Concentration of Airborne Staphylococcus aureus (MRSA and MSSA), Total Bacteria, and Endotoxins in Pig Farms.

Pigs are very often colonized by Staphylococcus aureus and transmission of such pig-associated S. aureus to humans can cause serious medical, hygiene, and economic problems. The transmission route of zoonotic pathogens colonizing farm animals to humans is not well established and bioaerosols could play an important role. The aim of this study was to assess the potential occupational risk of working with S. aureus-colonized pigs in Switzerland. We estimated the airborne contamination by S. aureus in 37 pig farms (20 nursery and 17 fattening units; 25 in summer, 12 in winter). Quantification of total airborne bacterial DNA, airborne Staphylococcus sp. DNA, fungi, and airborne endotoxins was also performed. In this experiment, the presence of cultivable airborne methicillin-resistant S. aureus (MRSA) CC398 in a pig farm in Switzerland was reported for the first time. Airborne methicillin-sensitive S. aureus (MSSA) was found in ~30% of farms. The average airborne concentration of DNA copy number of total bacteria and Staphylococcus sp. measured by quantitative polymerase chain reaction was very high, respectively reaching values of 75 (± 28) × 10(7) and 35 (± 9.8) × 10(5) copy numbers m(-3) in summer and 96 (± 19) × 10(8) and 40 (± 12) × 10(6) copy numbers m(-3) in winter. Total mean airborne concentrations of endotoxins (1298 units of endotoxin m(-3)) and fungi (5707 colony-forming units m(-3)) exceeded the Swiss recommended values and were higher in winter than in summer. In conclusion, Swiss pig farmers will have to tackle a new emerging occupational risk, which could also have a strong impact on public health. The need to inform pig farmers about biological occupational risks is therefore crucial.

Comparison of plantar pressure distribution in adolescent runners at low vs. high running velocity

This study aimed to compare foot plantar pressure distribution while jogging and running in highly trained adolescent runners. Eleven participants performed two constant-velocity running trials either at jogging (11.2 ± 0.9 km/h) or running (17.8 ± 1.4 km/h) pace on a treadmill. Contact area (CA in cm(2)), maximum force (F(max) in N), peak pressure (PP in kPa), contact time (CT in ms), and relative load (force time integral in each individual region divided by the force time integral for the total plantar foot surface, in %) were measured in nine regions of the right foot using an in-shoe plantar pressure device. Under the whole foot, CA, F(max) and PP were lower in jogging than in running (-1.2% [p<0.05], -12.3% [p<0.001] and -15.1% [p<0.01] respectively) whereas CT was higher (+20.1%; p<0.001). Interestingly, we found an increase in relative load under the medial and central forefoot regions while jogging (+6.7% and +3.7%, respectively; [p<0.05]), while the relative load under the lesser toes (-8.4%; p<0.05) was reduced. In order to prevent overloading of the metatarsals in adolescent runners, excessive mileage at jogging pace should be avoided.

The micro-architecture estimation by TBS discriminate women with and without osteoporotic fracture independently of age, BMI and BMD: The Osteo-Mobile Vaud cohort study.

Introduction: « Osteo-Mobile Vaud » is a mobile osteoporosis (OP) screening program. The women > 60 years living in the region Vaud will be offered OP screening with new equipment installed in a bus. The main goal is to evaluate the fracture risk with the combination of clinical risk factors (CRF) and informations extracted by a single DXA: bone mineral density (BMD), vertebral fracture assessment (VFA), and micro-architecture (MA) evaluation. MA is yet evaluable in daily practice by the Trabecular Bone Score (TBS) measure. TBS is a novel grey-level texture measurement reflecting bone MA based on the use of experimental variograms of 2D projection images. TBS is very simple to obtain, by reanalyzing a lumbar DXA-scan. TBS has proven to have diagnosis and prognosis value, partially independent of CRF and BMD. A 55-years follow- up is planned. Method: The Osteo-Mobile Vaud cohort (1500 women, > 60 years, living in the region Vaud) started in July 2010. CRF for OP, lumbar spine and hip BMD, VFA by DXA and MA evaluation by TBS are recorded. Preliminary results are reported. Results: In July 31th, we evaluated 510 women: mean age 67 years, BMI 26 kg/m². 72 women had one or more fragility fractures, 39 had vertebral fracture (VFx) grade 2/3. TBS decreases with age (-0.005 / year, p<0.001), and with BMI (-0.011 per kg/m², p<0.001). Correlation between BMD and site matched TBS is low (r=0.4, p<0.001). For the lowest T-score BMD, odds ratio (OR, 95% CI) for VFx grade 2/3 and clinical OP Fx are 1.8 (1.1-2.9) and 2.3 (1.5-3.4). For TBS, age-, BMI- and BMD adjusted ORs (per SD decrease) for VFx grade 2/3 and clinical OP Fx are 1.9 (1.2-3.0) and 1.8 (1.2-2.7). The TBS added value was independent of lumbar spine BMD or the lowest T-score (femoral neck, total hip or lumbar spine). Conclusion: As in the already published studies, these preliminary results confirm the partial independence between BMD and TBS. More importantly, a combination of TBS and BMD may increase significantly the identification of women with prevalent OP Fx. For the first time we are able to have complementary information about fracture (VFA), density (BMD), and micro-architecture (TBS) from a simple, low ionizing radiation and cheap device: DXA. The value of such informations in a screening program will be evaluated.

