Technological readiness and implementation of genomic-driven precision medicine for complex diseases.

The fields of human genetics and genomics have generated considerable knowledge about the mechanistic basis of many diseases. Genomic approaches to diagnosis, prognostication, prevention and treatment - genomic-driven precision medicine (GDPM) - may help optimize medical practice. Here, we provide a comprehensive review of GDPM of complex diseases across major medical specialties. We focus on technological readiness: how rapidly a test can be implemented into health care. Although these areas of medicine are diverse, key similarities exist across almost all areas. Many medical areas have, within their standards of care, at least one GDPM test for a genetic variant of strong effect that aids the identification/diagnosis of a more homogeneous subset within a larger disease group or identifies a subset with different therapeutic requirements. However, for almost all complex diseases, the majority of patients do not carry established single-gene mutations with large effects. Thus, research is underway that seeks to determine the polygenic basis of many complex diseases. Nevertheless, most complex diseases are caused by the interplay of genetic, behavioural and environmental risk factors, which will likely necessitate models for prediction and diagnosis that incorporate genetic and non-genetic data.

In vitro digestion of purified ß-casein variants A(1), A(2), B, and I: effects on antioxidant and angiotensin-converting enzyme inhibitory capacity.

Genetic polymorphisms of bovine milk proteins affect the protein profile of the milk and, hence, certain technological properties, such as casein (CN) number and cheese yield. However, reports show that such polymorphisms may also affect the health-related properties of milk. Therefore, to gain insight into their digestion pattern and bioactive potential, ß-CN was purified from bovine milk originating from cows homozygous for the variants A(1), A(2), B, and I by a combination of cold storage, ultracentrifugation, and acid precipitation. The purity of the isolated ß-CN was determined by HPLC, variants were verified by mass spectrometry, and molar extinction coefficients at λ=280nm were determined. ß-Casein from each of the variants was subjected to in vitro digestion using pepsin and pancreatic enzymes. Antioxidant and angiotensin-converting enzyme (ACE) inhibitory capacities of the hydrolysates were assessed at 3 stages of digestion and related to that of the undigested samples. Neither molar extinction coefficients nor overall digestibility varied significantly between these 4 variants; however, clear differences in digestion pattern were indicated by gel electrophoresis. In particular, after 60min of pepsin followed by 5min of pancreatic enzyme digestion, one ≈4kDa peptide with the N-terminal sequence (106)H-K-E-M-P-F-P-K- was absent from ß-CN variant B. This is likely a result of the (122)Ser to (122)Arg substitution in variant B introducing a novel trypsin cleavage site, leading to the changed digestion pattern. All investigated ß-CN variants exhibited a significant increase in antioxidant capacity upon digestion, as measured by the Trolox-equivalent antioxidant capacity assay. After 60min of pepsin + 120min of pancreatic enzyme digestion, the accumulated increase in antioxidant capacity was ≈1.7-fold for the 4 ß-CN variants. The ACE inhibitory capacity was also significantly increased by digestion, with the B variant reaching the highest inhibitory capacity at the end of digestion (60min of pepsin + 120min of pancreatic enzymes), possibly because of the observed alternative digestion pattern. These results demonstrate that genetic polymorphisms affect the digestion pattern and bioactivity of milk proteins. Moreover, their capacity for radical scavenging and ACE inhibition is affected by digestion.

Prediagnostic transcriptomic markers of Chronic lymphocytic leukemia reveal perturbations 10 years before diagnosis.

