Host lifespan and the evolution of resistance to multiple parasites.

Hosts are typically challenged by multiple parasites, but to date theory on the evolution of resistance has mainly focused on single infections. We develop a series of models that examine the impact of multiple parasites on the evolution of resistance under the assumption that parasites coexist at the host population scale as a consequence of superinfection. In this way, we are able to explicitly examine the impact of ecological dynamics on the evolutionary outcome. We use our models to address a key question of how host lifespan affects investment in resistance to multiple parasites. We show that investment in costly resistance depends on the specificity of the immune response and on whether or not the focal parasite leads to more acute infection than the co-circulating parasite. A key finding is that investment in resistance always increases as the immune response becomes more general independently of whether it is the focal or the co-circulating parasite that exploits the host most aggressively. Long-lived hosts always invest more than short-lived hosts in both general resistance and resistance that is specific to relatively acute focal parasites. However, for specific resistance to parasites that are less acute than co-circulating parasites it is the short-lived hosts that are predicted to invest most. We show that these results apply whatever the mode of defence, that is whether it is through avoidance or through increased recovery, with or without acquired immunity, or through acquired immunity itself. As a whole, our results emphasize the importance of considering multiple parasites in determining optimal immune investment in eco-evolutionary systems.

Premixed vs basal-bolus insulin regimen in Type 2 diabetes: comparison of clinical outcomes from randomized controlled trials and real-world data.

AIM: To evaluate the concordance between data derived from randomized controlled trial (RCT) and real-world estimates of HbA1c and weight change after 24 weeks of initiation of a basal-bolus compared with a premixed insulin regimen in people with Type 2 diabetes. METHODS: Data eight RCTs were pooled after a systematic review of studies examining basal-bolus (n = 1893) or premixed (n = 1517) regimens. Real-world data were extracted from the UK primary care dataset for people on basal-bolus (n = 7483) or premixed insulin regimens (n=10 744). The mean differences between HbA1c and weight from baseline were calculated using t-tests, while analysis of variance was used to compare the two treatment regimens. Linear regression analyses were used to determine the predictors of this change. RESULTS: Both insulin regimens were associated with HbA1c reductions (real-world data -0.28%; RCT data, -1.4%) and weight gain (real-world data, +0.27 kg; RCT data, +2.96 kg) but there were no significant differences between basal-bolus and premixed insulin. Discordances in the pattern of treatment response were observed, however, between real-world and RCT data for both insulin regimens. For any given baseline HbA1c concentration, the change in HbA1c in the RCTs was greater than in real-world conditions and for those with baseline weight above ~60 kg, RCT data showed overall weight gain in contrast to slight weight loss in the real-world population. Lastly, for both randomized controlled trial and real-world populations, while greater baseline weight was associated with reduced response to treatment, the association was much steeper in the RCT than in the real-world population. In addition, greater baseline weight was associated with greater weight reductions in both premixed insulin and basal-bolus insulin regimens, although to a lesser extent with the latter. CONCLUSION: These results highlight specific discrepancies in the HbA1c reduction and weight change in insulin regimen between real world versus RCT populations; with greater reduction in HbA1c and greater increase in weight observed in the RCT population than in the real-world population. Also, the basal-bolus regimens in both real-world and RCT populations showed greater reduction in HbA1c compared to the premix regimen (though more marked in RCTs), while the premix regimen showed greater increase in weight in real-world, as against basal-bolus in the RCT population.

The epidemiological feedbacks critical to the evolution of host immunity.

We examine in detail how epidemiological feedbacks combine with costs and benefits to determine the evolution of resistance by systematically analysing continuously stable strategies (CSS) for different host-parasite frameworks. The mode of resistance (innate versus acquired), the nature of the host (i.e. life-history and immunological memory) and the nature of the disease (effects on fertility or mortality) all impact on the feedbacks that are critical to the evolution of resistance. By identifying relationships between CSS investment and the underlying epidemiological feedback for each mode of resistance in each framework, we distil complex feedbacks into simple combinations of selection pressures. When the parasite does not affect fertility, CSS investment reflects only the benefit of resistance and we explain why this is markedly different for innate and acquired resistance. If infection has no effect on host fertility, CSS investment in acquired immunity increases with the square of disease prevalence. While in contrast for evolving innate resistance, CSS investment is greatest at intermediate prevalence. When disease impacts fertility, only a fraction of the host population reproduce, and this introduces new ecological feedbacks to both the cost of resistance and the damage from infection. The multiple feedbacks in this case lead to the alternative result that the higher the abundance of infecteds, the higher the investment in innate resistance. A key insight is that maximal investment occurs at intermediate lifespans in a range of different host-parasite interactions, but for disparate reasons which can only be understood by a detailed analysis of the feedbacks. We discuss the extension of our approach to structured host populations and parasite community dynamics.