Quadrant/octant sequencing and the role of coherent structures in bed load sediment entrainment

To permit the tracking of turbulent flow structures in an Eulerian frame from single-point measurements, we make use of a generalization of conventional two-dimensional quadrant analysis to three-dimensional octants. We characterize flow structures using the sequences of these octants and show how significance may be attached to particular sequences using statistical mull models. We analyze an example experiment and show how a particular dominant flow structure can be identified from the conditional probability of octant sequences. The frequency of this structure corresponds to the dominant peak in the velocity spectra and exerts a high proportion of the total shear stress. We link this structure explicitly to the propensity for sediment entrainment and show that greater insight into sediment entrainment can be obtained by disaggregating those octants that occur within the identified macroturbulence structure from those that do not. Hence, this work goes beyond critiques of Reynolds stress approaches to bed load entrainment that highlight the importance of outward interactions, to identifying and prioritizing the quadrants/octants that define particular flow structures. Key Points <list list-type=''bulleted'' id=''jgrf20196-list-0001''> <list-item id=''jgrf20196-li-0001''>A new method for analysing single point velocity data is presented <list-item id=''jgrf20196-li-0002''>Flow structures are identified by a sequence of flow states (termed octants) <list-item id=''jgrf20196-li-0003''>The identified structure exerts high stresses and causes bed-load entrainment

Glutamine and antioxidants in the critically ill patient: a post hoc analysis of a large-scale randomized trial.

BACKGROUND: The recent large randomized controlled trial of glutamine and antioxidant supplementation suggested that high-dose glutamine is associated with increased mortality in critically ill patients with multiorgan failure. The objectives of the present analyses were to reevaluate the effect of supplementation after controlling for baseline covariates and to identify potentially important subgroup effects. MATERIALS AND METHODS: This study was a post hoc analysis of a prospective factorial 2 × 2 randomized trial conducted in 40 intensive care units in North America and Europe. In total, 1223 mechanically ventilated adult patients with multiorgan failure were randomized to receive glutamine, antioxidants, both glutamine and antioxidants, or placebo administered separate from artificial nutrition. We compared each of the 3 active treatment arms (glutamine alone, antioxidants alone, and glutamine + antioxidants) with placebo on 28-day mortality. Post hoc, treatment effects were examined within subgroups defined by baseline patient characteristics. Logistic regression was used to estimate treatment effects within subgroups after adjustment for baseline covariates and to identify treatment-by-subgroup interactions (effect modification). RESULTS: The 28-day mortality rates in the placebo, glutamine, antioxidant, and combination arms were 25%, 32%, 29%, and 33%, respectively. After adjusting for prespecified baseline covariates, the adjusted odds ratio of 28-day mortality vs placebo was 1.5 (95% confidence interval, 1.0-2.1, P = .05), 1.2 (0.8-1.8, P = .40), and 1.4 (0.9-2.0, P = .09) for glutamine, antioxidant, and glutamine plus antioxidant arms, respectively. In the post hoc subgroup analysis, both glutamine and antioxidants appeared most harmful in patients with baseline renal dysfunction. No subgroups suggested reduced mortality with supplements. CONCLUSIONS: After adjustment for baseline covariates, early provision of high-dose glutamine administered separately from artificial nutrition was not beneficial and may be associated with increased mortality in critically ill patients with multiorgan failure. For both glutamine and antioxidants, the greatest potential for harm was observed in patients with multiorgan failure that included renal dysfunction upon study enrollment.