BACKGROUND: B-cell lymphomas are a diverse group of hematological neoplasms with differential etiology and clinical trajectories. Increased insights in the etiology and the discovery of prediagnostic markers have the potential to improve the clinical course of these neoplasms. METHODS: We investigated in a prospective study global gene expression in peripheral blood mononuclear cells of 263 incident B-cell lymphoma cases, diagnosed between 1 and 17 years after blood sample collection, and 439 controls, nested within two European cohorts. RESULTS: Our analyses identified only transcriptomic markers for specific lymphoma subtypes; few markers of multiple myeloma (N = 3), and 745 differentially expressed genes in relation to future risk of chronic lymphocytic leukemia (CLL). The strongest of these associations were consistently found in both cohorts and were related to (B-) cell signaling networks and immune system regulation pathways. CLL markers exhibited very high predictive abilities of disease onset even in cases diagnosed more than 10 years after blood collection. CONCLUSIONS: This is the first investigation on blood cell global gene expression and future risk of B-cell lymphomas. We mainly identified genes in relation to future risk of CLL that are involved in biological pathways, which appear to be mechanistically involved in CLL pathogenesis. Many but not all of the top hits we identified have been reported previously in studies based on tumor tissues, therefore suggesting that a mixture of preclinical and early disease markers can be detected several years before CLL clinical diagnosis.

Cognitive ability in early adulthood is associated with later suicide and suicide attempt: the role of risk factors over the life course.

BACKGROUND: Cognitive ability/intelligence quotient (IQ) in youth has previously been associated with subsequent completed and attempted suicide, but little is known about the mechanisms underlying the associations. This study aims to assess the roles of various risk factors over the life course in explaining the observed relationships. METHOD: The present investigation is a cohort study based on data on IQ test performance and covariates, recorded on 49 321 Swedish men conscripted in 1969-1970, at ages 18-20 years. Information on suicides and hospital admissions for suicide attempt up to the age of 57 years, childhood and adult socio-economic position, and adult family formation, was obtained from linkage to national registers. RESULTS: Lower IQ was associated with increased risks of both suicide and suicide attempt during the 36 years of follow-up. The associations followed a dose-response pattern. They were attenuated by approximately 45% in models controlling for social background, mental ill-health, aspects of personality and behavior, adult socio-economic position and family formation. Based on one-unit decreases in IQ test performance on a nine-point scale, the hazard ratios between ages 35 and 57 years were: for suicide 1.19 [95% confidence interval (CI) 1.13-1.25], fully adjusted 1.10 (95% CI 1.04-1.18); and for suicide attempt 1.25 (95% CI 1.20-1.31), fully adjusted 1.14 (95% CI 1.09-1.20). CONCLUSIONS: Cognitive ability was found to be associated with subsequent completed and attempted suicide. The associations were attenuated by 45% after controlling for risk factors measured over the life course. Psychiatric diagnosis, maladjustment and aspects of personality in young adulthood, and social circumstances in later adulthood, contributed in attenuating the associations.

Association of PHB 1630 C>T and MTHFR 677 C>T polymorphisms with breast and ovarian cancer risk in BRCA1/2 mutation carriers: results from a multicenter study.

BACKGROUND: The variable penetrance of breast cancer in BRCA1/2 mutation carriers suggests that other genetic or environmental factors modify breast cancer risk. Two genes of special interest are prohibitin (PHB) and methylene-tetrahydrofolate reductase (MTHFR), both of which are important either directly or indirectly in maintaining genomic integrity. METHODS: To evaluate the potential role of genetic variants within PHB and MTHFR in breast and ovarian cancer risk, 4102 BRCA1 and 2093 BRCA2 mutation carriers, and 6211 BRCA1 and 2902 BRCA2 carriers from the Consortium of Investigators of Modifiers of BRCA1 and BRCA2 (CIMBA) were genotyped for the PHB 1630 C>T (rs6917) polymorphism and the MTHFR 677 C>T (rs1801133) polymorphism, respectively. RESULTS: There was no evidence of association between the PHB 1630 C>T and MTHFR 677 C>T polymorphisms with either disease for BRCA1 or BRCA2 mutation carriers when breast and ovarian cancer associations were evaluated separately. Analysis that evaluated associations for breast and ovarian cancer simultaneously showed some evidence that BRCA1 mutation carriers who had the rare homozygote genotype (TT) of the PHB 1630 C>T polymorphism were at increased risk of both breast and ovarian cancer (HR 1.50, 95%CI 1.10-2.04 and HR 2.16, 95%CI 1.24-3.76, respectively). However, there was no evidence of association under a multiplicative model for the effect of each minor allele. CONCLUSION: The PHB 1630TT genotype may modify breast and ovarian cancer risks in BRCA1 mutation carriers. This association need to be evaluated in larger series of BRCA1 mutation carriers.