Modelling insertion behaviour of PVP (Polyvinylpyrrolidone) and PVA (Polyvinyl Alcohol) microneedles.

A comprehensive investigation into the effects of nonlinear material behaviour of polymeric (MN) and skin on the dynamics of the MN insertion in skin was undertaken in this study using experiments and numerical simulations. The nonlinearity of the material behaviour was incorporated by employing the Ramberg-Osgood and neo-Hookean equations for stress-strain relationships for the MN materials and skin, respectively. For this purpose, a characteristic type of dissolving MN array was selected. This type of MN is made by a combination of poly(vinyl alcohol) and poly(vinyl pyrrolidone). The numerical simulations were validated using experimental investigations where the MNs were fabricated using laser-engineered silicone micromould templates technology. Young's modulus, Poisson's ratio, and compression breaking force for the MN polymers were determined using a texture analyser. The alignment between experimental findings and simulation data underscores the accuracy of the parameters determined through mechanical testing and mathematical calculations for both MN materials (PVP/PVA) and skin behaviour during the MN insertion. This study has demonstrated a strong alignment between the experimental findings and computational simulations, confirming the accuracy of the established parameters for MNs and skin interactions for modelling MN insertion behaviour in skin, providing a solid foundation for future research in this area.

Seasonality selects for more acutely virulent parasites when virulence is density dependent.

Host condition is often likely to influence parasite virulence. Furthermore, condition may often be correlated with host density, and therefore, it is important to understand the role of density-dependent virulence (DDV). We examine the consequences of DDV to the evolution of parasites in both seasonal and non-seasonal environments. In particular, we consider seasonality in host birth rate that results in a fluctuating host density and therefore a variable virulence. We show that parasites are selected for lower exploitation, and therefore lower transmission and virulence as the strength of DDV increases without seasonality. This is an important insight from our models; DDV has the opposite effect on the evolution of parasites to that of higher baseline mortality. Our key result is that although seasonality does not affect the evolution of virulence in classical models, with DDV parasites in seasonal environments are predicted to evolve to be more acute. This suggests that in more seasonal environments wildlife disease is likely to be more rather than less virulent if DDV is widespread.

Optimal immune defence in the light of variation in lifespan.

There is good evidence for costs to both the uses of immune defences and their development and maintenance. The optimal defence will be a balance of these costs with the risk of infection and the virulence of the disease. It is therefore clear that the life-history characteristics of both host and parasite will impact the optimal level of defence, and that this may in part explain the variation in immune defence against different pathogens and parasites. For instance, it has traditionally been suggested that long-lived hosts should invest in immune memory. Ecological evolutionary theory can be used to examine in detail how different host characteristics will affect the optimal immune response that evolves. Here, we review theoretical studies on the impact of host lifespan on various immune defence characteristics including acquired immunity and highlight the importance of population-level epidemiological feedbacks on the outcome. In particular, we discuss when longer-lived hosts may invest less in acquired immunity and develop new theory to highlight the importance of the mechanism of host population regulation to the outcome. We finish by discussing where more theory is needed and how comparative and experimental studies may test the theory.

Incidence of cerebrovascular accident following head and neck free tissue transfer surgery.

The aim of this study was to determine the incidence of postoperative cerebrovascular accident (CVA) following head and neck free tissue transfer and to identify predictive risk factors. A retrospective audit was performed of patients who underwent head and neck reconstructive surgery at Queen Elizabeth University Hospital between 2009 and 2020. The patient records were analysed to identify those who developed CVA within 30 days after surgery. A total of 1109 patients underwent head and neck free tissue transfer surgery, including 1048 neck dissection procedures. Of these, 78.6% had one or more identified risk factors for perioperative stroke. Five patients (0.45%) developed postoperative CVA. The results showed that CVA correlated to patients with hypercholesterolemia (P = 0.007). This study demonstrates the safety of free tissue transfer. Despite underlying co-morbidities and risk factors, the incidence of CVA is low following surgery and manipulation of the major vasculature of the neck.

