In pursuit of the unicorn.

This short review was prompted by The Physiological Society's recent online symposium on variability. It does not deal with a specific methodology, but rather with the myth that certain environmentally-induced clinical conditions can be identified, quantified, simplified and monitored with a single methodology. Although this might be possible with some clinical conditions, others resist the prevailing reductionist approach of minimizing rather than exploring variation in pathogenesis and pathology, and will not be understood fully until the variation in cause and effect are embraced. This is likely to require comprehensive methodologies and collaboration.

Could patient-controlled thirst-driven fluid administration lead to more rapid rehydration than clinician-directed fluid management? An early feasibility study.

BACKGROUND: Fluid management is a major factor determining perioperative outcome, yet in reality, fluid administration practice is variable. Thirst however, is a highly sensitive and reliable indicator of fluid deficits. We explored the use of thirst sensation to trigger i.v. fluid boluses to guide individualized fluid management. METHODS: We performed a randomised double crossover trial on 16 healthy male volunteers, of mean age 31 yr and BMI 24.4 kg m-2. Twice, after administrations of oral furosemide (40 mg) and 12 h of oral fluid restriction, participants received a 4-h i.v. fluid infusion. In the experimental arm, participants pressed a trigger to relieve their thirst, administering a 200 ml bolus. In the control arm, i.v. fluid was infused following National Institute for Health and Clinical Excellence (NICE) guidelines at 1.25 ml kg-1 h-1 with a clinician delivered 500 ml i.v. bolus in response to clinical signs of dehydration. Plasma osmolality and urine specific gravity were measured before and after each infusion. RESULTS: More fluid was infused in response to thirst than by adherence to NICE guidelines, with a mean difference of 743 ml (P=0.0005). Thirst-driven fluid administration was fitted to an exponential function of time, plateauing after a mean half-life of 98.8 min. In the experimental arm there was a greater reduction in urine specific gravity and thirst score with mean differences 0.0053 g cm-3 (P=0.002) and 3.3 (P=0.003), respectively. Plasma osmolality demonstrated no fluid overload. CONCLUSIONS: A system delivering i.v. fluid in response to subjective thirst corrects fluid deficits in healthy participants. A clinical feasibility study will assess the potential use of this system in the perioperative setting. CLINICAL TRIAL REGISTRATION: NCT 03176043.

The future of UK healthcare: problems and potential solutions to a system in crisis.

The UK's Health System is in crisis, central funding no longer keeping pace with demand. Traditional responses-spending more, seeking efficiency savings or invoking market forces-are not solutions. The health of our nation demands urgent delivery of a radical new model, negotiated openly between public, policymakers and healthcare professionals. Such a model could focus on disease prevention, modifying health behaviour and implementing change in public policy in fields traditionally considered unrelated to health such as transport, food and advertising. The true cost-effectiveness of healthcare interventions must be balanced against the opportunity cost of their implementation, bolstering the central role of NICE in such decisions. Without such action, the prognosis for our healthcare system-and for the health of the individuals it serves-may be poor. Here, we explore such a new prescription for our national health.

Critical care at the end of life: balancing technology with compassion and agreeing when to stop.

Modern intensive care saves lives. However, the substantial related financial costs are, for many, married to substantial costs in terms of suffering. In the most sick, the experience of intensive care is commonly associated with the development of profound physical debility, which may last years after discharge. Likewise, the negative psychological impact commonly experienced by such patients during their care is now widely recognized, as is the persistence of psychological morbidity. Such issues become increasingly important as the population of the frail elderly increases, and the health and social care services face budgetary restriction. Efforts must be made to humanize intensive care as much as possible. Meanwhile, an open conversation must be held between those within the medical professions, and between such healthcare workers and the public in general, regarding the balancing of the positive and negative impacts of intensive care. Such conversations should extend to individual patients and their families when considering what care is genuinely in their best interests.

Total haemoglobin mass, but not haemoglobin concentration, is associated with preoperative cardiopulmonary exercise testing-derived oxygen-consumption variables.

