Health Economics

The economics of antibiotic resistance: a claim for personalised treatments

Patient responsiveness to a differential deductible: empirical results from The Netherlands Abstract Health insurers may use financial incentives to encourage their enrollees to choose preferred providers for medical treatment. Empirical evidence whether differences in cost-sharing rates across providers affects patient choice behavior is, especially from Europe, limited. This paper examines the effect of a differential deductible to steer patient provider choice in a Dutch regional market for varicose veins treatment. Using individual patients' choice data and information about their out-of-pocket payments covering the year of the experiment and 1 year before, we estimate a conditional logit model that explicitly controls for pre-existing patient preferences. Our results suggest that in this natural experiment designating preferred providers and waiving the deductible for enrollees using these providers significantly influenced patient choice. The average cross-price elasticity of demand is found to be 0.02, indicating that patient responsiveness to the cost-sharing differential itself was low. Unlike fixed cost-sharing differences, the deductible exemption was conditional on the patient's other medical expenses occurring in the policy year. The differential deductible did, therefore, not result in a financial benefit for patients with annual costs exceeding their total deductible.

Including intangible costs into the cost-of-illness approach: a method refinement illustrated based on the PM 2.5 economic burden in China Abstract The concentrations of particulate matter with aerodynamic diameters less than 2.5 µm (PM2.5) and 10 µm (PM10) is a widespread concern and has been demonstrated for 103 countries. During the past few years, the exposure–response function (ERf) has been widely used to estimate the health effects of air pollution. However, past studies are either based on the cost-of-illness or the willingness-to-pay approach, and therefore, either do not cover intangible costs or costs due to the absence of work. To address this limitation, a hybrid health effect and economic loss model is developed in this study. This novel approach is applied to a sample of environmental and cost data in China. First, the ERf is used to link PM2.5 concentrations to health endpoints of chronic mortality, acute mortality, respiratory hospital admission, cardiovascular hospital admission, outpatient visits—internal medicine, outpatient visits—pediatrics, asthma attack, acute bronchitis, and chronic bronchitis. Second, the health effect of PM2.5 is monetized into the economic loss. The mean economic loss due to PM2.5was much heavier in the North than the South of China. Furthermore, the empirical results from 76 cities in China show that the health effects and economic losses were over 4.98 million cases and 382.30 billion-yuan in 2014 and decreased dramatically compared with those in 2013.

Unemployment and suicide in Italy: evidence of a long-run association mitigated by public unemployment spending Abstract From the mid-1990s on, the suicide rate in Italy declined steadily, then apparently rose again after the onset of the Great Recession, along with a sharp increase in unemployment. The aim of this study is to test the association between the suicide rate and unemployment (i.e., the unemployment rate for males and females in the period 1977–2015, and the long-term unemployment rate in the period 1983–2012) in Italy, by means of cointegration techniques. The analysis was adjusted for public unemployment spending (referring to the period 1980–2012). The study identified a long-run relationship between the suicide rate and long-term unemployment. On the other hand, an association between suicide and unemployment rate emerged, though statistically weaker. A 1% increase in long-term unemployment increases the suicide rate by 0.83%, with a long-term effect lasting up to 18 years. Public unemployment spending (as percentage of the Italian gross domestic product) may mitigate this association: when its annual growth rate is higher than 0.18%, no impact of unemployment on suicide in detectable. A decrease in the suicide rate is expected for higher amounts of social spending, which may be able to compensate for the reduced level of social integration resulting from unemployment, helping the individual to continue to integrate into society. A corollary of this is that austerity in times of economic recession may exacerbate the impact of the economic downturn on mental health. However, a specific "flexicurity" system (intended as a combination of high employment protection, job satisfaction and labour-market policies) may have a positive impact on health.

Income distribution and health: can polarization explain health outcomes better than inequality? Abstract Utilizing data from the China Health and Nutrition Survey (CHNS) from 1991 to 2011, we aim to analyze the effects of income distribution on two risks for chronic diseases: body mass index (BMI) and blood pressure. Unlike the previous studies, we consider two different kinds of indicators of income distribution: inequality and polarization. Different from relative inequality indicators such as the Gini index, which measure income gaps only, the recently developed polarization indicator captures group clustering and social alienation, in addition to income gaps. Our empirical results demonstrate that both BMI and blood pressure are positively correlated with income polarization, while inequality is a weaker predictor of these health outcomes. Thus, polarization, rather than inequality, should be used when analyzing the relationship between health outcomes and income distribution. We also examine the polarization-to-health transmission mechanism using mediation and moderation analytic frameworks. The results suggest that social networks mediate the effect of polarization on BMI and neutralize the effect on blood pressure.

