The impact of peritoneal dialysis on oxypurinol and urate elimination in people with gout.

Gout affects 15%-30% of individuals with advanced kidney disease. Allopurinol which is rapidly and extensively metabolised to an active metabolite, oxypurinol, is the most commonly prescribed urate-lowering therapy. Oxypurinol is almost entirely eliminated by the kidneys (>95%) and has an elimination half-life of 18-30 h in those with normal kidney function. However, oxypurinol pharmacokinetics are poorly understood in individuals with kidney failure on peritoneal dialysis. This study characterised the elimination of oxypurinol and urate in people with gout receiving peritoneal dialysis. Oxypurinol steady-state oral clearance (CL/F), elimination half-life as well as kidney (CLk) and peritoneal (CLpd) clearances for oxypurinol and urate were calculated from the plasma, urine and dialysate concentration data for each individual. Our results demonstrate that oxypurinol and urate are removed by peritoneal dialysis, accounting for more than 50% of oxypurinol and urate clearances. An allopurinol dose about 50%-60% lower than the usual dose used for a patient with normal kidney function will provide adequate urate-lowering therapy.

Purcell-enhanced single photons at telecom wavelengths from a quantum dot in a photonic crystal cavity.

Quantum dots are promising candidates for telecom single photon sources due to their tunable emission across the different low-loss telecommunications bands, making them compatible with existing fiber networks. Their suitability for integration into photonic structures allows for enhanced brightness through the Purcell effect, supporting efficient quantum communication technologies. Our work focuses on InAs/InP QDs created via droplet epitaxy MOVPE to operate within the telecoms C-band. We observe a short radiative lifetime of 340 ps, arising from a Purcell factor of 5, owing to integration of the QD within a low-mode-volume photonic crystal cavity. Through in-situ control of the sample temperature, we show both temperature tuning of the QD's emission wavelength and a preserved single photon emission purity at temperatures up to 25K. These findings suggest the viability of QD-based, cryogen-free C-band single photon sources, supporting applicability in quantum communication technologies.

Geographical differences in the financial impacts of different forms of tobacco licence fees on small retailers in Scotland.

OBJECTIVE: Retailer licencing fees are a promising avenue to regulate tobacco availability. However, they face strong opposition from retailers and the tobacco industry, who argue significant financial impacts. This study compares the impacts of different forms of tobacco licence schemes on retailers' profits in Scotland. METHODS: We calculated gross profits from tobacco sales in 179 convenience stores across Scotland using 1 099 697 electronic point-of-sale records from 16 weeks between 2019 and 2022. We estimated different fees using universal, volumetric and separate urban/rural schemes. We identified the point at which 50% of retailers would no longer make a gross profit on tobacco sales for each scheme and modelled the financial impact of 10 incremental fee levels. The financial impact was assessed based on changes in retailers' tobacco gross profits. Differences by neighbourhood deprivation and urban/rural status were examined. RESULTS: The gross profit from tobacco per convenience store averaged £15 859/year. Profits were 2.29 times higher in urban (vs rural) areas and 1.59 times higher in high-deprivation (vs low-deprivation) areas, attributable to higher sales volumes. Tobacco gross profit decreased proportionally with increasing fee levels. Universal and urban/rural fees had greater gross profit reductions in rural and/or less deprived areas, where profits were lower, compared with volumetric fees. CONCLUSION: The introduction of tobacco licence fees offers a potential opportunity for reducing the availability of tobacco retailers. The likely impact of a tobacco licence fee is sensitive to the type of licence scheme implemented, the level at which fees are set and the retailers' location in relation to neighbourhood deprivation and rurality.

Estimation of integrated price elasticities for alcohol and tobacco in the United Kingdom using the living costs and food survey 2006-2017.