Background: Cardiopulmonary exercise testing (CPET) measures peak exertional oxygen consumption ( V˙O2peak ) and that at the anaerobic threshold ( V˙O2 at AT, i.e. the point at which anaerobic metabolism contributes substantially to overall metabolism). Lower values are associated with excess postoperative morbidity and mortality. A reduced haemoglobin concentration ([Hb]) results from a reduction in total haemoglobin mass (tHb-mass) or an increase in plasma volume. Thus, tHb-mass might be a more useful measure of oxygen-carrying capacity and might correlate better with CPET-derived fitness measures in preoperative patients than does circulating [Hb]. Methods: Before major elective surgery, CPET was performed, and both tHb-mass (optimized carbon monoxide rebreathing method) and circulating [Hb] were determined. Results: In 42 patients (83% male), [Hb] was unrelated to V˙O2 at AT and V˙O2peak ( r =0.02, P =0.89 and r =0.04, P =0.80, respectively) and explained none of the variance in either measure. In contrast, tHb-mass was related to both ( r =0.661, P <0.0001 and r =0.483, P =0.001 for V˙O2 at AT and V˙O2peak , respectively). The tHb-mass explained 44% of variance in V˙O2 at AT ( P <0.0001) and 23% in V˙O2peak ( P =0.001). Conclusions: In contrast to [Hb], tHb-mass is an important determinant of physical fitness before major elective surgery. Further studies should determine whether low tHb-mass is predictive of poor outcome and whether targeted increases in tHb-mass might thus improve outcome.

Atomic vs. quantum dot open shell spectra.

Hund's rules apply to pairs of atomic states which, in the limit of weak interelectronic repulsion, belong to a common configuration. We examine the asymptotic behavior of the energy difference between states belonging to such pairs (ΔE) as a function of the nuclear charge (Z) at both Z→∞ (ignoring relativistic effects) and at Z→Zc, where Zc is the critical charge below which the outermost electron is not bound. We find that the ratio ΔEZ2 is non-monotonic, having a maximum at some intermediate value of Z. This non-monotonicity is shown to account for the sign reversal in the difference between the corresponding interelectronic repulsion energies. For analogous open shell systems with confining potentials (such as Hooke's atom or the infinite spherical well), the corresponding function of the energy difference, in terms of which the interelectronic repulsion energy is given as a first derivative with respect to the parameter that characterizes the strength of the one-body potential (such as the harmonic force constant or the well radius, respectively), is monotonic in this parameter. This implies that the relative magnitude of the interelectronic repulsion energies that characterizes the strong one-body limit (usually, the ordering naively expected on the basis of Hund's rule) remains valid along the whole isoelectronic sequence.

Improving outcomes in patients with Acute Kidney Injury: the impact of hospital based automated AKI alerts.

BACKGROUND: Acute kidney injury (AKI) is a significant cause of morbidity and mortality. Early identification may improve the outcome and in 2012 our hospital introduced an automated AKI alert system for early detection and management of AKI. OBJECTIVES: Using an automated AKI alert system we analysed whether early review and intervention by the Critical Care and Outreach (CCOT) team improved patient outcomes in AKI and whether serum bicarbonate was useful in predicting outcomes in patients with AKI. METHODS: In a retrospective analysis we identified patients who triggered an AKI alert from 20 April 2012 to 20 September 2013 and collected data on mortality, length of stay, need for intensive care admission and renal replacement therapy (RRT). RESULTS: 994 AKI alerts were generated and analysed. Patients with bicarbonate outside the normal range had significantly higher mortality. Bicarbonate <22 mmol/L was associated with a mortality of 25.7% (49/191) compared with 16.9% (39/231) when 22-29 mmol/L (p=0.047, χ(2)). Those patients reviewed ≥1 day after AKI alert by CCOT compared with those seen on the day of the alert had a 2.4 times increase in mortality and were 7 times more likely to require RRT acutely. CONCLUSIONS: Electronically identified AKI alerts identify patients at high risk of morbidity and mortality. In this group AKI alerts preceded CCOT review by a mean of 2 days. This represents a window for supportive interventions, which may explain improved outcomes in those reviewed earlier. The addition of serum bicarbonate offers a further method of risk stratifying patients at greater risk of death.

Caudwell Xtreme Everest: An Overview.

The Caudwell Xtreme Everest (CXE) expedition in the spring of 2007 systematically studied 222 healthy volunteers as they ascended from sea level to Everest Base Camp (5300 m). A subgroup of climbing investigators ascended higher on Everest and obtained physiological measurements up to an altitude of 8400 m. The aim of the study was to explore inter-individual variation in response to environmental hypobaric hypoxia in order to understand better the pathophysiology of critically ill patients and other patients in whom hypoxaemia and cellular hypoxia are prevalent. This paper describes the aims, study characteristics, organization and management of the CXE expedition.

Hyperpolarizabilities of hydrogenlike atoms in Debye and dense quantum plasmas.