Distinct and overlapping genomic profiles and antiviral effects of Interferon-λ and -α on HCV-infected and noninfected hepatoma cells.

Recently, several SNPs in the region of the IL28B (IFN-λ) gene have been associated with spontaneous clearance of hepatitis C virus (HCV) and enhanced cure rates for IFN-alfa-based therapies, suggesting a potential correlation between IFN-λ and the ability to clear HCV. To understand the mechanism of IFN-λ's as compared to IFN-α's antiviral activity, we performed a comprehensive analysis of their anti-HCV effects, whole genome transcriptome profiling with validation, and signalling of IFN-α and IFN-λ using J6/JFH-1 and Huh7.5 cells in vitro. IFN-λ and IFN-α exhibited comparable anti-HCV activity and gene expression profiles in Huh7.5 cells. While the majority of genes induced by IFN-α and IFN-λ were similar, IFN-λ exhibits profound, but delayed kinetics of IFN-stimulated genes (ISG) induction, while IFN-α induced more rapid induction of ISGs. Furthermore, the increased induction of ISG expression by IFN-λ correlated with up-regulation of IFN-λ receptor (IL-28RA) expression and more prolonged activation of the Jak-STAT signalling pathway. The findings from our comparative analysis of IFN-α and IFN-λ in HCV-infected and noninfected cells support the clinical use of IFN-λ as a potential alternative to IFN-α in the treatment of chronic hepatitis C.

Assessment of lower limb microcirculation: exploring the reproducibility and clinical application of laser Doppler techniques.

PURPOSE OF STUDY: Non-invasive laser Doppler fluximetry (LDF) and laser Doppler imaging (LDI), combined with iontophoresis, have been used to study the microcirculation in a range of clinical conditions including lower limb venous disease. A prerequisite for an accurate measurement tool is that it is reproducible. However, there is currently no literature with respect to the reproducibility of LDF and LDI combined with iontophoresis in the lower limb (in general) and in the upright position (in specific). Furthermore, the two techniques have been used interchangeably by researchers and the association between these two different measurement methods has not been explored, nor have the factors that affect them been well described. Thus the aim of this study was to determine the reproducibility of LDF and LDI with iontophoresis in the lower limb and investigate factors that influence their clinical application. PROCEDURES: Cutaneous microvascular responses in the lower limb were measured in the supine and standing positions using LDF and LDI combined with iontophoretic administration of endothelial-dependent (acetylcholine, ACh) and -independent (sodium nitroprusside) vasodilators in 25 patients with uncomplicated isolated superficial venous incompetence (ISVI) and 26 healthy controls. RESULTS: Maximum perfusion had the best reproducibility assessed by LDF (CV 20.5-24.3%) and LDI (15.8-17.6%). Both techniques were positively influenced by iontophoretic dose (e.g. p = 0.0001 for LDF) and the use of vasodilator agents (e.g. p = 0.0001 for LDF), but negatively influenced in the standing position and/or in the presence of ISVI (p = 0.0016 and 0.045, respectively, for LDF). There was a statistically significant positive relationship between the two techniques, for example ACh maximum perfusion versus LDF ACh maximum perfusion (r = 0.404, p = 0.016). CONCLUSIONS: Both techniques are reproducible, in line with similar studies undertaken in other areas of the human body, and provide useful information for the study of the lower-limb microcirculation. Direct comparison between techniques based on absolute numbers should be avoided and the technique choice should be based on individual study needs.

Association of mutations in a lysosomal protein with classical late-infantile neuronal ceroid lipofuscinosis.

Classical late-infantile neuronal ceroid lipofuscinosis (LINCL) is a fatal neurodegenerative disease whose defective gene has remained elusive. A molecular basis for LINCL was determined with an approach applicable to other lysosomal storage diseases. When the mannose 6-phosphate modification of newly synthesized lysosomal enzymes was used as an affinity marker, a single protein was identified that is absent in LINCL. Sequence comparisons suggest that this protein is a pepstatin-insensitive lysosomal peptidase, and a corresponding enzymatic activity was deficient in LINCL autopsy specimens. Mutations in the gene encoding this protein were identified in LINCL patients but not in normal controls.