INTRODUCTION: Evidence shows that price is an important policy lever in reducing consumption of alcohol and tobacco. However, there is little evidence of the cross-price effect between alcohol and tobacco. METHODS: This paper uses an econometric model which estimates participation and consumption elasticities, on data from the UK Living Costs and Food Survey 2006-2017 and extends the literature by, for the first time, estimating joint price elasticities for disaggregated alcohol and tobacco products. This paper presents new price elasticities and compares them to the existing literature. RESULTS: The own-price elasticity estimates are all negative for both participation and consumption. There is no pattern to the estimates of cross-price elasticities. The elasticity estimates, when used in the Sheffield Tobacco and Alcohol Policy Model, produce bigger changes in consumption for the same change in price compared to other elasticity estimates in the existing literature. DISCUSSION AND CONCLUSIONS: Consumption of alcohol and tobacco are affected by the prices of one another. Policymakers should bear this in mind when devising alcohol or tobacco pricing policies.

Does cutting down on your food consumption lead to a net improvement in nutritional intake? A panel data approach using data from the UK Biobank.

BACKGROUND: Food diets are complex and a policy targeting one item of a person's diet does not affect their nutritional intake in a solely additive or subtractive manner. Policies tackling unhealthy diets are more likely to be adopted by governments if there is robust evidence to support them. To evaluate dietary policies, it is important to understand the correlations and interdependencies between food groups, as these can lead to unintended negative consequences. We aimed to see whether reductions in consumption of a particular group is related to a net improvement in nutritional intake, after taking into account patterns of consumption and substitution across food groups. METHODS: Detailed dietary data was collected using a 24-h online dietary assessment from the UK Biobank and Oxford Web Q (n = 185,611). We used panel data fixed effects methods to estimate changes in energy, saturated fat, total sugar, and fibre following a 100gram reduction across 44 food groups. We compare these estimates against the average nutritional value of that food group from the UK National Diet and Nutrition Survey. RESULTS: We find evidence of variation in whether a food is compensated between the main confectionery products. Crisps, savoury snacks, and sugar confectionery are less likely to be compensated, whereas chocolate confectionery, biscuits, and buns/cakes/pastries and pies are compensated. The result is particularly striking for chocolate confectionery which shows that while chocolate confectionery often has a high energy content, eating less chocolate confectionery is not associated with an equal reduction in energy. Instead, we find individuals switch or compensate for their reduction in chocolate confectionery consumption with other high energy food items. CONCLUSIONS: We find that sugar confectionery and crisps and savoury snacks are less likely to result in substitution than chocolate confectionery. This would suggest that food policies aiming to reduce the consumption of these food groups are more likely to result in overall lower consumption of unhealthy foods.

Mapping alcohol and tobacco tax policy interventions to inform health and economic impact analyses: A United Kingdom based qualitative framework analysis.

BACKGROUND: Alcohol and tobacco have different policy regimes and there is little understanding of how changes to policy on each commodity might combine to affect the same outcomes or to affect people who both drink and smoke. The aim of this study was to deepen understanding of the policy objectives of UK alcohol and tobacco tax options being considered at the time of the interviews with a set of UK policy participants in 2018, and the factors affecting the implementation and outcomes of the policy options discussed. METHODS: Ten tax policy experts were recruited from government arms-length organisations and advocacy groups in England and Scotland (4 alcohol, 4 tobacco, 2 alcohol and tobacco). Alcohol and tobacco experts were interviewed together in pairs and asked to discuss alcohol and tobacco tax policy objectives, options, and the mechanisms of effect. Interviews were semi-structured, supported by a briefing document and topic guide, audio-recorded, transcribed and then analysed deductively using framework analysis. RESULTS: Alcohol and tobacco tax policy share objectives of health improvement and there is a common set of policy options: increasing duty rates, duty escalators, multi-rate tax structures, industry levies and the hypothecation of tax revenue for investment in societal benefits. However, participants agreed that the harms caused by alcohol and tobacco and their industries are viewed differently, and that this influences the impacts that are prioritised in tax policymaking. Working-out how alcohol and tobacco taxes could work synergistically to reduce health inequalities was seen as desirable. Participants also highlighted the importance of avoiding the combined effects of price increases on alcohol and tobacco widening economic inequalities. CONCLUSIONS: Impact analyses should consider the combined effects of alcohol and tobacco tax policies on health and economic inequalities, and how the effects of changes to the tax on each commodity might trade-off.