Impact of the introduction of real-time therapeutic drug monitoring on empirical doses of carbapenems in critically ill burn patients.

PURPOSE: Adequate empirical antibiotic dose selection for critically ill burn patients is difficult due to extreme variability in drug pharmacokinetics. Therapeutic drug monitoring (TDM) may aid antibiotic prescription and implementation of initial empirical antimicrobial dosage recommendations. This study evaluated how gradual TDM introduction altered empirical dosages of meropenem and imipenem/cilastatin in our burn ICU. METHODS: Imipenem/cilastatin and meropenem use and daily empirical dosage at a five-bed burn ICU were analyzed retrospectively. Data for all burn admissions between 2001 and 2011 were extracted from the hospital's computerized information system. For each patient receiving a carbapenem, episodes of infection were reviewed and scored according to predefined criteria. Carbapenem trough serum levels were characterized. Prior to May 2007, TDM was available only by special request. Real-time carbapenem TDM was introduced in June 2007; it was initially available weekly and has been available 4 days a week since 2010. RESULTS: Of 365 patients, 229 (63%) received antibiotics (109 received carbapenems). Of 23 TDM determinations for imipenem/cilastatin, none exceeded the predefined upper limit and 11 (47.8%) were insufficient; the number of TDM requests was correlated with daily dose (r=0.7). Similar numbers of inappropriate meropenem trough levels (30.4%) were below and above the upper limit. Real-time TDM introduction increased the empirical dose of imipenem/cilastatin, but not meropenem. CONCLUSIONS: Real-time carbapenem TDM availability significantly altered the empirical daily dosage of imipenem/cilastatin at our burn ICU. Further studies are needed to evaluate the individual impact of TDM-based antibiotic adjustment on infection outcomes in these patients.

Cannabis use and other predictors of the onset of daily cigarette use in young men: what matters most? Results from a longitudinal study.

BACKGROUND: According to the gateway hypothesis, tobacco use is a gateway of cannabis use. However, there is increasing evidence that cannabis use also predicts the progression of tobacco use (reverse gateway hypothesis). Unfortunately, the importance of cannabis use compared to other predictors of tobacco use is less clear. The aim of this study was to examine which variables, in addition to cannabis use, best predict the onset of daily cigarette smoking in young men. METHODS: A total of 5,590 young Swiss men (mean age = 19.4 years, SD = 1.2) provided data on their substance use, socio-demographic background, religion, health, social context, and personality at baseline and after 18 months. We modelled the predictors of progression to daily cigarette smoking using logistic regression analyses (n = 4,230). RESULTS: In the multivariate overall model, use of cannabis remained among the strongest predictors for the onset of daily cigarette use. Daily cigarette use was also predicted by a lifetime use of at least 50 cigarettes, occasional cigarette use, educational level, religious affiliation, parental situation, peers with psychiatric problems, and sociability. CONCLUSIONS: Our results highlight the relevance of cannabis use compared to other potential predictors of the progression of tobacco use and thereby support the reverse gateway hypothesis.

Positive Emotions Program for Schizophrenia (PEPS): a pilot intervention to reduce anhedonia and apathy.

