chemoprevention is increasingly deployed as a malaria control measure, but there are no generally accepted methods of assessment. We propose a simple method of grading the parasitological response to chemoprevention (focusing on seasonal malaria chemoprevention) that is based on pharmacometric assessment.

Disease-specific wearable sensor algorithms for profiling activity, gait, and balance in individuals with Charcot-Marie-Tooth disease type 1A.

BACKGROUND/AIMS: Charcot-Marie-Tooth Disease type 1A (CMT1A), the most common inherited peripheral neuropathy, is characterized by progressive sensory loss and weakness, which results in impaired mobility. Increased understanding of the genetics and pathophysiology of CMT1A has led to development of potential therapeutic agents, necessitating clinical trial readiness. Wearable sensors may provide useful outcome measures for future trials. METHODS: Individuals with CMT1A and unaffected controls were recruited for this 12-month study. Participants wore sensors for in-clinic assessments and at-home, from which activity, gait, and balance metrics were derived. Mann-Whitney U tests were used to analyze group differences for activity, gait, and balance parameters. Test-retest reliability of gait and balance parameters and correlations of these parameters with clinical outcome assessments (COAs) were examined. RESULTS: Thirty individuals, 15 CMT1A, and 15 controls, participated. Gait and balance metrics demonstrated moderate to excellent reliability. CMT1A participants had longer step durations (p < .001), shorter step lengths (p = .03), slower gait speeds (p < .001), and greater postural sway (p < .001) than healthy controls. Moderate correlations were found between CMT-Functional Outcome Measure and step length (r = -0.59; p = .02), and gait speed (r = 0.64; p = .01); 11 out of 15 CMT1A participants demonstrated significant increases in stride duration between the first and last quarter of the 6-min walk test, suggesting fatigue. INTERPRETATION: In this initial study, gait and balance metrics derived from wearable sensors were reliable and associated with COAs in individuals with CMT1A. Larger longitudinal studies are needed to confirm our findings and evaluate sensitivity and utility of these disease-specific algorithms for clinical trial use.

Delivery Models and Health Economics of Supportive Care Services in England: A Multicentre Analysis.

AIMS: Improvements in cancer treatment have led to more people living with and beyond cancer. These patients have symptom and support needs unmet by current services. The development of enhanced supportive care (ESC) services may meet the longitudinal care needs of these patients, including at the end of life. This study aimed to determine the impact and health economic benefits of ESC for patients living with treatable but not curable cancer. MATERIALS AND METHODS: A prospective observational evaluation was undertaken over 12 months across eight cancer centres in England. ESC service design and costs were recorded. Data relating to patients' symptom burden were collected using the Integrated Palliative Care Outcome Scale (IPOS). For patients in the last year of life, secondary care use was compared against an NHS England published benchmark. RESULTS: In total, 4594 patients were seen by ESC services, of whom 1061 died during follow-up. Mean IPOS scores improved across all tumour groups. In total, £1,676,044 was spent delivering ESC across the eight centres. Reductions in secondary care usage for the 1061 patients who died saved a total of £8,490,581. CONCLUSIONS: People living with cancer suffer with complex and unmet needs. ESC services appear to be effective at supporting these vulnerable people and significantly reduce the costs of their care.

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.

Quantifying biomarkers of axonal degeneration in early glaucoma to find the disc at risk.

To evaluate regional axonal-related parameters as a function of disease stage in primary open angle glaucoma (POAG) and visual field (VF) sensitivity. Spectral domain optical coherence tomography was used to acquire 20° scans of POAG (n = 117) or healthy control (n = 52) human optic nerve heads (ONHs). Region specific and mean nerve fibre layer (NFL) thicknesses, border NFL and peripapillary NFL, minimum rim width (MRW)/ area (MRA) and prelamina thickness; and volume were compared across POAG disease stages and with visual field sensitivity. Differences identified between early glaucoma (EG), preperimetric glaucoma (PG) and control (C) ONHs included thinner PG prelamina regions than in controls (p < 0.05). Mean border NFL was thinner in EG (p < 0.001) and PG (p = 0.049) compared to control eyes; and EG mean, and inferior and ST, border NFL was thinner than in PG (p < 0.01). Mean, superior and inferior PG peripapillary NFL were thinner than in controls (p < 0.05), and EG ST peripapillary NFL was thinner than in PG (p = 0.023). MRW differences included: PG SN and inferior less than in controls (p < 0.05); thinner EG mean regional, inferior, nasal, and ST MRW versus PG MRW (p < 0.05). Regional border NFL, peripapillary NFL, MRW, MRA, prelamina thickness (except centre, p = 0.127) and prelamina volume (p < 0.05) were significantly associated with VF mean deviation (MD). Novel axon-derived indices hold potential as biomarkers to detect early glaucoma and identify ONHs at risk.