An Improved Method for Estimating Nephron Number and the Association of Resulting Nephron Number Estimates with Chronic Kidney Disease Outcomes.

SIGNIFICANCE STATEMENT: Nephron number currently can be estimated only from glomerular density on a kidney biopsy combined with cortical volume from kidney imaging. Because of measurement biases, refinement of this approach and validation across different patient populations have been needed. The prognostic importance of nephron number also has been unclear. The authors present an improved method of estimating nephron number that corrects for several biases, resulting in a 27% higher nephron number estimate for donor kidneys compared with a prior method. After accounting for comorbidities, the new nephron number estimate does not differ between kidney donors and kidney patients with tumor and shows consistent associations with clinical characteristics across these two populations. The findings also indicate that low nephron number predicts CKD independent of biopsy and clinical characteristics in both populations. BACKGROUND: Nephron number can be estimated from glomerular density and cortical volume. However, because of measurement biases, this approach needs refinement, comparison between disparate populations, and evaluation as a predictor of CKD outcomes. METHODS: We studied 3020 living kidney donors and 1354 patients who underwent radical nephrectomy for tumor. We determined cortex volume of the retained kidney from presurgical imaging and glomerular density by morphometric analysis of needle core biopsy of the donated kidney and wedge sections of the removed kidney. Glomerular density was corrected for missing glomerular tufts, absence of the kidney capsule, and then tissue shrinkage on the basis of analysis of 30 autopsy kidneys. We used logistic regression (in donors) and Cox proportional hazard models (in patients with tumor) to assess the risk of CKD outcomes associated with nephron number. RESULTS: Donors had 1.17 million nephrons per kidney; patients with tumor had 0.99 million nephrons per kidney. A lower nephron number was associated with older age, female sex, shorter height, hypertension, family history of ESKD, lower GFR, and proteinuria. After adjusting for these characteristics, nephron number did not differ between donors and patients with tumor. Low nephron number (defined by <5th or <10th percentile by age and sex in a healthy subset) in both populations predicted future risk of CKD outcomes independent of biopsy and clinical characteristics. CONCLUSIONS: Compared with an older method for estimating nephron number, a new method that addresses several sources of bias results in nephron number estimates that are 27% higher in donors and 1% higher in patients with tumor and shows consistency between two populations. Low nephron number independently predicts CKD in both populations.

Physiological relationship between cardiorespiratory fitness and fitness for surgery: a narrative review.

Epidemiological evidence has highlighted a strong relationship between cardiorespiratory fitness and surgical outcomes; specifically, fitter patients possess heightened resilience to withstand the surgical stress response. This narrative review draws on exercise and surgical physiology research to discuss and hypothesise the potential mechanisms by which higher fitness affords perioperative benefit. A higher fitness, as indicated by higher peak rate of oxygen consumption and ability to sustain metabolic homeostasis (i.e. higher anaerobic threshold) is beneficial postoperatively when metabolic demands are increased. However, the associated adaptations with higher fitness, and the related participation in regular exercise or physical activity, might also underpin the observed perioperative benefit through a process of hormesis, a protective adaptive response to the moderate and intermittent stress of exercise. Potential mediators discussed include greater antioxidant capacity, metabolic flexibility, glycaemic control, lean body mass, and improved mood.

High-intensity interval aerobic and resistance training to counteract low relative lean soft tissue mass in middle age: A randomized controlled trial.