Primary brain tumours and specific serum immunoglobulin E: a case-control study nested in the European Prospective Investigation into Cancer and Nutrition cohort.

BACKGROUND: Case-control studies suggest that patients with allergic diseases have a lower risk of developing glioma but not meningioma or schwannoma. However, those data can be differentially biased. Prospective studies with objective measurements of immunologic biomarkers, like immunoglobulin E (IgE), in blood obtained before cancer diagnosis could help to clarify whether an aetiological association exists. METHODS: The present case-control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) measured specific serum IgE as a biomarker for the most common inhalant allergens in 275 glioma, 175 meningioma and 49 schwannoma cases and 963 matched controls using the ImmunoCAP specific IgE test. Subjects with an IgE level ≥0.35 kUA/l (kilo antibody units per litre) were classified as sensitized by allergens. Odds ratios (OR) and 95% confidence intervals (CI) were estimated by adjusted conditional logistic regression models for each tumour subtype. The effect of dose-response relationship was assessed in five increasing IgE level categories to estimate P-values for trend. RESULTS: The risk of glioma was inversely related to allergic sensitization (OR = 0.73; 95% CI 0.51-1.06), especially pronounced in women (OR = 0.53; 95% CI 0.30-0.95). In dose-response analyses, for high-grade glioma, the lowest OR was observed in sera with the highest IgE levels (P for trend = 0.04). No association was seen for meningioma and schwannoma. CONCLUSION: The results, based on serum samples prospectively collected in a cohort study, provide some support for the hypothesis that individuals with allergic sensitization are at reduced risk of glioma and confirm results from previous case-control studies.

Genetic variations in VEGF and VEGFR2 and glioblastoma outcome.

Vascular endothelial growth factor (VEGF) and its receptors (VEGFR) are central components in the development and progression of glioblastoma. To investigate if genetic variation in VEGF and VEGFR2 is associated with glioblastoma prognosis, we examined blood samples from 154 glioblastoma cases collected in Sweden and Denmark between 2000 and 2004. Seventeen tagging single nucleotide polymorphisms (SNPs) in VEGF and 27 in VEGFR2 were genotyped and analysed, covering 90% of the genetic variability within the genes. In VEGF, we found no SNPs associated with survival. In VEGFR2, we found two SNPs significantly associated to survival, namely rs2071559 and rs12502008. However, these results are likely to be false positives due to multiple testing and could not be confirmed in a separate dataset. Overall, this study provides little evidence that VEGF and VEGFR2 polymorphisms are important for glioblastoma survival.

Guidelines on management of low-grade gliomas: report of an EFNS-EANO Task Force.

BACKGROUND: Diffuse infiltrative low-grade gliomas of the cerebral hemispheres in the adult are a group of tumors with distinct clinical, histological and molecular characteristics, and there are still controversies in management. METHODS: The scientific evidence of papers collected from the literature was evaluated and graded according to EFNS guidelines, and recommendations were given accordingly. RESULTS AND CONCLUSIONS: WHO classification recognizes grade II astrocytomas, oligodendrogliomas and oligoastrocytomas. Conventional MRI is used for differential diagnosis, guiding surgery, planning radiotherapy and monitoring treatment response. Advanced imaging techniques can increase the diagnostic accuracy. Younger age, normal neurological examination, oligodendroglial histology and 1p loss are favorable prognostic factors. Prophylactic antiepileptic drugs are not useful, whilst there is no evidence that one drug is better than the others. Total/near total resection can improve seizure control, progression-free and overall survival, whilst reducing the risk of malignant transformation. Early post-operative radiotherapy improves progression-free but not overall survival. Low doses of radiation are as effective as high doses and better tolerated. Modern radiotherapy techniques reduce the risk of late cognitive deficits. Chemotherapy can be useful both at recurrence after radiotherapy and as initial treatment after surgery to delay the risk of late neurotoxicity from large-field radiotherapy. Neurocognitive deficits are frequent and can be caused by the tumor itself, tumor-related epilepsy, treatments and psychological distress.