The hyperpolarizabilities of the hydrogenlike atoms in Debye and dense quantum plasmas are calculated using the sum-over-states formalism based on the generalized pseudospectral method. The Debye-Hückel and exponential-cosine screened Coulomb potentials are employed to model the screening effects in, respectively, Debye and dense quantum plasmas. Our numerical calculation demonstrates that the present method shows exponential convergence in calculating the hyperpolarizabilities of one-electron systems and the obtained results significantly improve previous predictions in the strong screening environment. The asymptotic behavior of hyperpolarizability near the system bound-continuum limit is investigated and the results for some low-lying excited states are reported. By comparing the fourth-order corrected energies in terms of hyperpolarizability with the resonance energies using the complex-scaling method, we empirically conclude that the applicability of hyperpolarizability in perturbatively estimating the system energy in Debye plasmas lies in the range of [0,F_{max}/2], where F_{max} refers to the maximum electric field strength at which the fourth-order energy correction is equal to the second-order term.

The metabolic effects of intermittent versus continuous feeding in critically ill patients.

Intermittent (or bolus) feeding regimens in critically ill patients have been of increasing interest to clinicians and scientists. Changes in amino acid, fat and carbohydrate metabolites over time might yet deliver other benefits (e.g. modulation of the circadian rhythm and sleep, and impacts on ghrelin secretion, insulin resistance and autophagy). We set out to characterise these changes in metabolite concentration. The Intermittent versus Continuous Feeding in Critically Ill paitents study (NCT02358512) was an eight-centre single-blinded randomised controlled trial. Patients were randomised to received a continuous (control arm) or intermittent (6x/day, intervention arm) enteral feeding regimen. Blood samples were taken on trial days 1, 7 and 10 immediately before and 30 min after intermittent feeds, and at equivalent timepoints in the control arm. A pre-planned targeted metabolomic analysis was performend using Nuclear Resonance Spectroscopy. Five hundred and ninety four samples were analysed from 75 patients. A total of 24 amino acid-, 19 lipid based-, and 44 small molecule metabolite features. Across the main two axes of variation (40-60% and 6-8% of variance), no broad patterns distinguished between intermittent or continuous feeding arms, across intra-day sampling times or over the 10 days from initial ICU admission. Logfold decreases in abundance were seen in metabolites related to amino acids (Glutamine - 0.682; Alanine - 0.594), ketone body metabolism (Acetone - 0.64; 3-Hydroxybutyric Acid - 0.632; Acetonacetic Acid - 0.586), fatty acid (carnitine - 0.509) and carbohydrate metabolism ( Maltose - 0.510; Citric Acid - 0.485). 2-3 Butanediol, a by-product of sugar-fermenting microbial metabolism also decreased (- 0.489). No correlation was seen with change in quadriceps muscle mass for any of the 20 metabolites varying with time (all p > 0.05). Increasing severity of organ failure was related to increasing ketone body metabolism (3 Hydroxybutyric Acid-1 and - 3; p = 0.056 and p = 0.014), carnitine deficiency (p = 0.002) and alanine abundancy (p - 0.005). A 6-times a day intermittent feeding regimen did not alter metabolite patterns across time compared to continuous feeding in critically ill patients, either within a 24 h period or across 10 days of intervention. Future research on intermittent feeding regimens should focus on clinical process benefits, or extended gut rest and fasting.

Preoperative exercise capacity in adult inflammatory bowel disease sufferers, determined by cardiopulmonary exercise testing.

BACKGROUND AND AIMS: Aerobic exercise capacity appears impaired in children with inflammatory bowel disease (IBD). Whether this holds true in adults with IBD is not known. Using cardiopulmonary exercise testing (CPET), we assessed anaerobic threshold (AT) in such patients comparing data with reference values and other elective surgical patients. We also sought to confirm whether the presence of a fistula further reduced AT. METHODS: CPET was performed between November 2007 and December 2010 on patients awaiting abdominopelvic surgery. Gender-specific normal reference values were used for comparison. Unadjusted comparison between two groups was made using Mann-Whitney U test and by unpaired t test. Data were adjusted by analysis of covariance, using age and sex as covariates. Differences between patients' observed values and reference values were tested using paired t tests. RESULTS: Four hundred and fourteen patients (234 male) were studied (mean ± SD age, 56.6 ± 16.4 years; weight, 74.2 ± 15.6 kg). Adjusted AT values in Crohn's disease (CD) were lower than colorectal cancer (11.4 ± 3.4 vs 13.2 ± 3.5 ml.kg(-1).min(-1), p = 0.03) and for all other colorectal disease groups combined (12.6 ± 3.5 ml.kg(-1).min(-1), p = 0.03). AT of Ulcerative colitis (UC) and CD patients together were reduced compared to population reference values (p < 0.05). CONCLUSION: After adjusting for age and sex, CD patients had a reduced AT compared to patients with colorectal cancer and other colorectal disease groups combined. The pathogenesis of this low AT remains to be defined and warrants further investigation.