Co-ordination of health care: the case of hospital emergency admissions Abstract The recognition that chronic care delivery is suboptimal has led many health authorities around the world to redesign it. In Norway, the Department of Health and Care Services implemented the Coordination Reform in January 2012. One policy instrument was to build emergency bed capacity (EBC) as an integrated part of primary care service provided by municipalities. The explicit aim was to reduce the rate of avoidable admissions to state-owned hospitals. Using five different sources of register data and a quasi-experimental framework—the "difference-in-differences" regression approach—we estimated the association between changes in EBC on changes in aggregate emergency hospital admissions for eight ambulatory care sensitive conditions (ACSC). The results show that EBC is negatively associated with changes in aggregate ACSC emergency admissions. The associations are largely consistent with alternative model specifications. We also estimated the relationship between changes in EBC on changes in each ACSC condition separately. Our results are mixed. EBC is negatively associated with emergency hospital admissions for asthma, angina and chronic obstructive pulmonary disease but not congestive heart failure and diabetes. The main implication of the study is that EBC within primary care is potentially a sensible way of redesigning chronic care.

Impact of early primary care follow-up after discharge on hospital readmissions Abstract Reducing repeated hospitalizations of patients with chronic conditions is a policy objective for improving system efficiency. We test the hypothesis that the risk of readmission is associated with the timing and intensity of primary care follow-up after discharge, focusing on patients hospitalized for heart failure in France. We propose a discrete-time model which takes into account that primary care treatments have a lagged and cumulative effect on readmission risk, and an instrumental variable approach, exploiting geographical differences in availability of generalists. We show that the early consultations with a GP after discharge can reduce the 28-day readmission risk by almost 50%, and that patients with higher ambulatory care utilization have smaller odds of readmission. Furthermore, geographical disparities in primary care affect indirectly the readmission risk. These results suggest that interventions which strengthen communication between hospitals and generalists are elemental for reducing readmissions and for developing effective strategies at the hospital level, it is also necessary to consider primary care resources that are available to patients.

The Great Recession, financial strain and self-assessed health in Ireland Abstract In this paper, we study the effects of the 2008 economic crisis on general health in one of the most severely affected EU economies—Ireland. We examine the relationship between compositional changes in demographic and socio-economic factors, such as education, income, and financial strain, and changes in the prevalence of poor self-assessed health over a 5-year period (2008–2013). We apply a generalised Oaxaca–Blinder decomposition approach for non-linear regression models proposed by Fairlie (1999, 2005). Results show that the increased financial strain explained the largest part of the increase in poor health in the Irish population and different sub-groups. Changes in the economic activity status and population structure also had a significant positive effect. The expansion of education had a significant negative effect, preventing further increases in poor health. Wealthier and better educated individuals experienced larger relative increases in poor health, which led to reduced socio-economic health inequalities.

An evaluation of the 1987 French Disabled Workers Act: better paying than hiring Abstract This paper presents the first evaluation of the French Disabled Workers Act of 1987, which aimed to promote the employment of disabled people in the private sector. We use a panel data set, which includes both the health and the labour market histories of workers. We account both for unobserved heterogeneity and for the change in the disabled population over time. We find that the law had a negative impact on the employment of disabled workers in the private sector. This counterproductive effect likely comes from the possibility to pay a fine instead of hiring disabled workers.

Denosumab versus bisphosphonates for the treatment of bone metastases from solid tumors: a systematic review Abstract Background Bone metastases are highly prevalent in breast, prostate, lung and colon cancers. Their symptoms negatively affect quality of life and functionality and optimal management can mitigate these problems. There are two different targeted agents to treat them: bisphosphonates (pamidronate and zoledronic acid) and the monoclonal antibody denosumab. Estimates of cost-effectiveness are still mixed. Objective To conduct a systematic review of economic studies that compares these two options. Method Literature search comprised eight databases and keywords for bone metastases, bisphosphonates, denosumab, and economic studies were used. Data were extracted regarding their methodologic characteristics and cost-effectiveness analyses. All studies were evaluated regarding to its methodological quality. Results A total of 263 unique studies were retrieved and six met inclusion criteria. All studies were based on clinical trials and other existing literature data, and they had high methodological quality. Most found unfavorable cost-effectiveness for denosumab compared with zoledronic acid, with adjusted ICERS that ranged from $4638–87,354 per SRE avoided and from US$57,274–4.81 M. per QALY gained, which varied widely according to type of tumor, time horizon, among others. Results were sensitive to drug costs, time to first skeletal-related event (SRE), time horizon, and utility. Conclusions Denosumab had unfavorable cost-effectiveness compared with zoledronic acid in most of the included studies. New economic studies based on real-world data and longer time horizons comparing these therapeutic options are needed.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Public Health

Direct healthcare costs of spinal disorders in Brazil Abstract Objectives To estimate the direct healthcare costs of spinal disorders in Brazil over 2016. Methods This is a prevalence-based cost-of-illness study with a top-down approach from the perspective of the public healthcare system. All international Classification of Diseases codes related to spinal disorders were included. The following costs were obtained: (1) hospitalization; medical professional service costs; intensive care unit costs; companion daily stay; (2) outpatient (services/procedures). Data were analyzed descriptively and costs presented in US$. Results The healthcare system spent US$ 71.4 million, and inpatient care represented 58%. The number of inpatient days was 250,426, and there were 36,654 hospital admissions (dorsalgia and disk disorders representing 70% of the costs). More than 114,000 magnetic resonance scans and 107,000 computerized tomography scans were adopted. Men had more inpatient days (138,215) than women (112,211). Overall, the inpatient/outpatient cost ratio was twice as high for men. Conclusions We demonstrated that the direct costs of spinal disorders in Brazil in 2016 were considerable. We also found a substantial amount of financial resources spent on diagnostic imaging. This is relevant as the routine use of diagnostic imaging for back pain is discouraged in international guidelines.