BACKGROUND: Recent literature has distinguished the negative symptoms associated with a diminished capacity to experience (apathy, anhedonia) from symptoms associated with a limited capacity for expression (emotional blunting, alogia). The apathy-anhedonia syndrome tends to be associated with a poorer prognosis than the symptoms related to diminished expression. The efficacy of drug-based treatments and psychological interventions for these symptoms in schizophrenia remains limited. There is a clear clinical need for new treatments. METHODS: This pilot study tested the feasibility of a program to reduce anhedonia and apathy in schizophrenia and assessed its impact on 37 participants meeting the ICD-10 criteria for schizophrenia or schizoaffective disorders. Participants were pre- and post-tested using the Scale for the Assessment of Negative Symptoms (SANS) and the Calgary Depression Scale for Schizophrenia (CDSS). They took part in eight sessions of the Positive Emotions Program for Schizophrenia (PEPS)--an intervention that teaches participants skills to help overcome defeatist thinking and to increase the anticipation and maintenance of positive emotions. RESULTS: Thirty-one participants completed the program; those who dropped out did not differ from completers. Participation in the program was accompanied by statistically significant reductions in the total scores for Avolition-Apathy and Anhedonia-Asociality on the SANS, with moderate effect sizes. Furthermore, there was a statistically significant reduction of depression on the CDSS, with a large effect size. Emotional blunting and alogia remain stable during the intervention. DISCUSSION: Findings indicate that PEPS is both a feasible intervention and is associated with an apparently specific reduction of anhedonia and apathy. However, these findings are limited by the absence of control group and the fact that the rater was not blind to the treatment objectives. CONCLUSIONS: PEPS is a promising intervention to improve anhedonia and apathy which need to be tested further in a controlled study. TRIAL REGISTRATION NUMBER: ISRCTN registry ISRCTN74048461, registered 18 may 2015.

Once-daily dolutegravir versus darunavir plus ritonavir for treatment-naive adults with HIV-1 infection (FLAMINGO): 96 week results from a randomised, open-label, phase 3b study.

BACKGROUND: The primary analysis of the FLAMINGO study at 48 weeks showed that patients taking dolutegravir once daily had a significantly higher virological response rate than did those taking ritonavir-boosted darunavir once daily, with similar tolerability. We present secondary efficacy and safety results analysed at 96 weeks. METHODS: FLAMINGO was a multicentre, open-label, phase 3b, non-inferiority study of HIV-1-infected treatment-naive adults. Patients were randomly assigned (1:1) to dolutegravir 50 mg or darunavir 800 mg plus ritonavir 100 mg, with investigator-selected combination tenofovir and emtricitabine or combination abacavir and lamivudine background treatment. The main endpoints were plasma HIV-1 RNA less than 50 copies per mL and safety. The non-inferiority margin was -12%. If the lower end of the 95% CI was greater than 0%, then we concluded that dolutegravir was superior to ritonavir-boosted darunavir. This trial is registered with ClinicalTrials.gov, number NCT01449929. FINDINGS: Of 595 patients screened, 488 were randomly assigned and 484 included in the analysis (242 assigned to receive dolutegravir and 242 assigned to receive ritonavir-boosted darunavir). At 96 weeks, 194 (80%) of 242 patients in the dolutegravir group and 164 (68%) of 242 in the ritonavir-boosted darunavir group had HIV-1 RNA less than 50 copies per mL (adjusted difference 12·4, 95% CI 4·7-20·2; p=0·002), with the greatest difference in patients with high viral load at baseline (50/61 [82%] vs 32/61 [52%], homogeneity test p=0·014). Six participants (three since 48 weeks) in the dolutegravir group and 13 (four) in the darunavir plus ritonavir group discontinued because of adverse events. The most common drug-related adverse events were diarrhoea (23/242 [10%] in the dolutegravir group vs 57/242 [24%] in the darunavir plus ritonavir group), nausea (31/242 [13%] vs 34/242 [14%]), and headache (17/242 [7%] vs 12/242 [5%]). INTERPRETATION: Once-daily dolutegravir is associated with a higher virological response rate than is once-daily ritonavir-boosted darunavir. Dolutegravir compares favourably in efficacy and safety to a boosted darunavir regimen with nucleoside reverse transcriptase inhibitor background treatment for HIV-1-infected treatment-naive patients. FUNDING: ViiV Healthcare and Shionogi & Co.

A qualitative study of adolescents with medically unexplained symptoms and their parents. Part 1: Experiences and impact on daily life.

Medically unexplained symptoms (MUS) are common among adolescents and are frequently encountered in primary care. Our aim was to explore how these adolescents and their parents experience the condition and its impact on their daily lives and to provide recommendations for health professionals. Using a qualitative approach, six focus groups and two individual interviews were conducted. These involved a total of ten adolescents with different types of MUS and sixteen parents. The respondents were recruited in a university hospital in Switzerland. A thematic analysis was conducted according to the Grounded Theory. The analysis of the data highlighted four core themes: disbelief, being different, concealing symptoms, and priority to adolescent's health. Transcending these themes was a core issue regarding the discrepancy between the strategies that adolescents and their parents use to cope with the symptoms. Health professionals should be made aware of the emotional needs of these patients and their families.