Cognitive ability in adolescence and mortality in middle age: a prospective life course study.

BACKGROUND: An association between childhood cognitive ability measured by IQ tests and mortality has been reported recently. It is not clear from those studies to what extent the increased relative risk associated with lower IQ scores may be attenuated by adjustment for other risk factors. This study aims to investigate the association between cognitive ability measured at age 18-20 years and mortality among middle-aged men adjusting for risk factors for mortality over the life course. METHODS: Data on cognitive ability, and other risk factors for premature mortality (indicators of mental health and social adjustment and behavioural factors), were collected among 49 321 men, born in 1949-51, at conscription for compulsory military training in 1969-70. Information on socioeconomic factors in childhood and adulthood, as well as information on mortality, was collected through national registers. RESULTS: Cognitive ability showed an inverse and graded association with mortality between 40 and 53 years of age (1297 cases, crude hazard ratio (HR) 1.15, 95% CI 1.12 to 1.18, for one-point decrease on the nine-point IQ scale). Adjustment for indicators of social misbehaviour, mental health problems and behavioural risk factors, measured in late adolescence, and adult social circumstances strongly attenuated the increased risks of mortality, and it was no longer significantly increased (adjusted HR 1.02, 95% CI 0.99 to 1.06, for one-point decrease on the nine-point IQ scale). CONCLUSION: The association between IQ and mortality among men below 54 years of age was almost completely attenuated by adjustment for risk factors captured by our measures of achieved social positions.

Self-efficacy beliefs predict sustained long-term sick absenteeism in individuals with chronic musculoskeletal pain.

Recovery beliefs are assumed to predict rehabilitation outcomes and return-to-work in various clinical conditions but are less frequently assessed in musculoskeletal disorders. We tested the hypothesis that recovery beliefs constitute a risk factor for sustained long-term sick absenteeism in men and women suffering from nonspecific chronic musculoskeletal disorders. A total of 233 subjects with a recent or ongoing experience of long-term sick leave were included in a prospective design. Subjects answered a postal baseline questionnaire and were followed up via register data for 1 year. Multivariate logistic regression analyses indicated that subjects with negative recovery beliefs (OR: 2.41; CI: 1.22-4.77), low sense of mastery (OR: 2.08; CI: 1.27-3.40), perceived high mental demands at work (OR: 1.77; CI: 1.05-2.99), and prior experiences of long-term sick absenteeism (OR: 1.86; CI: 1.02-3.37) had an increased probability of receiving sickness benefits at follow-up. We conclude that prolonged sickness absence contributes strongly to increase patients' sense of helplessness, lower self-efficacy, and hinder future work return. To improve work return, patients' maladaptive beliefs should be clarified and challenged early in the rehabilitation process.

Substrate utilization during prolonged exercise with ingestion of (13)C-glucose in acute hypobaric hypoxia (4,300 m).