Roma health: Do we know enough?

Reducing socioeconomic inequalities in life expectancy among municipalities: the Brazilian experience Abstract Objectives This study analyzed the evolution of regional and socioeconomic inequality in life expectancy (LE) at birth and the probability of living up to 40 (LU40) and up to 60 years of age (LU60) in Brazilian municipalities between 1991 and 2010. Methods We analyzed data from the last three national census (1991, 2000 and 2010) computed for the 5565 Brazilian municipalities. They were divided into centiles according to the average per capita income. Poisson regression was performed to calculate the ratios between the poorest and the richest centiles. Results The average LE (+ 8.8 years), LU40 [6.7 percentage points (pp)] and LU60 increased (12.2 pp) between 1991 and 2010. The ratio of LE between the 1% of richest counties and the 1% of poorest counties decreased from 1.20 in 1991 to 1.09 in 2010. While in the poorest municipalities there was a gain of around 12 years of life, among the richest this increase was around 7 years. Conclusions There was a remarkable decrease in regional and socioeconomic inequality in LE, LU40 and LU60 in Brazil between 1991 and 2010.

Clusters of risk behaviors for noncommunicable diseases in the Brazilian adult population Abstract Objectives To identify clusters of risk behaviors among Brazilian adults, by sex, and to associate clusters with sociodemographic factors and self-perception of health. Methods We assessed 46,785 adults from the Brazilian National Health Survey. The risk behaviors were low consumption of fruits and vegetables—LFV (< 5 times/week), physical inactivity—PI (< 150 min/week), smoking (yes/no) and excessive consumption of alcohol—EA (5 doses for male, 4 doses for female). We used Venn diagram, cluster analysis and multinomial regression models. Results We found 9 clusters. The cluster of four risk behaviors was more common in males (3.2% vs. 0.83%). Despite a greater potential for aggregation of behaviors in females (O/E = 2.48) than in males (O/E = 1.62), the women were less likely to have all risk behaviors jointly (OR 0.24, 95% CI 0.19; 0.31), and this was found for the other clusters. In general, Brazilian black/brown, younger, with low education level and who had a self-perception of bad health, were more likely to engage in clusters of risk behaviors. Conclusions The prevalence of Brazilian adults engaging in clusters of risk behaviors is high, mainly among males, those who reported a bad health and with low socioeconomic status.

Palliative care in universal health coverage: What about humanitarian emergency assistance?

Migrant mental health, Hickam's dictum, and the dangers of oversimplification

Road map towards a harmonized pan-European surveillance of obesity-related lifestyle behaviours and their determinants in children and adolescents Abstract Objectives To develop a road map towards a harmonized pan-European surveillance system for children and adolescents. Methods Representatives of five European surveillance systems and the German Health Interview and Examination Survey for Children and Adolescents contributed to the road map through a structured workshop in 2016. Results A conceptual framework for this road map was developed with seven action points (APs) guiding the successive cross-country harmonization. First, key indicators of health behaviour and their determinants in children and adolescents will be identified (AP1, 2); short screening instruments will be developed and implemented to assess and monitor key indicators (AP3, 4). In parallel, optional supplementary modules could be implemented to provide objective data (AP5). This would allow mutual calibration and improvement of existing instruments before their progressive replacement by more comparable measurement tools (AP6). The establishment of a competence platform is envisaged for guiding the harmonization process (AP7). Conclusions This approach builds on existing systems, provides comparable key health indicators across European regions, helps to assess temporal trends and—once in place—will facilitate health reporting and monitoring of national and international health targets.

Association of objectively measured and perceived environment with accelerometer-based physical activity and cycling: a Swiss population-based cross-sectional study of children Abstract Objectives We tested whether objectively assessed neighbourhood characteristics are associated with moderate-to vigorous physical activity (MVPA) and cycling in Swiss children and adolescents and assessed the mediating role of the perception of the environment. Methods The cross-sectional analyses were based on data of 1306 participants aged 6–16 years of the population-based SOPHYA study. MVPA was measured by accelerometry, time spent cycling and the perceived environment by questionnaire. Objective environmental parameters at the residential address were GIS derived. In all analyses, personal, social and environmental factors were considered. Results MVPA showed significant positive associations with perceived personal safety and perceived access to green spaces but not with respective objective parameters. Objectively assessed main street density and shorter distance to the next public transport were associated with less cycling in adolescents. Parents' perceptions did not mediate the observed associations of the objectively assessed environment with MVPA and cycling. Conclusions Associations between the environment and physical activity differ by domain. In spatial planning efforts to improve objective environments should be complemented with efforts to increase parental sense of security.