Exenatide compared with long-acting insulin to achieve glycaemic control with minimal weight gain in patients with type 2 diabetes: results of the Helping Evaluate Exenatide in patients with diabetes compared with Long-Acting insulin (HEELA) study.

AIM: The Helping Evaluate Exenatide in overweight patients with diabetes compared with Long-Acting insulin (HEELA) study was designed to examine whether the glucagon-like peptide-1 (GLP-1) receptor agonist, exenatide, could improve HbA1c (< or =7.4%) with minimal weight gain (< or =1 kg) compared with insulin glargine. METHODS: Patients [body mass index (BMI) >27 kg/m(2)] with elevated cardiovascular risk and type 2 diabetes inadequately controlled on two or three oral antidiabetes drugs (OADs) were randomized to add-on exenatide 5-10 microg b.i.d. (n = 118) or insulin glargine o.d. (titrated to target fasting plasma glucose < or =5.6 mmol/l; n = 117) for 26 weeks. RESULTS: The study population had baseline mean (s.d.) age of 56.5 (9.1) years and BMI of 34.1 (5.3) kg/m(2), and 58.5% of patients were taking two OADs. Mean baseline HbA1c was 8.65 (0.68)% in the exenatide group and 8.48 (0.66)% in the insulin glargine group. The proportions of patients achieving the composite endpoint of HbA1c < or =7.4% with weight gain < or =1 kg were 53.4% for the exenatide group and 19.8% for the insulin glargine group (p < 0.001 for exenatide vs. insulin glargine). Exenatide and insulin glargine did not demonstrate a significant difference in HbA1c improvements [least square (LS) mean [s.e.m.]: -1.25 [0.09]% and -1.26 [0.09]% respectively; p = 0.924], but had divergent effects on body weight (-2.73 [0.31] vs. +2.98 [0.31] kg respectively, p < 0.001) after 26 weeks. There were more treatment-related adverse events with exenatide but a lower incidence of nocturnal hypoglycaemia, with no differences in overall or severe hypoglycaemia. CONCLUSIONS: Additional treatment with exenatide resulted in significantly more overweight and obese patients with an elevated cardiovascular risk and type 2 diabetes achieving better glycaemic control with minimal weight gain compared with insulin glargine.

Partial restoration of impaired interleukin-2 production and Tac antigen (putative interleukin-2 receptor) expression in patients with acquired immune deficiency syndrome by isoprinosine treatment in vitro.

The in vitro effects of isoprinosine (ISO) on interleukin-2 (IL-2) production, the expression of Tac antigen (IL-2 receptor) on lymphocytes, and the ability of Leu 3(+) cells to absorb interleukin-1 (IL-1) were investigated in 10 patients with acquired immune deficiency syndrome (AIDS). In 9 of the 10 patients, production of IL-2 from mononuclear cells and Leu 3(+) cells was depressed; expression of Tac antigen on mononuclear cells and Leu 2(+) cells was found to be depressed in 9 of 10 patients. The ability of the Leu 3(+) lymphocytes to absorb IL-1 was depressed in all (four of four) patients studied. After ISO treatment, IL-2 production, Tac antigen expression and IL-1 absorption were restored to normal or near normal levels in most of the patients. These results suggest that ISO has an immunostimulating capacity in AIDS patients and that the potential of ISO in immune response restoration in AIDS patients deserves critical consideration.

Does temporal artery biopsy influence the management of temporal arteritis?