BACKGROUND: Age-related loss of skeletal muscle mass and function begins in early middle age, yet research to date has focused on older individuals, limiting our understanding of interventions earlier in the lifespan. To date, no high-intensity interval training studies have been conducted in middle-aged adults with low relative lean soft tissue mass. METHODS: Eighty-two middle-aged adults (40-50 years of age) with low appendicular lean soft tissue mass index confirmed with dual energy x-ray absorptiometry (DXA) were randomly allocated (1:1) to group-based, 20-week, three times a week, high-intensity aerobic and resistance training (HIART) program or 60-min education session (Control). The primary outcome was change in total lean soft tissue mass measured by DXA. Secondary outcomes included cardiorespiratory fitness, physical function (handgrip strength, gait speed, 30-seconds sit-to-stand, quadriceps strength and muscle quality). Measures were obtained at baseline (0 weeks), mid-intervention (10 weeks) and post-intervention (20 weeks). RESULTS: Mean age in HIART was 44.8 (SD 3.2) and 45.4 (SD 2.9) in Control group. The majority of the participants were female with 88 % in HIART and 83 % in Control group. Mean BMI in HIART was 25.8 kg/m2 (SD 3.5) and 26.4 kg/m2 (SD 4.1) Control group. Intention to treat analysis showed that post-intervention, HIART increased significantly more total lean soft tissue mass (0.8 kg, 95%CI 0.15, 1.46), appendicular lean soft tissue mass index (0.2 kg/m2, 95%CI 0.09, 0.33), peak oxygen uptake (5.18 mL/min/kg, 2.97 to 7.39 95%CI), grip strength (2.2 kg, 95%CI 0.09, 4.32), and 30-s sit-to-stand (1.3 times, 95%CI 0.43, 2.12) with significantly greater reductions in body fat percentage (-1.1 %, 95%CI -2.03, -0.10) and maximum gait speed (-0.2 m/s, 95 % CI -0.34, -0.03) compared Control. CONCLUSION: The HIART program is an effective exercise intervention to increase total lean soft tissue mass in middle-aged adults with low relative lean soft tissue mass compared to a waitlist control group.

Self-regulation training for people with knee osteoarthritis: a protocol for a feasibility randomised control trial (MiNT trial).

Introduction: Knee osteoarthritis (OA) is a chronic secondary musculoskeletal pain condition resulting in disability, reduced quality of life, and high societal costs. Pain associated with knee OA is linked to increased sensitivity in sensory, cognitive, and emotional areas of the brain. Self-regulation training targeting brain functioning related to pain experience could reduce pain and its associated disability. Self-regulatory treatments such as mindfulness meditation (MM) and electroencephalography neurofeedback (EEG-NF) training improve clinical outcomes in people with knee OA. A feasibility clinical trial can address factors that could inform the design of the full trial investigating the effectiveness of self-regulation training programmes in people with knee OA. This clinical trial will evaluate the feasibility, safety, acceptability, experience and perceptions of the self-regulatory training programmes. Methods: The proposed feasibility trial is based on a double-blind (outcome assessor and investigators), three-arm (MM usual care, EEG-NF + usual care and usual care control group) randomised controlled parallel clinical trial. Participants with knee OA will be recruited from the community and healthcare practices. A research assistant (RA) will administer both interventions (20-min sessions, four sessions each week, and 12 sessions over three successive weeks). Feasibility measures (participant recruitment rate, adherence to interventions, retention rate), safety, and acceptability of interventions will be recorded. An RA blinded to the group allocation will record secondary outcomes at baseline, immediately post-intervention (4th week), and 3 months post-intervention. The quantitative outcome measures will be descriptively summarised. The qualitative interviews will evaluate the participants' experiences and perceptions regarding various aspects of the trial, which includes identifying the barriers and facilitators in participating in the trial, evaluating their opinions on the research procedures, such as their preferences for the study site, and determining the level of acceptability of the interventions as potential clinical treatments for managing knee OA. Maori participant perceptions of how assessment and training practices could be acceptable to a Maori worldview will be explored. The interviews will be audio-recorded and analysed thematically. Discussion: This trial will provide evidence on the feasibility, safety, and acceptability of the MM and EEG-NF training in people with knee OA, thus informing the design of a full randomised clinical control trial.