Influence on Strength and Flexibility of a Swing Phase-Specific Hamstring Eccentric Program in Sprinters' General Preparation

Guex, KJ, Lugrin, V, Borloz, S, and Millet, GP. Influence on strength and flexibility of a swing phase-specific hamstring eccentric program in sprinters' general preparation. J Strength Cond Res 30(2): 525-532, 2016-Hamstring injuries are common in sprinters and mainly occur during the terminal swing phase. Eccentric training has been shown to reduce hamstring injury rate by improving several risk factors. The aim of this study was to test the hypothesis that an additional swing phase-specific hamstring eccentric training in well-trained sprinters performed at the commencement of the winter preparation is more efficient to improve strength, ratio, optimum angle, and flexibility than a similar program without hamstring eccentric exercises. Twenty sprinters were randomly allocated to an eccentric (n = 10) or a control group (n = 10). Both groups performed their usual track and field training throughout the study period. Sprinters in the eccentric group performed an additional 6-week hamstring eccentric program, which was specific to the swing phase of the running cycle (eccentric high-load open-chain kinetic movements covering the whole hamstring length-tension relationship preformed at slow to moderate velocity). Isokinetic and flexibility measurements were performed before and after the intervention. The eccentric group increased hamstring peak torques in concentric at 60 degrees .s by 16% (p < 0.001) and at 240 degrees .s by 10% (p < 0.01), in eccentric at 30 degrees .s by 20% (p < 0.001) and at 120 degrees .s by 22% (p < 0.001), conventional and functional ratios by 12% (p < 0.001), and flexibility by 4 degrees (p < 0.01), whereas the control group increased hamstring peak torques only in eccentric at 30 degrees .s by 6% (p </= 0.05) and at 120 degrees .s by 6% (p < 0.01). It was concluded that an additional swing phase-specific hamstring eccentric training in sprinters seems to be crucial to address different risk factors for hamstring strain injuries, such as eccentric and concentric strength, hamstring-to-quadriceps ratio ratio, and flexibility.

Moderate glycemic control safe in critically ill adult burn patients: A 15 year cohort study.

INTRODUCTION: Hyperglycemia is a metabolic alteration in major burn patients associated with complications. The study aimed at evaluating the safety of general ICU glucose control protocols applied in major burns receiving prolonged ICU treatment. METHODS: 15year retrospective analysis of consecutive, adult burn patients admitted to a single specialized centre. EXCLUSION CRITERIA: death or length of stay <10 days, age <16years. VARIABLES: demographic variables, burned surface (TBSA), severity scores, infections, ICU stay, outcome. Metabolic variables: total energy, carbohydrate and insulin delivery/24h, arterial blood glucose and CRP values. Analysis of 4 periods: 1, before protocol; 2, tight doctor driven; 3, tight nurse driven; 4, moderate nurse driven. RESULTS: 229 patients, aged 45±20 years (mean±SD), burned 32±20% TBSA were analyzed. SAPSII was 35±13. TBSA, Ryan and ABSI remained stable. Inhalation injury increased. A total of 28,690 blood glucose samples were analyzed: the median value remained unchanged with a narrower distribution over time. After the protocol initiation, the normoglycemic values increased from 34.7% to 65.9%, with a reduction of hypoglycaemic events (no extreme hypoglycemia in period 4). Severe hyperglycemia persisted throughout with a decrease in period 4 (9.25% in period 4). Energy and glucose deliveries decreased in periods 3 and 4 (p<0.0001). Infectious complications increased during the last 2 periods (p=0.01). CONCLUSION: A standardized ICU glucose control protocol improved the glycemic control in adult burn patients, reducing glucose variability. Moderate glycemic control in burns was safe specifically related to hypoglycemia, reducing the incidence of hypoglycaemic events compared to the period before. Hyperglycemia persisted at a lower level.

Aerosol therapy in intensive and intermediate care units: prospective observation of 2808 critically ill patients.