Energy substrate oxidation was measured using indirect respiratory calorimetry combined with tracer technique in five healthy young male subjects, during a 80-min exercise period on ergocycle with ingestion of 140 g of (13)C-labelled glucose, in normoxia and acute hypobaric hypoxia (445 mmHg or 4,300 m), at the same relative [77% V(.-)((O)(2)(max))] and absolute workload (161+/-8 W, corresponding to 77 and 54% V(.-)((O)(2)(max)) in hypoxia and normoxia). The oxidation rate of exogenous glucose was not significantly different in the three experimental situations: 21.4+/-2.9, 20.2+/-1.2 and 17.2+/-0.6 g over the last 40 min of exercise at approximately 77 and approximately 54% V(.-)((O)(2)(max)) in normoxia and in hypoxia, respectively, providing 12.5+/-1.5, 16.8+/-1.1 and 14.9+/-1.1% of the energy yield, although ingestion of glucose during exercise resulted in a higher plasma glucose concentration in hypoxia than normoxia. The contribution of carbohydrate (CHO) oxidation to the energy yield was significantly higher in hypoxia (92.0+/-2.1%) than in normoxia for both a given absolute (75.3+/-5.2%) and relative workload (78.1+/-1.8%). This greater reliance on CHO oxidation in hypoxia was entirely due to the significantly larger contribution of endogenous glucose oxidation to the energy yield: 75.9+/-1.7% versus 66.6+/-3.3 and 55.2+/-3.7% in normoxia at the same relative and absolute workload.

Comparison of passive heat or exercise-induced dehydration on renal water and electrolyte excretion: the hormonal involvement.

The effects of hydromineral hormones and catecholamines on renal water and electrolyte excretion were examined during and after dehydration induced by either passive heat or exercise. Eight healthy young Caucasian subjects participated in three separate trials, each including three consecutive phases. Phases 1 and 3 involved a 90-min period at rest in a thermoneutral environment, while phase 2 involved a 120-min period designed to provide: (1) euhydration (control trial), (2) passive heat-induced dehydration of 2.8% body mass, or (3) exercise-induced dehydration of 2.8% body mass. During the two dehydration procedures, the decreases in urine flow and sodium excretion were more marked during exercise (P < 0.05). An increase in plasma catecholamines occurred only during exercise, together with a reduction in creatinine clearance and more marked increases in plasma renin and aldosterone than during passive heat exposure (P < 0.05). Although plasma vasopressin was elevated during the two dehydration procedures, urine osmolality did not change and, moreover, free water clearance increased during exercise (P < 0.05). Plasma levels of atrial natriuretic peptide increased markedly only during exercise compared to the other trials (P < 0.05). After the dehydration procedures, urine flow decreased again and urine osmolality increased markedly (P < 0.05), while plasma vasopressin remained elevated. These results suggest that sympathoadrenal activation during exercise plays a major role in the more marked reduction in diuresis and natriuresis than during passive heat exposure. Despite high plasma vasopressin concentrations during the two dehydrating events, the observed antidiuresis was not due to an increased renal concentrating ability, and the vasopressin was more effective after the dehydration procedures.

[Sports and extreme conditions. Cardiovascular incidence in long term exertion and extreme temperatures (heat, cold)]. / Sports et conditions extrêmes. Incidence cardiovasculaire des efforts de longue durée et des températures extrêmes (chaleur, froid).

During ultra-endurance exercise, both increase in body temperature and dehydration due to sweat losses, lead to a decrease in central blood volume. The heart rate drift allows maintaining appropriate cardiac output, in order to satisfy both muscle perfusion and heat transfer requirements by increasing skin blood flow. The resulting dehydration can impair thermal regulation and increase the risks of serious accidents as heat stroke. Endurance events, lasting more than 8 hours, result in large sweat sodium chloride losses. Thus, ingestion of large amounts of water with poor salt intake can induce symptomatic hyponatremia (plasma sodium < 130 mEq/L) which is also a serious accident. Heat environment increases the thermal constraint and when the air humidity is high, evaporation of sweat is compromise. Thus, thermal stress becomes uncompensable which increases the risk of cardiovascular collapse. Cold exposure induces physiological responses to maintain internal temperature by both limiting thermal losses and increasing metabolic heat production. Cold can induce accidental hypothermia and local frost-bites; moreover, it increases the risk of arrhythmia during exercise. Some guidelines (cardiovascular fitness, water and electrolyte intakes, protective clothing) are given for each extreme condition.

Effects of fluid ingestion on cognitive function after heat stress or exercise-induced dehydration.