Routine screening for hepatitis C in pregnancy is cost-effective in a large urban population in Ireland: a retrospective study.

OBJECTIVE: To investigate whether risk factor-based screening in pregnancy is failing to identify women with hepatitis C virus (HCV) infection and to assess the cost-effectiveness of universal screening. DESIGN: Retrospective study and model-based economic evaluation. SETTING: Two urban tertiary referral maternity units, currently using risk factor-based screening for HCV infection. POPULATION: Pregnant women who had been tested for hepatitis B, HIV but not HCV. METHODS: Anonymised sera were tested for HCV antibody. Positive sera were tested for HCV antigen. A cost-effectiveness analysis of a change to universal screening was performed using a Markov model to simulate disease progression and Monte Carlo simulations for probabilistic sensitivity analysis. MAIN OUTCOME MEASURES: Presence of HCV antigen and cost per quality-adjusted life year (QALY). RESULTS: In all, 4655 samples were analysed. Twenty had HCV antibodies and five HCV antigen. This gives an active infection rate of 5/4655, or 0.11%, compared with a rate of 0.15% in the risk-factor group. This prevalence is 65% lower than a previous study in the same hospitals from 2001 to 2005. The calculated incremental cost-effectiveness ratio (ICER) for universal screening was €3,315 per QALY gained. CONCLUSION: This study showed that the prevalence of HCV infection in pregnant women in the Dublin region has declined by 65% over the past two decades. Risk factor-based screening misses a significant proportion of infections. A change to universal maternal screening for hepatitis C would be cost-effective in our population. TWEETABLE ABSTRACT: Universal maternal screening for hepatitis C is cost-effective in this urban Irish population.

A Short Report Examining the Introduction of Routine Use of Patient-Reported Outcome Measures in a Mixed Oncology Population.

AIMS: People living with treatable but not curable cancer often experience a range of symptoms related to their cancer and its treatment. During the COVID-19 pandemic, face-to-face consultations were reduced and so remote monitoring of these needs was necessary. University Hospitals Sussex implemented the routine use of electronic remote patient-reported outcome measures (PROMs) in a mixed oncology population, focusing on those with treatable but not curable cancers. MATERIALS AND METHODS: Over a 9-month period, patients were invited to register with My Clinical Outcomes (MCO) - a secure online platform for the collection of electronic PROMs. They were prompted by e-mail to complete assessments (EORTC QLQ-C30, EQ-5D-3L and EQ-5D VAS) routinely every 2 weeks. The team monitored patient scores and changes in these prompted clinical interventions. RESULTS: In total, 324 patients completed at least one assessment. The median number of assessments completed by each patient was eight. The most represented tumour groups were secondary breast (28%), prostate (25%) and other (32%). Median scores for the assessments did not deteriorate in a clinically or numerically significant way for patients living with non-curable conditions for the majority of patients monitored. CONCLUSION: Routine collection of electronic remote PROMs is an effective and useful strategy to provide real-time clinical feedback to teams. With integration into existing systems, online platforms (such as MCO) could provide efficient and patient-centred information for those providing care for people with cancer.

Using explainable machine learning to identify patients at risk of reattendance at discharge from emergency departments.

Short-term reattendances to emergency departments are a key quality of care indicator. Identifying patients at increased risk of early reattendance could help reduce the number of missed critical illnesses and could reduce avoidable utilization of emergency departments by enabling targeted post-discharge intervention. In this manuscript, we present a retrospective, single-centre study where we created and evaluated an extreme gradient boosting decision tree model trained to identify patients at risk of reattendance within 72 h of discharge from an emergency department (University Hospitals Southampton Foundation Trust, UK). Our model was trained using 35,447 attendances by 28,945 patients and evaluated on a hold-out test set featuring 8847 attendances by 7237 patients. The set of attendances from a given patient appeared exclusively in either the training or the test set. Our model was trained using both visit level variables (e.g., vital signs, arrival mode, and chief complaint) and a set of variables available in a patients electronic patient record, such as age and any recorded medical conditions. On the hold-out test set, our highest performing model obtained an AUROC of 0.747 (95% CI 0.722-0.773) and an average precision of 0.233 (95% CI 0.194-0.277). These results demonstrate that machine-learning models can be used to classify patients, with moderate performance, into low and high-risk groups for reattendance. We explained our models predictions using SHAP values, a concept developed from coalitional game theory, capable of explaining predictions at an attendance level. We demonstrated how clustering techniques (the UMAP algorithm) can be used to investigate the different sub-groups of explanations present in our patient cohort.