BACKGROUND: Temporal arteritis (TA) is the commonest form of primary vasculitis. Symptoms are variable, and therefore the diagnosis (or exclusion) of TA is often difficult. Surgeons are frequently asked to perform a temporal artery biopsy (TAB), but whether the histological result actually influences clinical management is unclear. AIM: To assess whether, in routine clinical practice, a TAB affects clinical decision-making in patients with suspected TA. DESIGN: Retrospective audit. METHODS: All patients who underwent a TAB in a single hospital over a 2-year period were identified. This included patients referred from different specialist departments. Individual patient records were examined to document the TAB result, and in particular, the timings of commencement and discontinuation of corticosteroid therapy. RESULTS: A total of 44 patients were included. TAB was positive in seven patients and negative in 37. In 31, there was no change in their clinical management despite a negative biopsy result: 18 continued with corticosteroids for >6 months with a clinical diagnosis of TA, and in 13 patients a decision to stop steroids, or an alternative diagnosis, was made before the biopsy result was known. DISCUSSION: In this retrospective study, only a small number of TABs provided positive histological confirmation of TA, and in most patients undergoing TAB, there was little evidence that clinical decision-making with respect to corticosteroid therapy was influenced by the TAB result.

Drug-Induced Diabetes Mellitus: Evidence for Statins and Other Drugs Affecting Glucose Metabolism.

Abnormalities of glucose metabolism and glucose tolerance, either because of a reduction in tissue sensitivity to insulin (e.g., in liver, skeletal muscle, and adipose tissues) and/or a reduction in pancreatic insulin secretion, are associated with a number of unwanted health outcomes. Even small increases in circulating glucose levels (often described as dysglycemia or prediabetes) may confer an increased risk of cardiovascular (CV) disease and progression to overt type 2 diabetes. A number of drug therapies, many of them used long term in chronic disease management, have adverse effects on glucose metabolism, diabetes risk, and glycemic control among patients with preexisting diabetes. In this study, we review the evidence, underlying mechanisms, and the clinical significance of drug-related adverse effects on glucose metabolism.

Comparison of cardiovascular and metabolic outcomes in people with type 2 diabetes on insulin versus non-insulin glucose-lowering therapies (GLTs): A systematic review and meta-analysis of clinical trials.

OBJECTIVES: To compare the cardiovascular and metabolic outcomes of Insulin versus non-insulin glucose lowering therapy (GLT). METHODS: We included randomised control trials (RCTs) which randomised patients aged >18years with Type 2 Diabetes (T2D) to insulin vs non-insulin GLT. We used risk ratios (RR), risk difference (RD) and odds ratios (OR) with 95% confidence interval (95%CI) to analyse the treatment effects of dichotomous outcomes and mean differences (with 95% CI) for continuous outcomes. RESULTS: We included 18 RCTs with 19,300 participants. There was no significant difference in the risk of all-cause mortality and CV events between the groups (RR=1.01; 95%CI: 0.96-1.06; p=0.69). In 16 trials, insulin showed greater efficacy in glycaemic control (mean diff=-0.20; 95%CI: -0.28 to -0.11) but the proportion achieving HbA1c level of either ⩽7.0% or 7.4% (53 or 57mmol/mol) was similar in both (OR=1.55; 95%CI=0.92-2.62). The non-insulin group had a significant reduction in weight (mean diff=-3.41; 95%CI: -4.50 to -2.32) and an increase in the proportion of adverse events (54.7% vs 45.3%, p=0.044), but the insulin group showed an (RR=1.90; 95%CI: 1.44-2.51) increased risk of hypoglycaemia. CONCLUSION: There was no difference in the risk of all-cause mortality and adverse cardiovascular (CV) events between Insulin and non-insulin GLTs. Insulin was associated with superior reduction in HbA1c; least reduction in weight and higher risk of hypoglycaemia. Both showed similar proportion of patients achieving HbA1c target. Non-insulin GLTs were associated with a higher risk in reported adverse drug events.

Nutritional management in head and neck cancer: United Kingdom National Multidisciplinary Guidelines.