Cardiopulmonary exercise testing predicts postoperative outcome in patients undergoing gastric bypass surgery.

BACKGROUND: For several types of non-cardiac surgery, the cardiopulmonary exercise testing (CPET)-derived variables anaerobic threshold (AT), peak oxygen consumption (VO2 peak), and ventilatory equivalent for CO(2) (VE/VCO2 ) are predictive of increased postoperative risk: less physically fit patients having a greater risk of adverse outcome. We investigated this relationship in patients undergoing gastric bypass surgery. METHODS: All patients (<190 kg) who were referred for CPET and underwent elective gastric bypass surgery at the Whittington Hospital NHS Trust between September 1, 2009, and February 25, 2011, were included in the study (n=121). Fifteen patients did not complete CPET. CPET variables (VO2 peak, AT, and VE/VCO2 ) were derived for 106 patients. The primary outcome variables were day 5 morbidity and hospital length of stay (LOS). The independent t-test and Fisher's exact test were used to test for differences between surgical outcome groups. The predictive capacity of CPET markers was determined using receiver operating characteristic (ROC) curves. RESULTS: The AT was lower in patients with postoperative complications than in those without [9.9 (1.5) vs 11.1 (1.7) ml kg(-1) min(-1), P=0.049] and in patients with a LOS>3 days compared with LOS ≤ 3 days [10.4 (1.4) vs 11.3 (1.8) ml kg(-1) min(-1), P=0.023]. ROC curve analysis identified AT as a significant predictor of LOS>3 days (AUC 0.640, P=0.030). The VO2 peak and VE/VCO2 were not associated with postoperative outcome. CONCLUSIONS: AT, determined using CPET, predicts LOS after gastric bypass surgery.

The virial theorem for the smoothly and sharply, penetrably and impenetrably confined hydrogen atom.

Confinement of atoms by finite or infinite boxes containing sharp (discontinuous) jumps has been studied since the fourth decade of the previous century, modelling the effect of external pressure. Smooth (continuous) counterparts of such confining potentials, that depend on a parameter such that in an appropriate limit they coincide with the sharp confining potentials, are investigated, with an emphasis on deriving the corresponding virial and Hellmann-Feynman theorems.

The relationship between minority stress factors and suicidal ideation and behaviours amongst transgender and gender non-conforming adults: A systematic review.

BACKGROUND: The impact of Minority Stress (MS) upon suicidal ideation and behaviours amongst Transgender and Gender Non-Conforming (TGNC) adults is not sufficiently understood, hence our intervention efforts on an individual and societal level are limited. This review aims to evaluate recent literature that reports on the association between MS and suicidal ideation and behaviours amongst TGNC adults. METHODS: PsycINFO, Web of Science, MEDLINE, CINAHL and EMBASE were systematically searched for relevant articles. Peer reviewed and grey literature were considered. Included papers reported quantitative analyses on associations between MS factors and suicidal ideation and behaviours amongst TGNC adults. The quality of papers was assessed. RESULTS: 28 papers were identified as eligible. Findings suggested positive associations between external and internal minority stressors and suicidal ideation and behaviour. Dysfunctional individual coping was associated with a greater likelihood of suicide attempts. Community resilience was negatively associated with suicidal outcomes, but did not consistently buffer the effects of minority stress. LIMITATIONS: Overall quality of included papers was 'poor'. Almost all papers were cross-sectional by design, therefore causality cannot be inferred. Many papers measured variables using non-standardised measures undermining the reliability and validity of reported results. CONCLUSIONS: Findings offer support to the application of MS theory to the understanding of suicidal ideation and behaviour amongst TGNC. Future research should use standardised measures and longitudinal designs to better support the investigation of directionality and causality. More research is needed to understand the complex interactions between minority stress factors and the role of resilience in this population.

Prolongation of the corrected QT complex--a cause of sudden cardiac death in the mountain environment?

In the mountain environment sudden cardiac death (SCD) has been shown to be responsible for the deaths of up to 52% of downhill skiers and 30% of hikers. The majority of SCD's are precipitated by a ventricular arrhythmia. Although most are likely to result from structural abnormalities associated with conditions such as ischaemic heart disease, a small but significant number may be due to abnormalities in ion channel activity, commonly known as, "channelopathies". Channelopathies have the potential to lengthen the time between ventricular depolarisation and repolarisation that can result in prolongation of the corrected QT interval (QTc) and episodes of polymorphic ventricular tachycardia (PVT) and eventually, ventricular fibrillation. This review examines the factors that prolong the QTc interval in the mountain environment and outlines a practical framework for preventing the life threatening arrhythmias that are associated with this condition.