This study investigated the effects of heat exposure, exercise-induced dehydration and fluid ingestion on cognitive performance. Seven healthy men, unacclimatized to heat, were kept euhydrated or were dehydrated by controlled passive exposure to heat (H, two sessions) or by treadmill exercise (E, two sessions) up to a weight loss of 2.8%. On completion of a 1-h recovery period, the subjects drank a solution containing 50 g l(-1) glucose and 1.34 g l(-1) NaCl in a volume of water corresponding to 100% of his body weight loss induced by dehydration. (H1 and E1) or levels of fluid deficit were maintained (H0, E0). In the E0, H0 and control conditions, the subject drank a solution containing the same quantity of glucose diluted in 100 ml of water. Psychological tests were administered 30 min after the dehydration phase and 2 h after fluid ingestion. Both dehydration conditions impaired cognitive abilities (i.e. perceptive discrimination, short-term memory), as well as subjective estimates of fatigue, without any relevant differences between the methods. By 3.5 h after fluid deficit, dehydration (H0 and E0) no longer had any adverse effect, although the subjects felt increasingly tired. Thus, there was no beneficial effect of fluid ingestion (H1 and E1) on the cognitive variables. However, long-term memory retrieval was impaired in both control and dehydration situations, whereas there was no decrement in performance in the fluid ingestion condition (H1, E1).

Surface EMG and psychophysiological stress reactions in women during repetitive work.

In order to understand the high prevalence of musculoskeletal disorders associated with stressful work, it is important to explore the relationship between muscle activity and psychophysiological stress responses. The present real-life study examines surface trapezius electromyographic (sEMG) activity, heart rate, blood pressure, and levels of urinary catecholamines and salivary cortisol among 31 female employees working at supermarkets, where the prevalence of neck and shoulder disorders is high (60-70%). As expected, the results show that psychophysiological arousal was high during work. Significant correlations were found between self-reports indicating negative stress (stressed, exhausted, tense) and sEMG activity during work. No significant correlations were found between self-reports of positive reactions (stimulated, concentrated, happy) and sEMG activity. No associations were found between sEMG activity and pain or between negative stress ratings and pain. Objectively measured workload and physiological stress responses did not correlate significantly with sEMG activity. Thus, our data indicate that perceived negative stress may have a specific influence on muscle activity, which may be of importance for musculoskeletal disorders in jobs with low-to-moderate physical load and negative psychosocial factors.

Trapezius muscle activity, neck and shoulder pain, and subjective experiences during monotonous work in women.

The electromyographic (EMG) activity patterns of 18 female supermarket employees reporting neck and shoulder pain were compared with those of 6 of their female colleagues reporting no pain when doing cash-register work. It was found that the EMG activity of the trapezius muscle tended to show a lack of low and high levels among pain subjects, and that the time the trapezius muscle was at rest was longer in the group reporting no pain. In the non-dominant side, the muscle rest time was significantly longer (P < 0.05) in the group reporting no pain, and this group also showed a larger EMG activity difference between the dominant and non-dominant sides, indicating a less static bilateral muscle activation. Self-reports of negative experiences (stressed, exhausted and tense) were somewhat higher in the group reporting pain, while positive experiences during work (concentrated, stimulated and happy) appeared to be similar in the two groups of supermarket employees.

Use of bioelectrical impedance analysis to estimate body fluid compartments after acute variations of the body hydration level.

Physiological measurements including body mass, plasma osmolality, natremia, plasma volume measured by Evans Blue dilution, and total body water (TBW) and extracellular water (ECW) volumes estimated by bioelectrical impedance analysis (BIA) were recorded in eight healthy young Caucasian subjects before and after acute variations of their body hydration state on four separate occasions: 1) euhydration or control trial (C); 2) heat-induced dehydration of 2.8% body mass (D); 3) exercise-induced dehydration of 2.8% body mass (E); and 4) glycerol-hyperhydration (H). Heart rate, rectal and mean skin temperatures were also recorded throughout the experiment. The main result of the study is that BIA only half predicted the body water loss after exercise, although conditions were standardized (electrode placement, side of the body, limb position, posture, and ambient temperature). Differences in body temperatures cannot explain such an unexpected result, nor did the study of plasma osmolality and sodium concentration. If BIA appears to adequately predict changes in TBW after heat-induced dehydration and glycerol hyperhydration, further studies including measures of TBW and ECW by dilution tracer methods would be necessary to establish the validity of using the BIA method to measure such changes and to interpret ECW variations.