Global influence of mantle temperature and plate thickness on intraplate volcanism.

The thermochemical structure of lithospheric and asthenospheric mantle exert primary controls on surface topography and volcanic activity. Volcanic rock compositions and mantle seismic velocities provide indirect observations of this structure. Here, we compile and analyze a global database of the distribution and composition of Neogene-Quaternary intraplate volcanic rocks. By integrating this database with seismic tomographic models, we show that intraplate volcanism is concentrated in regions characterized by slow upper mantle shear-wave velocities and by thin lithosphere (i.e. <100 km). We observe a negative correlation between shear-wave velocities at depths of 125-175 km and melt fractions inferred from volcanic rock compositions. Furthermore, mantle temperature and lithospheric thickness estimates obtained by geochemical modeling broadly agree with values determined from tomographic models that have been converted into temperature. Intraplate volcanism often occurs in regions where uplifted (but undeformed) marine sedimentary rocks are exposed. Regional elevation of these rocks can be generated by a combination of hotter asthenosphere and lithospheric thinning. Therefore, the distribution and composition of intraplate volcanic rocks through geologic time will help to probe past mantle conditions and surface processes.

Laser ablation sample preparation for atom probe tomography and transmission electron microscopy.

Laser ablation is capable of removing large volumes of material with micron scale precision at very high speeds. This makes it an ideal tool for the initial stage of preparation of samples for atom probe and electron microscopy studies. However, the thermal nature of the laser ablation process is such that thermal and mechanical damage is induced in the samples in the form of zones of recrystallisation and stress induced deformation. For the analysis of nanometer-sized samples, such as those required for atom probe tomography and transmission electron microscopy, it is necessary to ensure that any damage induced during sample preparation will not introduce artefacts and that specimens are representative of the microstructure of the bulk sample. Here we have undertaken an analysis of the damage caused during sample preparation through a study of pure aluminium and phosphorous doped silicon wafers. Our findings indicate that recrystallisation and stress induced misorientations occur in pure aluminium at the micron scale, however, no detectable damage is observed in the silicon sample.

Changes in soil microbial communities in post mine ecological restoration: Implications for monitoring using high throughput DNA sequencing.

The ecological restoration of ecosystem services and biodiversity is a key intervention used to reverse the impacts of anthropogenic activities such as mining. Assessment of the performance of restoration against completion criteria relies on biodiversity monitoring. However, monitoring usually overlooks soil microbial communities (SMC), despite increased awareness of their pivotal role in many ecological functions. Recent advances in cost, scalability and technology has led to DNA sequencing being considered as a cost-effective biological monitoring tool, particularly for otherwise difficult to survey groups such as microbes. However, such approaches for monitoring complex restoration sites such as post-mined landscapes have not yet been tested. Here we examine bacterial and fungal communities across chronosequences of mine site restoration at three locations in Western Australia to determine if there are consistent changes in SMC diversity, community composition and functional capacity. Although we detected directional changes in community composition indicative of microbial recovery, these were inconsistent between locations and microbial taxa (bacteria or fungi). Assessing functional diversity provided greater understanding of changes in site conditions and microbial recovery than could be determined through assessment of community composition alone. These results demonstrate that high-throughput amplicon sequencing of environmental DNA (eDNA) is an effective approach for monitoring the complex changes in SMC following restoration. Future monitoring of mine site restoration using eDNA should consider archiving samples to provide improved understanding of changes in communities over time. Expansion to include other biological groups (e.g. soil fauna) and substrates would also provide a more holistic understanding of biodiversity recovery.

Reproductive seasonality and rate of increase of wild sambar deer (Rusa unicolor) in a new environment, Victoria, Australia.