Nutritional support and intervention is an integral component of head and neck cancer management. Patients can be malnourished at presentation, and the majority of patients undergoing treatment for head and neck cancer will need nutritional support. This paper summarises aspects of nutritional considerations for this patient group and provides recommendations for the practising clinician. Recommendations • A specialist dietitian should be part of the multidisciplinary team for treating head and neck cancer patients throughout the continuum of care as frequent dietetic contact has been shown to have enhanced outcomes. (R) • Patients with head and neck cancer should be nutritionally screened using a validated screening tool at diagnosis and then repeated at intervals through each stage of treatment. (R) • Patients at high risk should be referred to the dietitian for early intervention. (R) • Offer treatment for malnutrition and appropriate nutrition support without delay given the adverse impact on clinical, patient reported and financial outcomes. (R) • Use a validated nutrition assessment tool (e.g. scored Patient Generated-Subjective Global Assessment or Subjective Global Assessment) to assess nutritional status. (R) • Offer pre-treatment assessment prior to any treatment as intervention aims to improve, maintain or reduce decline in nutritional status of head and neck cancer patients who have malnutrition or are at risk of malnutrition. (G) • Patients identified as well-nourished at baseline but whose treatment may impact on their future nutritional status should receive dietetic assessment and intervention at any stage of the pathway. (G) • Aim for energy intakes of at least 30 kcal/kg/day. As energy requirements may be elevated post-operatively, monitor weight and adjust intake as required. (R) • Aim for energy and protein intakes of at least 30 kcal/kg/day and 1.2 g protein/kg/day in patients receiving radiotherapy or chemoradiotherapy. Patients should have their weight and nutritional intake monitored regularly to determine whether their energy requirements are being met. (R) • Perform nutritional assessment of cancer patients frequently. (G) • Initiate nutritional intervention early when deficits are detected. (G) • Integrate measures to modulate cancer cachexia changes into the nutritional management. (G) • Start nutritional therapy if undernutrition already exists or if it is anticipated that the patient will be unable to eat for more than 7 days. Enteral nutrition should also be started if an inadequate food intake (60 per cent of estimated energy expenditure) is anticipated for more than 10 days. (R) • Use standard polymeric feed. (G) • Consider gastrostomy insertion if long-term tube feeding is necessary (greater than four weeks). (R) • Monitor nutritional parameters regularly throughout the patient's cancer journey. (G) • Pre-operative: ○ Patients with severe nutritional risk should receive nutrition support for 10-14 days prior to major surgery even if surgery has to be delayed. (R) ○ Consider carbohydrate loading in patients undergoing head and neck surgery. (R) • Post-operative: ○ Initiate tube feeding within 24 hours of surgery. (R) ○ Consider early oral feeding after primary laryngectomy. (R) • Chyle Leak: ○ Confirm chyle leak by analysis of drainage fluid for triglycerides and chylomicrons. (R) ○ Commence nutritional intervention with fat free or medium chain triglyceride nutritional supplements either orally or via a feeding tube. (R) ○ Consider parenteral nutrition in severe cases when drainage volume is consistently high. (G) • Weekly dietetic intervention is offered for all patients undergoing radiotherapy treatment to prevent weight loss, increase intake and reduce treatments interruptions. (R) • Offer prophylactic tube feeding as part of locally agreed guidelines, where oral nutrition is inadequate. (R) • Offer nutritional intervention (dietary counselling and/or supplements) for up to three months after treatment. (R) • Patients who have completed their rehabilitation and are disease free should be offered healthy eating advice as part of a health and wellbeing clinic. (G) • Quality of life parameters including nutritional and swallowing, should be measured at diagnosis and at regular intervals post-treatment. (G).

Dynamics in insulin requirements and treatment safety.

AIMS: The majority of insulin users have elevated HbA1c. There is growing recognition that the low success rates are due to variations in insulin requirements. Thus, frequent dosage adjustments are needed. In practice, adjustments occur sporadically due to limited provider availability. We investigated intra-individual dynamics of insulin requirements using data from a service evaluation of the d-Nav® Insulin Guidance Service. This service facilitates automated insulin dosage adjustments, as often as needed, to achieve and maintain optimal glycemic balance. METHODS: Data were collected from subjects who have been using the service for more than a year. Events of considerable and persistent decrease in insulin requirements were identified by drops in total daily insulin ≥25%. RESULTS: Overall, 62 patients were studied over an average period of 2.1±0.5 (mean±standard deviation) years. Stability in HbA1c was attained after ~3 quarters at 7.4%±0.2% (57.4mmol/mol±1mmol/mol). Events were identified in 56.5% of the patients. On average, each affected patient had 0.8±0.4 events per year, lasting 9.7±6.6weeks, while total daily insulin dosage decreased by 41.4±13.4%. CONCLUSIONS: Our findings may call attention to a major contributing factor to hypoglycemia among insulin users. In reality, insulin dosage is seldom adjusted and thus transient periods of decrease in insulin requirements and overtreatment are usually overlooked.