Personal sampling in parallel with open-face filter cassettes and IOM samplers for inhalable dust--implications for occupational exposure limits.

Parallel personal sampling was carried out with the open-face filter cassette and the IOM sampler for inhalable dust for nine types of organic dust. Parallel samples numbering 749 were obtained from 152 plants. Extremely large values and outliers were disregarded, and the remaining data for each type of dust were divided into subsets according to type of product or work task, and analyzed with the aid of linear regression. The coefficient of regression for each subset ranged between 0.2 and 0.7. Hypothetical occupational exposure limits (OELs) for inhalable dust were calculated based on the linear relation obtained between the dust concentrations measured with the open-face filter cassette and the IOM sampler. The fraction of person days with time-weighted average (TWA) concentrations exceeding the calculated hypothetical OELs for inhalable dust was obtained from the distribution of measured TWA inhalable dust concentrations. Based on the results of this study and the difference in sampling efficiency for large particles between the two samplers, it was concluded that the numerical value of the OEL for inhalable dust may be set at approximately twice the numerical value of the corresponding limit value for "total dust." Additional consideration of recently discovered health effects, and technical and economical factors may result in other numerical values of future OELs for inhalable dust.

Determination of the velocity associated with VO2max.

PURPOSE: The theoretical velocity associated with VO2max (vVO2max) defined by Daniels (1985) is extrapolated from the submaximal VO2-velocity relationship. VO2 is generally determined by assuming that the aerobic response reacts like a linear first-order system at the beginning of square-wave exercise with a steady-state reached by the 4th minute. However, at supra-ventilatory threshold work rates, the steady state in VO2 is delayed or not attained. METHODS: The present study was carried out to compare three values for vVO2max determined with Daniels' method, but with VO2 either measured at the 4th minute (vVO2max4), the 6th minute (vVO2max6), or after the attainment of the true steady-state (vVO2maxSS). The metabolic response during square-wave exercise at each of the three vVO2max were also assessed. RESULTS: These velocities were significantly different (P < 0.05), but vVOmaxSS and vVO2max6 were highly correlated (r = 0.98; P < 0.05). Blood lactate concentrations measured after exercise at velocities very close to the three vVO2max were similar and the end-exercise VO2 were not different from VO2max, but the time required to elicit 95% VO2max during these three square-wave tests were significantly different. CONCLUSION: Therefore, when vVO2max is determined by extrapolation from the submaximal VO2-velocity relationships, submaximal VO2 should be measured beyond the 6th minute of square-wave exercise (at least if it takes 30 s to reach the desired velocity) to ensure that all vVO2max reported in future studies describe a similar quantitative index.

Psychophysiological stress responses, muscle tension, and neck and shoulder pain among supermarket cashiers.

This study examined psychological and physiological stress, as well as muscle tension and musculoskeletal symptoms, among 72 female supermarket cashiers. Stress levels were found to be significantly elevated at work, as reflected in the catecholamines, blood pressure, heart rate, electromyographic (EMG) activity, and self-reports. Fifty cashiers (70%) suffering from neck-shoulder pain (trapezius myalgia) were found to have higher EMG activity at work and reported more tension after work. Women who kept a diary for 1 week and reported more musculoskeletal pain (above the median) were older, had higher blood pressure, and reported more work stress and psychosomatic symptoms. The elevated stress levels at work are consistent with data from workers involved in other types of repetitive tasks and can be important for the high prevalence of neck and shoulder symptoms among the cashiers.