PURPOSE: Unlike in the outpatient setting, delivery of aerosols to critically ill patients may be considered complex, particularly in ventilated patients, and benefits remain to be proven. Many factors influence aerosol delivery and recommendations exist, but little is known about knowledge translation into clinical practice. METHODS: Two-week cross-sectional study to assess the prevalence of aerosol therapy in 81 intensive and intermediate care units in 22 countries. All aerosols delivered to patients breathing spontaneously, ventilated invasively or noninvasively (NIV) were recorded, and drugs, devices, ventilator settings, circuit set-up, humidification and side effects were noted. RESULTS: A total of 9714 aerosols were administered to 678 of the 2808 admitted patients (24 %, CI95 22-26 %), whereas only 271 patients (10 %) were taking inhaled medication before admission. There were large variations among centers, from 0 to 57 %. Among intubated patients 22 % (n = 262) received aerosols, and 50 % (n = 149) of patients undergoing NIV, predominantly (75 %) inbetween NIV sessions. Bronchodilators (n = 7960) and corticosteroids (n = 1233) were the most frequently delivered drugs (88 % overall), predominantly but not exclusively (49 %) administered to patients with chronic airway disease. An anti-infectious drug was aerosolized 509 times (5 % of all aerosols) for nosocomial infections. Jet-nebulizers were the most frequently used device (56 %), followed by metered dose inhalers (23 %). Only 106 (<1 %) mild side effects were observed, despite frequent suboptimal set-ups such as an external gas supply of jet nebulizers for intubated patients. CONCLUSIONS: Aerosol therapy concerns every fourth critically ill patient and one-fifth of ventilated patients.

Constrained Total Energy Expenditure and Metabolic Adaptation to Physical Activity in Adult Humans.

Current obesity prevention strategies recommend increasing daily physical activity, assuming that increased activity will lead to corresponding increases in total energy expenditure and prevent or reverse energy imbalance and weight gain [1-3]. Such Additive total energy expenditure models are supported by exercise intervention and accelerometry studies reporting positive correlations between physical activity and total energy expenditure [4] but are challenged by ecological studies in humans and other species showing that more active populations do not have higher total energy expenditure [5-8]. Here we tested a Constrained total energy expenditure model, in which total energy expenditure increases with physical activity at low activity levels but plateaus at higher activity levels as the body adapts to maintain total energy expenditure within a narrow range. We compared total energy expenditure, measured using doubly labeled water, against physical activity, measured using accelerometry, for a large (n = 332) sample of adults living in five populations [9]. After adjusting for body size and composition, total energy expenditure was positively correlated with physical activity, but the relationship was markedly stronger over the lower range of physical activity. For subjects in the upper range of physical activity, total energy expenditure plateaued, supporting a Constrained total energy expenditure model. Body fat percentage and activity intensity appear to modulate the metabolic response to physical activity. Models of energy balance employed in public health [1-3] should be revised to better reflect the constrained nature of total energy expenditure and the complex effects of physical activity on metabolic physiology.

Sociodemographic, behavioral and genetic determinants of allostatic load in a Swiss population-based study.

Allostatic load (AL) is a marker of physiological dysregulation which reflects exposure to chronic stress. High AL has been related to poorer health outcomes including mortality. We examine here the association of socioeconomic and lifestyle factors with AL. Additionally, we investigate the extent to which AL is genetically determined. We included 803 participants (52% women, mean age 48±16years) from a population and family-based Swiss study. We computed an AL index aggregating 14 markers from cardiovascular, metabolic, lipidic, oxidative, hypothalamus-pituitary-adrenal and inflammatory homeostatic axes. Education and occupational position were used as indicators of socioeconomic status. Marital status, stress, alcohol intake, smoking, dietary patterns and physical activity were considered as lifestyle factors. Heritability of AL was estimated by maximum likelihood. Women with a low occupational position had higher AL (low vs. high OR=3.99, 95%CI [1.22;13.05]), while the opposite was observed for men (middle vs. high OR=0.48, 95%CI [0.23;0.99]). Education tended to be inversely associated with AL in both sexes(low vs. high OR=3.54, 95%CI [1.69;7.4]/OR=1.59, 95%CI [0.88;2.90] in women/men). Heavy drinking men as well as women abstaining from alcohol had higher AL than moderate drinkers. Physical activity was protective against AL while high salt intake was related to increased AL risk. The heritability of AL was estimated to be 29.5% ±7.9%. Our results suggest that generalized physiological dysregulation, as measured by AL, is determined by both environmental and genetic factors. The genetic contribution to AL remains modest when compared to the environmental component, which explains approximately 70% of the phenotypic variance.