Carotid body hyperexcitability underlies heat-induced hyperventilation in exercising humans.

Physical activity is the most common source of heat strain for humans. The thermal strain of physical activity causes overbreathing (hyperventilation) and this has adverse physiological repercussions. The mechanisms underlying heat-induced hyperventilation during exercise are unknown, but recent evidence supports a primary role of carotid body hyperexcitability (increased tonic activity and sensitivity) underpinning hyperventilation in passively heated humans. In a repeated-measures crossover design, 12 healthy participants (6 female) completed two low-intensity cycling exercise conditions (25% maximal aerobic power) in randomized order, one with core temperature (TC) kept relatively stable near thermoneutrality, and the other with progressive heat strain to +2°C TC. To provide a complete examination of carotid body function under graded heat strain, carotid body tonic activity was assessed indirectly by transient hyperoxia, and its sensitivity estimated by responses to both isocapnic and poikilocapnic hypoxia. Carotid body tonic activity was increased by 220 ± 110% during cycling alone, and by 400 ± 290% with supplemental thermal strain to +1°C TC, and 600 ± 290% at +2°C TC (interaction, P = 0.0031). During exercise with heat stress at both +1°C and +2°C TC, carotid body suppression by hyperoxia decreased ventilation below the rates observed during exercise without heat stress (P < 0.0147). Carotid body sensitivity was increased by up to 230 ± 190% with exercise alone, and by 290 ± 250% with supplemental heating to +1°C TC and 510 ± 470% at +2°C TC (interaction, P = 0.0012). These data indicate that the carotid body is further activated and sensitized by heat strain during exercise and this largely explains the added drive to breathe.NEW & NOTEWORTHY Physical activity is the most common way humans increase their core temperature, and excess breathing in the heat can limit heat tolerance and performance, and may increase the risk of heat-related injury. Dose-dependent increases in carotid body tonic activity and sensitivity with core heating provide compelling evidence that carotid body hyperexcitability is the primary cause of heat-induced hyperventilation during exercise.

Adjunct Methods for the Detection of Patent Foramen Ovale: The Contribution of Transcranial Doppler and the Valsalva Manoeuvre.

A patent foramen ovale (PFO) is present in 25% of the population. In some patients, especially those without traditional stroke risk factors and with no immediately apparent cause, a cryptogenic stroke may be caused by an embolus passing through the PFO to the systemic circulation. The identification, or indeed exclusion, of a PFO is sought in these patients, most commonly using contrast-enhanced transthoracic or transoesophageal echocardiography. Another method for detecting a PFO is transcranial Doppler, which allows the detection of PFO possibly without the need for an echo laboratory, and with arguably improved sensitivity. This review will focus on transcranial Doppler detection of PFO, with a brief summary of echocardiographic techniques and the use of ultrasound contrast agents, and the role of provocations to increase diagnostic accuracy, specifically the Valsalva manoeuvre. We discuss the phases alongside the direct and indirect signs of an adequate Valsalva manoeuvre.

Contribution of the carotid body to thermally mediated hyperventilation in humans.