Sambar (Rusa unicolor) are the most numerous and rapidly expanding of Australia's six introduced deer species, however, there is little information about the reproductive biology of sambar deer in their natural habitat. To better predict and manage wild sambar populations in Australia it is important to understand their reproductive seasonality and rate of population growth. From results of the present study, there is reporting of field estimates of age at first breeding, reproductive lifespan, juvenile survival, adult bodyweights and fecundity to derive estimates of the current and intrinsic rates of increase for sambar in Victoria, Australia. Mean age of first reproduction was estimated to be 1.8 years, approximately 80 % of hinds calved between April and August, juvenile survival was estimated as 0.81 and age of last reproduction 12.75 years. Seasonality of reproduction is apparently compressed at 36° latitude compared to sambar at the equator indicating a response to photoperiod. Demographic data were used to estimate the current rate of growth of the Victorian population using the two stage Lotke-Euler equation and age-specific schedules of survival and fecundity in a lifetable. These estimates of r were 0.21 and 0.14, respectively, inferring annual rates of population increase of 24 % and 15 %. These data are in the context of a population which, even though there is a marked harvesting, is reportedly growing and dispersing northwards. Suggestions for how this information can inform management decisions directed at the conservation for sustainable use and/or population reduction in Australia are made.

Real-time prediction of patient immune cell modulation during irreversible electroporation therapy.

Immunotherapies have demonstrated limited efficacy in pancreatic ductal adenocarcinoma (PDAC) patients despite their success in treating other tumor types. This limitation is largely due to the relatively immunosuppressive environment surrounding the tumor. A focal ablative technique called irreversible electroporation (IRE) has been shown to modulate this environment, enhancing the efficacy of immunotherapy. One enhancing factor related to improved prognosis is a decrease in regulatory T cells (Treg). This decrease has been previously unpredictable for clinicians using IRE, who currently have limited real-time metrics for determining the activation of the patient's immune response. Here, we report that larger overall changes in output current are correlated with larger decreases in T cell populations 24 hours post-treatment. This result suggests that clinicians can make real-time decisions regarding optimal follow-up therapy based on the range of output current delivered during treatment. This capability could maximize the immunomodulating effect of IRE in synergy with follow-up immunotherapy. Additionally, these results suggest that feedback from a preliminary IRE treatment of the local tumor may help inform clinicians regarding the timing and choice of subsequent therapies, such as resection, immunotherapy, chemotherapy, or follow-up thermal or non-thermal ablation.

The rise and fall of long-latency Plasmodium vivax.

Until World War II the only clinical phenotype of Plasmodium vivax generally recognised in medicine was one associated with either a long (8-9 months) incubation period or a similarly long interval between initial illness and the first relapse. Long-latency P. vivax 'strains' were the first in which relapse, drug resistance and pre-erythrocytic development were described. They were the infections in which primaquine radical cure dosing was developed. A long-latency 'strain' was the first to be fully sequenced. Although long-latency P. vivax is still present in some parts of Asia, North Africa and the Americas, in recent years it has been largely forgotten.

Combined Patellar Tendon lengthening and partial Extensor Mechanism Allograft reconstruction for the treatment of patella infera: A case report.

Patella infera is an uncommon but potentially crippling pathology of the knee, resulting in stiffness and anterior knee pain. Several surgical methods have been described for its treatment, but there remains no clear technique of choice. We present the case of a 63-year-old male with patella infera, affecting a native knee, following Complex Regional Pain Syndrome. This patient was treated with a combined technique of Patellar Tendon lengthening and partial Hourglass Extensor Mechanism Allograft reconstruction. The results were excellent at 24 months of follow-up. To our knowledge, this technique has not yet been published, and we present it as a promising treatment option in selected cases.

Increased valgus laxity in flexion with greater tibial resection depth following total knee arthroplasty.