Angiotensin-converting enzyme genotype and encephalopathy in Chernobyl cleanup workers.

BACKGROUND AND PURPOSE: To identify, using a genetic model, a key role for the renin-angiotensin system (RAS) in the development of dyscirculatory encephalopathy (DE) in Chernobyl cleanup workers (CCW). The insertion/deletion polymorphism of the angiotensin-converting enzyme (ACE) gene denotes a substantial individual variation in RAS activity with the D-allele being associated with higher ACE activity. METHODS: Ninety-three male, Caucasian CCW were recruited from those under regular review at the All-Russia Centre of Emergency and Radiation Medicine, St. Petersburg. The presence or absence of DE was determined using existing institutional guidelines. ACE genotype was determined using internationally accepted methodologies. RESULTS: Angiotensin-converting enzyme genotype distribution in 59 subjects with DE was II: 10 (17%), ID: 31 (53%), DD: 18 (30%), D-allele frequency 56.8%. Whereas in those without the condition the distribution was II: 12 (35%), ID: 19 (56%), DD 3 (9%) and D-allele frequency 35.9% (P = 0.02). CONCLUSIONS: These data are the first to identify an association between the ACE D-allele and DE in CCW. They provide evidence of a significant role for the RAS in the development of DE and suggest that clinical trials of ACE inhibition would be profitable in this group.

Mountain mortality: a review of deaths that occur during recreational activities in the mountains.

The growing popularity of activities such as hiking, climbing, skiing and snowboarding has ensured that the number of visitors to mountain environments continues to increase. Since such areas place enormous physical demands on individuals, it is inevitable that deaths will occur. Differences in the activities, conditions and methods of calculation make meaningful mortality rates difficult to obtain. However, it is clear that the mortality rate for some mountain activities is comparable to hang gliding, parachuting, boxing and other pastimes that are traditionally viewed as dangerous. Deaths in the mountains are most commonly due to trauma, high altitude illness, cold injury, avalanche burial and sudden cardiac death. This review describes the mortality rates of those who undertake recreational activities in the mountains and examines the aetiology that lies behind them.

Level of ex vivo interleukin 6 expression in human peripheral fat compared with other tissues.

OBJECTIVES: Adipose tissue is able to secrete a variety of active mediators into the circulation. One of these is Interleukin 6 (IL6). IL6 may play a causal role in the development of atherosclerosis. It has therefore been suggested that IL6 may form part of the link between obesity and vascular disease. The aim of this study was to quantify the relative IL6 expression in adipose tissue compared to other tissues. METHODS: Tissue (vein, fat, muscle, blood) was collected from 32 patients undergoing varicose vein surgery. RNA was extracted and mRNA measured using RT-PCR relative quantification. The mean relative IL6 mRNA levels were compared between tissues using the Mann Whitney U test and the independent t-test. Tissue levels were compared for individuals using the Wilcoxon signed rank test. RESULTS: Mean relative IL6 mRNA levels (mean+/-SEM) were significantly greater in adipose tissue 44.8+/-16.1 than in other tissues (leukocytes 1.1+/-0.3, vein 2.0+/-0.8, muscle 0.06+/-0.03: p<0.001). mRNA expression levels were also significantly higher in fat than in all other tissue types in individuals (p<0.001). CONCLUSIONS: IL6 mRNA expression is significantly higher in adipose than in many other tissues known to express IL6.

High altitude arrhythmias.

OBJECTIVE: To investigate the cause and nature of palpitations occurring at high altitude. METHODS: Implantable loop recorders were inserted subcutaneously in the left pectoral region of 9 healthy male volunteers. Subjects flew to Kathmandu (1,250 m) and then Lukla (2,800 m) before immediately commencing an identical ascent and descent profile to high altitude. The loop recorders were activated with any episode of palpitations and during exercise, rest and sleep. Arterial oxygen saturation was assessed concomitant with device activation. RESULTS: Above 5,000 m all subjects reported palpitations during exercise. All subjects demonstrated sinus tachycardia and marked sinus arrhythmia; one subject demonstrated atrial flutter; one subject had non-conducted p waves, and a further subject had marked ST segment depression. CONCLUSIONS: Significant arrhythmias occur at high altitude. In view of the increased risk of sudden cardiac death at high altitude, and considering that the elderly account for 15% of the 100 million visitors to altitude annually, further investigation is required.