Humans hyperventilate under heat and cold strain. This hyperventilatory response has detrimental consequences including acid-base dysregulation, dyspnoea, decreased cerebral blood flow and accelerated brain heating. The ventilatory response to hypoxia is exaggerated under whole-body heating and cooling, indicating that altered carotid body function might contribute to thermally mediated hyperventilation. To address whether the carotid body might contribute to heat- and cold-induced hyperventilation, we indirectly measured carotid body tonic activity via hyperoxia, and carotid body sensitivity via hypoxia, under graded heat and cold strain in 13 healthy participants in a repeated-measures design. We hypothesised that carotid body tonic activity and sensitivity would be elevated in a dose-dependent manner under graded heat and cold strain, thereby supporting its role in driving thermally mediated hyperventilation. Carotid body tonic activity was increased in a dose-dependent manner with heating, reaching 175% above baseline (P < 0.0005), and carotid body suppression with hyperoxia removed all of the heat-induced increase in ventilation (P = 0.9297). Core cooling increased carotid body activity by up to 250% (P < 0.0001), but maximal values were reached with mild cooling and thereafter plateaued. Carotid body sensitivity to hypoxia was profoundly increased by up to 180% with heat stress (P = 0.0097), whereas cooling had no detectable effect on hypoxic sensitivity. In summary, cold stress increased carotid body tonic activity and this effect was saturated with mild cooling, whereas heating had clear dose-dependent effects on carotid body tonic activity and sensitivity. These dose-dependent effects with heat strain indicate that the carotid body probably plays a primary role in driving heat-induced hyperventilation. KEY POINTS: Humans over-breathe (hyperventilate) when under heat and cold stress, and though this has detrimental physiological repercussions, the mechanisms underlying this response are unknown. The carotid body, a small organ that is responsible for driving hyperventilation in hypoxia, was assessed under incremental heat and cold strain. The carotid body drive to breathe, as indirectly assessed by transient hyperoxia, increased in a dose-dependent manner with heating, reaching 175% above baseline; cold stress similarly increased the carotid body drive to breathe, but did not show dose-dependency. Carotid body sensitivity, as indirectly assessed by hypoxic ventilatory responses, was profoundly increased by 70-180% with mild and severe heat strain, whereas cooling had no detectable effect. Carotid body hyperactivity and hypersensitivity are two interrelated mechanisms that probably underlie the increased drive to breathe with heat strain, whereas carotid body hyperactivity during mild cooling may play a subsidiary role in cold-induced hyperventilation.

Engineering Chiral Light-Matter Interactions in a Waveguide-Coupled Nanocavity.

Spin-dependent, directional light-matter interactions form the basis of chiral quantum networks. In the solid state, quantum emitters commonly possess circularly polarized optical transitions with spin-dependent handedness. We demonstrate numerically that spin-dependent chiral coupling can be realized by embedding such an emitter in a waveguide-coupled nanocavity, which supports two near-degenerate, orthogonally polarized cavity modes. The chiral behavior arises due to direction-dependent interference between the cavity modes upon coupling to two single-mode output waveguides. Notably, an experimentally realistic cavity design simultaneously supports near-unity chiral contrast, efficient (>95%) cavity-waveguide coupling and enhanced light-matter interaction strength (Purcell factor F P > 70). In combination, these parameters enable the development of highly coherent spin-photon interfaces ready for integration into nanophotonic circuits.

The impact of increasing the United Kingdom national minimum wage on self-reported health.

There is a growing but mixed literature on the health effects of minimum wages. If minimum wage changes have a statistically significant impact on health, this suggests health effects should be incorporated into cost-benefit analyses to capture wider policy impacts. Whilst most existing UK based literature examines the introduction of a minimum wage, this paper exploits the 2016, 2017 and 2018 UK National Minimum Wage (NMW) increases as natural experiments using a series of difference-in-differences models. Short Form-12 (SF-12) mental and physical component summary scores are used as dependent variables. In the base case and all sensitivity analyses, the estimated impact of NMW increases on mental and physical health are insignificant. The policy implication is that health effects should not be included in cost-benefit analyses examining the NMW.

Does the intact nephron hypothesis provide a reasonable model for metformin dosing in chronic kidney disease?

This research explored the intact nephron hypothesis (INH) as a model for metformin dosing in patients with chronic kidney disease (CKD). The INH assumes that glomerular filtration rate (GFR) will account for all kidney drug handling even for drugs eliminated by tubular secretion like metformin. We conducted two studies: (1) a regression analysis to explore the relationship between metformin clearance and eGFR metrics, and (2) a joint population pharmacokinetic analysis to test the relationship between metformin renal clearance and gentamicin clearance. The relationship between metformin renal clearance and eGFR metrics and gentamicin clearance was found to be linear, suggesting that a proportional dose reduction based on GFR in patients with CKD is reasonable.