PURPOSE: Soft tissue balancing is of central importance to outcome following total knee arthroplasty (TKA). However, there are lack of data analysing the effect of tibial bone cut thickness on valgus laxity. A cadaveric study was undertaken to assess the biomechanical consequences of tibial resection depth on through range knee joint valgus stability. We aimed to establish a maximum tibial resection depth, beyond which medial collateral ligament balancing becomes challenging, and a constrained implant should be considered. METHODS: Eleven cadaveric specimens were included for analysis. The biomechanical effects of increasing tibial resection were studied, with bone cuts made at 6, 10, 14, 18 and 24 mm from the lateral tibial articular surface. A computer navigation system was used to perform the tibial resection and to measure the valgus laxity resulting from a torque of 10 Nm. Measurements were taken in four knee positions: 0° or extension, 30°, 60° and 90° of flexion. Intra-observer reliability was assessed. A minimum sample size of eight cadavers was necessary. Statistical analysis was performed using a nonparametric Spearman's ranking correlation matrix at the different stages: in extension, at 30°, 60° and 90° of knee flexion. Significance was set at p < 0.05. RESULTS: There was no macroscopic injury to the dMCL or sMCL in any of the specimens during tibial resection. There was no significant correlation found between the degree of valgus laxity and the thickness of the tibial cut with the knee in extension. There was a statistically significant correlation between valgus laxity and the thickness of the tibial cut in all other knee flexion positions: 30° (p < 0.0001), 60° (p < 0.001) and 90° (p < 0.0001). We identified greater than 5° of valgus laxity, at 90° of knee flexion, after a tibial resection of 14 mm. CONCLUSION: Increased tibial resection depth is associated with significantly greater valgus laxity when tested in positions from 30° to 90° of flexion, despite stability in extension. Greater than 5° of laxity was identified with a tibial resection of 14 mm. When a tibial bone cut of 14 mm or greater is necessary, as may occur with severe preoperative coronal plane deformity, it is recommended to consider the use of a constrained knee prosthesis.

Region-Specific Microstructure in the Neonatal Ventricles of a Porcine Model.

The neonate transitions from placenta-derived oxygen, to supply from the pulmonary system, moments after birth. This requires a series of structural developments to divert more blood through the right heart and onto the lungs, with the tissue quickly remodelling to the changing ventricular workload. In some cases, however, the heart structure does not fully develop causing poor circulation and inefficient oxygenation, which is associated with an increase in mortality and morbidity. This study focuses on developing an enhanced knowledge of the 1-day old heart, quantifying the region-specific microstructural parameters of the tissue. This will enable more accurate mathematical and computational simulations of the young heart. Hearts were dissected from 12, 1-day-old deceased Yorkshire piglets (mass: 2.1-2.4 kg, length: 0.38-0.51 m), acquired from a breeding farm. Evans blue dye was used to label the heart equator and to demarcate the left and right ventricle free walls. Two hearts were used for three-dimensional diffusion-tensor magnetic resonance imaging, to quantify the fractional anisotropy (FA). The remaining hearts were used for two-photon excited fluorescence and second-harmonic generation microscopy, to quantify the cardiomyocyte and collagen fibril structures within the anterior and posterior aspects of the right and left ventricles. FA varied significantly across both ventricles, with the greatest in the equatorial region, followed by the base and apex. The FA in each right ventricular region was statistically greater than that in the left. Cardiomyocyte and collagen fibre rotation was greatest in the anterior wall of both ventricles, with less dispersion when compared to the posterior walls. In defining these key parameters, this study provides a valuable insight into the 1-day-old heart that will provide a valuable platform for further investigation the normal and abnormal heart using mathematical and computational models.

An investigation into the incidence of pain flare in patients undergoing radiotherapy for symptomatic bone metastases.

INTRODUCTION: External Beam Radiotherapy (EBRT) is a recognised intervention for symptomatic pain relief from bone metastases. Pain flare is a reported EBRT toxicity, described in 16-41% of steroid-naïve patients. This study aimed to determine incidence and duration of pain flare amongst patients within one Oncology Centre. METHODS: Patients receiving EBRT for bone metastases were recruited to a prospective cohort study. Baseline pain scores and a daily pain/analgesia diary were recorded during EBRT and for 14 days thereafter. Pain flare was defined as a two-point increase on a pain scale or 25% increase in analgesia intake, with a return to baseline. RESULTS: Of the thirty-two participants, 69% (n = 22) completed the diary. 41% (n = 9) patients experienced pain flare, the median duration being 3 days. Of the evaluable patients, 55% (n = 12) were male, 45% (n = 9) female. The median age was 73 years (range 40-83). The common primary sites of disease were Breast (32%) and Prostate (32%), with other sites making up the remaining 36%. The most frequent EBRT site was the spine (63%), with other treatment sites including pelvis (23%) and extremities (14%). EBRT regimes were restricted to 20 Gy in 5 treatments, received by 32% (n = 7) of patients and 8 Gy in 1 treatment (68% (n = 14)). Of these two regimes, pain flare was reported by 29% and 47% respectively. CONCLUSION: Pain flare is a common toxicity of EBRT for bone metastases. Taking the small sample size into consideration, the incidence and duration of pain flare in patients within this single-centre study are comparable with those found in international studies.