Leveraging Virtual Reality and Augmented Reality to Combat Chronic Pain in Youth: Position Paper From the Interdisciplinary Network on Virtual and Augmented Technologies for Pain Management.

BACKGROUND: Virtual reality (VR) and augmented reality (AR) interventions are emerging as promising tools in the treatment of pediatric chronic pain conditions. However, in this young field, there is little consensus to guide the process of engaging in the development and evaluation of targeted VR-based interventions. OBJECTIVE: The INOVATE-Pain (Interdisciplinary Network on Virtual and Augmented Technologies for Pain management) consortium aims to advance the field of VR for pediatric chronic pain rehabilitation by providing guidance for best practices in the design, evaluation, and dissemination of VR-based interventions targeting this population. METHODS: An interdisciplinary meeting of 16 academics, clinicians, industry partners, and philanthropy partners was held in January 2020. RESULTS: Reviewing the state of the field, the consortium identified important directions for research-driven innovation in VR and AR clinical care, highlighted key opportunities and challenges facing the field, and established a consensus on best methodological practices to adopt in future efforts to advance the research and practice of VR and AR in pediatric pain. The consortium also identified important next steps to undertake to continue to advance the work in this promising new area of digital health pain interventions. CONCLUSIONS: To realize the promise of this realm of innovation, key ingredients for success include productive partnerships among industry, academic, and clinical stakeholders; a uniform set of outcome domains and measures for standardized evaluation; and widespread access to the latest opportunities, tools, and resources. The INOVATE-Pain collaborative hopes to promote the creation, rigorous yet efficient evaluation, and dissemination of innovative VR-based interventions to reduce pain and improve quality of life for children.

Influence of the mode of heating on cerebral blood flow, non-invasive intracranial pressure and thermal tolerance in humans.

KEY POINTS: The human brain is particularly vulnerable to heat stress; this manifests as impaired cognition, orthostatic tolerance, work capacity and eventually, brain death. The brain's limitation in the heat is often ascribed to inadequate cerebral blood flow (CBF), but elevated intracranial pressure is commonly observed in mammalian models of heat stroke and can on its own cause functional impairment. The CBF response to incremental heat strain was dependent on the mode of heating, decreasing by 30% when exposed passively to hot, humid air (sauna), while remaining unchanged or increasing with passive hot-water immersion (spa) and exercising in a hot environment. Non-invasive intracranial pressure estimates (nICP) were increased universally by 18% at volitional thermal tolerance across all modes of heat stress, and therefore may play a contributing role in eliciting thermal tolerance. The sauna, more so than the spa or exercise, poses a greater challenge to the brain under mild to severe heating due to lower blood flow but similarly increased nICP. ABSTRACT: The human brain is particularly vulnerable to heat stress; this manifests as impaired cognitive function, orthostatic tolerance, work capacity, and eventually, brain death. This vulnerability is often ascribed to inadequate cerebral blood flow (CBF); however, elevated intracranial pressure (ICP) is also observed in mammalian models of heat stroke. We investigated the changes in CBF with incremental heat strain under three fundamentally different modes of heating, and assessed whether heating per se increased ICP. Fourteen fit participants (seven female) were heated to thermal tolerance or 40°C core temperature (Tc ; oesophageal) via passive hot-water immersion (spa), passive hot, humid air exposure (sauna), cycling exercise, and cycling exercise with CO2 inhalation to prevent heat-induced hypocapnia. CBF was measured with duplex ultrasound at each 0.5°C increment in Tc and ICP was estimated non-invasively (nICP) from optic nerve sheath diameter at thermal tolerance. At thermal tolerance, CBF was decreased by 30% in the sauna (P < 0.001), but was unchanged in the spa or with exercise (P ≥ 0.140). CBF increased by 17% when end-tidal PCO2 was clamped at eupnoeic pressure (P < 0.001). On the contrary, nICP increased universally by 18% with all modes of heating (P < 0.001). The maximum Tc was achieved with passive heating, and preventing hypocapnia during exercise did not improve exercise or thermal tolerance (P ≥ 0.146). Therefore, the regulation of CBF is dramatically different depending on the mode and dose of heating, whereas nICP responses are not. The sauna, more so than the spa or exercise, poses a greater challenge to the brain under equivalent heat strain.

Metformin doses to ensure efficacy and safety in patients with reduced kidney function.

We aimed to develop a metformin dosing strategy to optimise efficacy and safety in patients with reduced kidney function. Metformin data from two studies stratified by kidney function were analysed. The relationship between metformin clearance and kidney function estimates was explored using a regression analysis. The maintenance dose range was predicted at different bands of kidney function to achieve an efficacy target of 1 mg/L for steady-state plasma concentrations. The dosing strategy was evaluated using simulations from a published metformin pharmacokinetic model to determine the probability of concentrations exceeding those associated with lactic acidosis risk, i.e. a steady-state average concentration of 3 mg/L and a maximum (peak) concentration of 5 mg/L. A strong relationship between metformin clearance and estimated kidney function using the Cockcroft and Gault (r2 = 0.699), MDRD (r2 = 0.717) and CKD-Epi (r2 = 0.735) equations was found. The probability of exceeding the safety targets for plasma metformin concentration was <5% for most doses and kidney function levels. The lower dose of 500 mg daily was required to maintain concentrations below the safety limits for patients with an eGFR of 15-29 mL/min. Our analysis suggests that a maximum daily dose of 2250, 1700, 1250, 1000, and 500 in patients with normal kidney function, CKD stage 2, 3a, 3b and 4, respectively, will provide a reasonable probability of achieving efficacy and safety. Our results support the cautious of use metformin at appropriate doses in patients with impaired kidney function.

Do dual purchasers behave differently? An analysis of purchasing data for households that buy both alcohol and tobacco in the United Kingdom.

BACKGROUND AND AIMS: Dual purchasers of alcohol and tobacco are at increased health risk from the interacting health impacts of alcohol and tobacco use. They are also at financial risk from exposure to the dual financial cost of policies that increase alcohol and tobacco prices. Understanding whose alcohol and tobacco use exposes them to these health and financial risks is important for understanding the inequality impacts of control policies. This study explores the extent to which household spending on alcohol and tobacco combined varies between socio-economic groups and compares this with results for households which purchase only one of the commodities. DESIGN: Cross-sectional analysis of household-level alcohol and tobacco purchasing data. SETTING: United Kingdom, 2012-17. PARTICIPANTS/CASES: A total of 26 021 households. MEASUREMENTS: We analysed transaction-level data from individual 14-day spending diaries in the Living Cost and Food Survey (LCFS). We used this to calculate expenditure, volumes of alcohol and tobacco purchased, and the price paid per unit of alcohol (1 unit = 8 g) and per stick of tobacco. This was compared with equivalized total expenditure and quintiles of equivalized household income. Prices were calibrated and pack sizes were imputed using empirical sales data from Nielsen/CGA to correct for reporting bias. FINDINGS: Dual purchasing households spent [95% confidence interval] more on alcohol and more on tobacco than their single-purchasing counterparts. In general, lower-income households spent less on both alcohol and tobacco than higher-income households. Furthermore, dual purchasing households in the lowest income group were most exposed to potential increases in price than were other income groups, with (CI = 12.41-13.15%) of their total household budget spent on alcohol and tobacco. CONCLUSIONS: Dual purchasers of alcohol and tobacco in the United Kingdom appear to be concentrated evenly among income groups. However, dual purchasers may experience particularly large effects from pricing policies, as they spend a substantially higher proportion of their overall household expenditure on alcohol and tobacco than do households that purchase only one of the commodities.