Obesity risk in women of childbearing age in New Zealand: a nationally representative cross-sectional study Abstract Objectives To investigate risk factors for women with obesity of childbearing age. Methods A cross-sectional survey of New Zealand women (15–49 years) with measured height and weight was used [unweighted (n = 3625) and weighted analytical sample (n = 1,098,372)] alongside sociodemographic-, behavioural- and environmental-level predictors. Multilevel logistic regression weighted for non-response of height and weight data was used. Results Meeting physical activity guidelines (AOR (adjusted odds ratio) 0.66, 95% CI 0.54–0.80), Asian (AOR 0.15, 95% CI 0.10–0.23) and European/other ethnicity (AOR 0.46, 95% CI 0.36–0.58) and an increased availability of public greenspace (Q4 AOR 0.55, 95% CI 0.41–0.75) were related to decreased obesity risk. Older age (45–49 years AOR 3.01, 95% CI 2.17–4.16), Pacific ethnicity (AOR 2.81, 95% CI 1.87–4.22), residing in deprived areas (AOR 1.65, 95% CI 1.16–2.35) or secondary urban areas (AOR 1.49, 95% CI 1.03–2.18) were related to increased obesity risk. When examined by rural/urban classification, private greenspace was only related to increased obesity risk in main urban areas. Conclusions This study highlights factors including but not limited to public greenspace, which inform obesity interventions for women of childbearing age in New Zealand.

Source-country individualism, cultural shock, and depression among immigrants Abstract Objectives To determine whether there is a relationship between source-country individualism and depression among different immigrant groups. Methods Pooled data from the 2009–2014 waves of the Canadian Community Health Survey (CCHS) were used. The CCHS is a cross-sectional, nationally representative household survey. A sample of 4347 immigrants in Canada were studied, representing 101 source countries. Results Multi-level logistic regression analysis showed a curvilinear relationship between source-country individualism and depression. A positive relationship was found among immigrants from countries with mid- to high levels of individualism. However, an inverse relationship was observed among immigrants from countries with low to mid-levels of individualism. Depression was significantly associated with the linear form of the source-country individualism measure [odds ratio (OR) 0.950; 95% confidence interval (CI) 0.915–0.987] and its squared term (OR 1.063; 95% CI 1.026–1.102). Conclusions A high level of source-country individualism tends to increase the prevalence of depression among immigrants. There is also a cultural shock effect: the prevalence of depression was stronger in the initial years after immigration for those who migrated from countries with low levels of individualism.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Pediatric Critical Care Medicine

Antibiotic Prophylaxis for Open Chest Management After Pediatric Cardiac Surgery Objectives: Although open chest management optimizes hemodynamics after cardiac surgery, it increases postoperative infections and leads to increased mortality. Despite the importance of antibiotic prophylaxis during open chest management, no specific recommendations exist. We aimed to compare the occurrence rates of bloodstream infection and surgical site infection between the different prophylactic antibiotic regimens for open chest management after pediatric cardiac surgery. Design: Retrospective, single-center, observational study. Setting: PICU at a tertiary children's hospital. Patients: Consecutive patients less than or equal to 18 years old with open chest management after cardiac surgery followed by delayed sternal closure, between January 2012 and June 2018. Interventions: None. Measurements and Main Results: We compared the composite occurrence rate of postoperative bloodstream infection and surgical site infection within 30 days after cardiac surgery between three prophylactic antibiotic regimens: 1) cefazolin, 2) cefazolin + vancomycin, and 3) vancomycin + meropenem. In 63 pediatric cardiac surgeries with open chest management, 17 bloodstream infections, and 12 surgical site infections were identified postoperatively. The composite occurrence rates of bloodstream infection and surgical site infection were 10 of 15 (67%), 10 of 19 (53%), and nine of 29 (31%) in the cefazolin, cefazolin + vancomycin, and vancomycin + meropenem regimens, respectively (p = 0.07). After adjusting for age, open chest management duration, extracorporeal membrane oxygenation use, and nasal methicillin-resistant Staphylococcus aureus colonization in multivariable analysis, there was no significant difference between the cefazolin and the cefazolin + vancomycin regimens (p = 0.19), while the vancomycin + meropenem regimen had a lower occurrence rate of bloodstream infection and surgical site infection than the cefazolin regimen (odds ratio, 0.0885; 95% CI, 0.0176–0.446; p = 0.003). Conclusions: In this study, a lower occurrence rate of postoperative bloodstream infection and surgical site infection was observed among patients with broad-spectrum antibiotic regimen after pediatric cardiac surgery with open chest management. Further studies, ideally randomized controlled studies investigating the efficacy of broad-spectrum antibiotics and their complications, are warranted before routine implementation of broad-spectrum prophylactic antibiotic regimen. The authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: hatachi@wch.opho.jp ©2019The Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies

Noninvasive Determination of Blood Pressure by Heart Sound Analysis Compared With Intra-Arterial Monitoring in Critically Ill Children—A Pilot Study of a Novel Approach Objectives: To develop a novel device to predict systolic and diastolic blood pressure based on measured heart sound signals and evaluate its accuracy in comparison to intra-arterial blood pressure readings. Study Design: Prospective, observational pilot study. Setting: PICU. Patients: Critically ill children (0–18 yr) undergoing continuous blood pressure monitoring via radial artery intra-arterial catheters were enrolled in the study after informed consent. The study included medical, cardiac, and surgical PICU patients. Interventions: Along with intra-arterial blood pressure, patient's heart sounds were recorded simultaneously by a highly sensitive sensor taped to the chest. Additional hardware included a data acquisition unit and laptop computer. Subsequently, advanced signal processing technologies were used to minimize random interfering signals and extract and separate S1 and S2 signals. A computerized model was then developed using artificial neural network systems to estimate blood pressure from the extracted heart sound analysis. Measurements and Main Outcomes: We found a statistically significant correlation for systolic (r = 0.964; R2 = 0.928) and diastolic (r = 0.935; R2 = 0.868) blood pressure readings (n = 491) estimated by the novel heart-sound signal–based method and those recorded by intra-arterial catheters. The mean difference of the individually paired determinations of the blood pressure between the heart-sound–based method and intra-arterial catheters was 0.6 ± 7 mm Hg for systolic blood pressure and –0.06 ± 5 mm Hg for diastolic blood pressure, which was within the recommended range of 5 ± 8 mm Hg for any new blood pressure devices. Conclusions: Our findings provide proof of concept that the heart-sound signal-based method can provide accurate, noninvasive blood pressure monitoring. Drs. Kapur and Chen contributed equally to the article. This work was supported by the 21st Century Jobs Trust Fund received through the Michigan Strategic Fund from the State of Michigan and administered by the Michigan Economic Development Corporation (www.michiganbusiness.org). Dr. Kapur's institution received funding from Alexion; a nonprovisional patent (number PCT/US18/17178) titled, "Method and Apparatus for Determining Blood Pressure on Measured Heart Sounds," based on this research was submitted on 02/07/2018 (to Drs. Kapur, Chen, Xu, and Wu listed as co-inventors); and he disclosed off-label product use of the technology reported in the article, which is currently investigational and not approved by the U.S. Food and Drug Administration for any purposes. Drs. Kapur and Chen disclosed that this work was supported by the 21st Century Jobs Trust Fund received through the Michigan Strategic Fund from the State of Michigan and administered by the Michigan Economic Development Corporation. Dr. Xu disclosed work for hire. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: gkapur@med.wayne.edu ©2019The Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies

Relationship Between Diaphragmatic Electrical Activity and Esophageal Pressure Monitoring in Children Objectives: Mechanical ventilation is an essential life support technology, but it is associated with side effects in case of over or under-assistance. The monitoring of respiratory effort may facilitate titration of the support. The gold standard for respiratory effort measurement is based on esophageal pressure monitoring, a technology not commonly available at bedside. Diaphragmatic electrical activity can be routinely monitored in clinical practice and reflects the output of the respiratory centers. We hypothesized that diaphragmatic electrical activity changes accurately reflect changes in mechanical efforts. The objectives of this study were to characterize the relationship between diaphragmatic electrical activity and esophageal pressure. Design: Prospective crossover study. Setting: Esophageal pressure and diaphragmatic electrical activity were simultaneously recorded using a specific nasogastric tube in three conditions: in pressure support ventilation and in neurally adjusted ventilatory support in a random order, and then after extubation. Patients: Children in the weaning phase of mechanical ventilation. Interventions: The maximal swing in esophageal pressure and esophageal pressure-time product, maximum diaphragmatic electrical activity, and inspiratory diaphragmatic electrical activity integral were calculated from 100 consecutive breaths. Neuroventilatory efficiency was estimated using the ratio of tidal volume/maximum diaphragmatic electrical activity. Measurements and Main Results: Sixteen patients, with a median age of 4 months (interquartile range, 0.5–13 mo), and weight 5.8 kg (interquartile range, 4.1–8 kg) were included. A strong linear correlation between maximum diaphragmatic electrical activity and maximal swing in esophageal pressure (r2 > 0.95), and inspiratory diaphragmatic electrical activity integral and esophageal pressure-time product (r2 > 0.71) was observed in all ventilatory conditions. This correlation was not modified by the type of ventilatory support. Conclusions: On a short-term basis, diaphragmatic electrical activity changes are strongly correlated with esophageal pressure changes. In clinical practice, diaphragmatic electrical activity monitoring may help to inform on changes in respiratory efforts. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (http://journals.lww.com/pccmjournal). Dr. Baudin received funding from Maquet Critical Care (speaking fees and nonfinancial support). Dr. Beck received funding from Maquet Critical Care (she and her husband have made inventions related to neural control of mechanical ventilation that are patented. The patents are assigned to the academic institution[s] where inventions were made. The license for these patents belongs to Maquet Critical Care. Future commercial uses of this technology may provide financial benefit to them through royalties) and Neurovent Research Inc (NVR) (she and her husband own 50% of NVR, which is a research and development company that builds the equipment and catheters for research studies. NVR has a consulting agreement with Maquet Critical Care). Dr. Jouvet's institution received funding from Air Liquide Santé (grant and lecture), and he received salary and grant funding from the Ministry of Health of Quebec, Sainte Justine Hospital, and Public Research Agency of Quebec. Dr. Emeriaud's institution received funding from Fonds de Recherche du Québec—Santé and Maquet Critical Care (currently supporting a feasibility study in neonatal ventilation which Dr. Emeriaud is leading). The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: sandrine.essouri.hsj@ssss.gouv.qc.ca ©2019The Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies

International Study of the Epidemiology of Platelet Transfusions in Critically Ill Children With an Underlying Oncologic Diagnosis Objectives: To describe the epidemiology of platelet transfusions in critically ill children with an underlying oncologic diagnosis and to examine effects of prophylactic versus therapeutic transfusions. Design: Subgroup analysis of a prospective, observational study. Setting: Eighty-two PICUs in 16 countries. Patients: All children (3 d to 16 yr old) who received a platelet transfusion during one of the six predefined screening weeks and had received chemotherapy in the previous 6 months or had undergone hematopoietic stem cell transplantation in the last year. Interventions: None. Measurements and Main Results: Of the 548 patients enrolled in the parent study, 237 (43%) had an underlying oncologic diagnosis. In this population, 71% (168/237) of transfusions were given prophylactically, and 59% (139/237) of transfusions were given at a total platelet count greater than 20 × 109/L, higher than the current recommendations. Those with an underlying oncologic diagnosis were significantly older, and received less support including less mechanical ventilation, fewer medications that affect platelet function, and less use of extracorporeal life support than those without an underlying oncologic diagnosis. In this subpopulation, there were no statistically significant differences in median (interquartile range) platelet transfusion thresholds when comparing bleeding or nonbleeding patients (50 × 109/L [10–50 × 109/L] and 30 × 109/L [10–50 × 109/L], respectively [p = 0.166]). The median (interquartile range) interval transfusion increment in children with an underlying oncologic diagnosis was 17 × 109/L (6–52 × 109/L). The presence of an underlying oncologic diagnosis was associated with a poor platelet increment response to platelet transfusion in this cohort (adjusted odds ratio, 0.46; 95% CI, 0.22–0.95; p = 0.035). Conclusions: Children with an underlying oncologic diagnosis receive nearly half of platelet transfusions prescribed by pediatric intensivists. Over half of these transfusions are prescribed at total platelet count greater than current recommendations. Studies must be done to clarify appropriate indications for platelet transfusions in this vulnerable population. The Point Prevalence Study of Platelet Transfusions in Critically Ill Children (P3T) Investigators are listed in the Acknowledgments. Dr. Cushing received funding from Cerus Corporation, Octapharma, and Instrumentation Laboratory. Dr. Steiner's institution received funding from the National Institutes of Health and Boeringer-Ingelheim, and she received funding from Cerus (travel for study design consultation regarding pathogen-inactivated red cells). The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: man9026@med.cornell.edu ©2019The Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies

Parent Medical Traumatic Stress and Associated Family Outcomes After Pediatric Critical Illness: A Systematic Review Objectives: To critically review, analyze, and synthesize the literature on parent medical traumatic stress from a child's critical illness requiring PICU admission and its association with outcomes of parent mental and physical health, and family functioning. Data Sources: Systematic literature search of Pubmed, Embase, CINAHL, and PsychInfo. Study Selection: Two reviewers identified peer-reviewed published articles with the following criteria: 1) published between January 1, 1980, and August 1, 2018; 2) published in English; 3) study population of parents of children with a PICU admission; and 4) quantitative studies examining factors associated with outcomes of parent mental health, parent physical health, or family functioning. Data Extraction: Literature search yielded 2,476 articles, of which 23 studies met inclusion criteria. Study data extracted included study characteristics, descriptive statistics of parent outcomes after critical illness, and variables associated with parent and family outcomes. Data Synthesis: Studies examined numerous variables associated with parent and family outcomes and used multiple survey measures. These variables were categorized according to their phase in the Integrative Trajectory Model of Pediatric Medical Traumatic Stress, which included peri-trauma, acute medical care, and ongoing care or discharge from care. The majority of objective elements of a child's illness, such as severity of illness and length of hospitalization, did not have a clear relationship with parent and family outcomes. However, familial preexisting factors, a parent's subjective experience in the PICU, and family life stressors after discharge were often associated with parent and family outcomes. Conclusions: This systematic literature review suggests that parent and family outcomes after pediatric critical illness are impacted by familial preexisting factors, a parent's subjective experience in the PICU, and family life stressors after discharge. Developing parent interventions focused on modifying the parent's subjective experience in the PICU could be an effective approach to improve parent outcomes. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (http://journals.lww.com/pccmjournal). This work was supported by the Department of Pediatrics at Children's Hospital of Michigan and the Department of Pediatrics at the University of Michigan. The authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: lyagiela@dmc.org ©2019The Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies

Severe Sepsis in Pediatric Liver Transplant Patients: The Emergence of Multidrug-Resistant Organisms Objectives: To describe characteristics of liver transplant patients with severe sepsis in the PICU. Design: Retrospective descriptive analysis. Setting: Tertiary children's hospital PICU. Patients: Liver transplant recipients admitted January 2010 to July 2016 for pediatric severe sepsis. Interventions: None. Measurements and Main Results: Between January 2010 and July 2016, 173 liver transplants were performed, and 36 of these patients (21%) were admitted with severe sepsis (54 episodes total). Median age at admission was 2 years (1–6.5 yr), 47.2% were male. Bacterial infections were the most common (77.8%), followed by culture negative (12.9%) and viral infections (7.4%). Fungal infections accounted for only 1.9%. Median time from transplant for viral and culture negative infections was 18 days (8.25–39.75 d) and 25 days (9–41 d), whereas 54.5 days (17–131.25 d) for bacterial infections. Bloodstream and intra-abdominal were the most common bacterial sites (45% and 22.5%, respectively). Multidrug-resistant organisms accounted for 47.6% of bacterial sepsis. Vancomycin-resistant Enterococcus and extended-spectrum beta-lactamase producers were the most frequently identified multidrug-resistant organisms. Patients with multidrug-resistant organism sepsis demonstrated higher admission Pediatric Logistic Organ Dysfunction scores (p = 0.043) and were noted to have an odds ratio of 3.8 and 3.6 for mechanical ventilation and multiple organ dysfunction syndrome, respectively (p = 0.047 and p = 0.044). Overall mortality was 5.5% (n = 2 patients), with both deaths occurring in multidrug-resistant organism episodes. Conclusions: We report that multidrug-resistant organisms are increasingly being identified as causative pathogens for sepsis in pediatric liver transplant recipients and are associated with significantly higher odds for mechanical ventilation and higher organ failure. The emergence of multidrug-resistant organism infections in pediatric liver transplant patients has implications for patient outcomes, antibiotic stewardship, and infection prevention strategies. Supported, in part, by grant from National Institutes of Health (NIH) T32-HD40686 (to Dr. Alcamo) and NIH R01-GM108618 (to Dr. Carcillo). Dr. Alcamo's institution received funding from National Institutes of Health (NIH) T32 HD040686. Drs. Alcamo, Carcillo, and Aneja received support for article research from the NIH. Dr. Carcillo's institution received funding from the NIH/National Institute of General Medical Sciences. Dr. Michaels' institution received funding from Pfizer (unrelated study grant), and she received funding as an American Society of Transplantation board member (travel and room for meetings, no honoraria) and from National Institute of Allergy and Infectious Diseases (honoraria and travel and room for Data and Safety Monitoring Board meetings). Dr. Aneja received royalties from UpToDate. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: Alicia.Alcamo@chp.edu ©2019The Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies

State of the Unit: Physician Gender Diversity in Pediatric Critical Care Medicine Leadership Gender disparities in leadership are receiving increased attention throughout medicine and medical subspecialties. Little is known about the disparities in Pediatric Critical Care Medicine. In this piece, we explore gender disparities in Pediatric Critical Care Medicine physician leadership. We examine physician leadership in the Accreditation Council for Graduate Medical Education fellowship programs, as well as a limited sample of major Pediatric Critical Care Medicine textbooks and societies. Overall, the gender composition of division directors is not significantly different from that of workforce composition, although regional differences exist. More women than men lead fellowship programs, at a higher ratio compared with workforce composition. However, greater gender disparities are present in editorial leadership in this limited analysis. We conclude by recommending potential paths forward for further study and intervention, such as tracking gender diversity and being cognizant of the unique challenges that women currently experience in professional advancement. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (http://journals.lww.com/pccmjournal). Dr. Riley receives support from the Institute for Healthcare Improvement to develop measurement framework and measures for the 100 Million Healthier Lives Initiative. Dr. Stalets received funding from Fisher & Paykel (hotel and flight accommodations to attend a conference). The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: Andrea.Maxwell@cchmc.org ©2019The Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies

Association of Organ Dysfunction Scores and Functional Outcomes Following Pediatric Critical Illness Objectives: Short-term and long-term morbidity and mortality are common following pediatric critical illness. Severe organ dysfunction is associated with significant in-hospital mortality in critically ill children; however, the performance of pediatric organ dysfunction scores as predictors of functional outcomes after critical illness has not been previously assessed. Design: Secondary analysis of a prospective observational cohort. Setting: A multidisciplinary, tertiary, academic PICU. Patients: Patients less than or equal to 18 years old admitted between June 2012 and August 2012. Interventions: None. Measurements and Main Results: The maximum pediatric Sequential Organ Failure Assessment and Pediatric Logistic Organ Dysfunction-2 scores during admission were calculated. The Functional Status Scale score was obtained at baseline, 6 months and 3 years following discharge. New morbidity was defined as a change in Functional Status Scale greater than or equal to 3 points from baseline. The performance of organ dysfunction scores at discriminating new morbidity or mortality at 6 months and 3 years was measured using the area under the curve. Seventy-three patients met inclusion criteria. Fourteen percent had new morbidity or mortality at 6 months and 23% at 3 years. The performance of the maximum pediatric Sequential Organ Failure Assessment and Pediatric Logistic Organ Dysfunction-2 scores at discriminating new morbidity or mortality was excellent at 6 months (areas under the curves 0.9 and 0.88, respectively) and good at 3 years (0.82 and 0.79, respectively). Conclusions: Severity of organ dysfunction is associated with longitudinal change in functional status and short-term and long-term development of new morbidity and mortality. Maximum pediatric Sequential Organ Failure Assessment and Pediatric Logistic Organ Dysfunction-2 scores during critical illness have good to excellent performance at predicting new morbidity or mortality up to 3 years after critical illness. Use of these pediatric organ dysfunction scores may be helpful for prognostication of longitudinal functional outcomes in critically ill children. All authors conceptualized, designed, analyzed, drafted the article for important intellectual content, and collected the data. The authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: travis.matics@advocatehealth.com ©2019The Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies

The Inadequate Oxygen Delivery Index and Low Cardiac Output Syndrome Score As predictors of Adverse Events Associated With Low Cardiac Output Syndrome Early After Cardiac Bypass Objectives: To evaluate the effectiveness of two scoring systems, the inadequate oxygen delivery index, a risk analytics algorithm (Etiometry, Boston, MA) and the Low Cardiac Output Syndrome Score, in predicting adverse events recognized as indicative of low cardiac output syndrome within 72 hours of surgery. Design: A retrospective observational pair-matched study. Setting: Tertiary pediatric cardiac ICU. Patients: Children undergoing cardiac bypass for congenital heart defects. Cases experienced an adverse event linked to low cardiac output syndrome in the 72 hours following surgery (extracorporeal membrane oxygenation, renal replacement therapy, cardiopulmonary resuscitation, and necrotizing enterocolitis) and were matched with a control patient on criteria of procedure, diagnosis, and age who experienced no such event. Interventions: None. Measurements and Main Results: Of a total 536 bypass operations in the study period, 38 patients experienced one of the defined events. Twenty-eight cases were included in the study after removing patients who suffered an event after 72 hours or who had insufficient data. Clinical and laboratory data were collected to derive scores for the first 12 hours after surgery. The inadequate oxygen delivery index was calculated by Etiometry using vital signs and laboratory data. A modified Low Cardiac Output Syndrome Score was calculated from clinical and therapeutic markers. The mean inadequate oxygen delivery and modified Low Cardiac Output Syndrome Score were compared within each matched pair using the Wilcoxon signed-rank test. Inadequate oxygen delivery correctly differentiated adverse events in 13 of 28 matched pairs, with no evidence of inadequate oxygen delivery being higher in cases (p = 0.71). Modified Low Cardiac Output Syndrome Score correctly differentiated adverse events in 23 of 28 matched pairs, with strong evidence of a raised score in low cardiac output syndrome cases (p < 0.01). Conclusions: Although inadequate oxygen delivery is an Food and Drug Administration approved indicator of risk for low mixed venous oxygen saturation, early postoperative average values were not linked with medium-term adverse events. The indicators included in the modified Low Cardiac Output Syndrome Score had a much stronger association with the specified adverse events. This work was undertaken at Great Ormond Street Hospital/UCL Institute of Child Health, which received a proportion of funding from the Department of Health's National Institute of Health Research Biomedical Research Centre's funding scheme. Drs. Ray and Peters' institutions received funding from Great Ormond Street Hospital Children's Charity (GOSHCC). Dr. Peters received funding from Faron pharmaceuticals (advisory board) and Therakind. Drs. Peters and Brown received support for article research from GOSHCC. Dr. Brown received other support from GOSHCC PICU infrastructure grant supporting Libby Rogers. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: samiran.ray@gosh.nhs.uk ©2019The Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies

Decision-Making About Intracranial Pressure Monitor Placement in Children With Traumatic Brain Injury Objectives: Little is known about how clinicians make the complex decision regarding whether to place an intracranial pressure monitor in children with traumatic brain injury. The objective of this study was to identify the decisional needs of multidisciplinary clinician stakeholders. Design: Semi-structured qualitative interviews with clinicians who regularly care for children with traumatic brain injury. Setting: One U.S. level I pediatric trauma center. Subjects: Twenty-eight clinicians including 17 ICU nurses, advanced practice providers, and physicians and 11 pediatric surgeons and neurosurgeons interviewed between August 2017 and February 2018. Interventions: None. Measurements and Main Results: Participants had a mean age of 43 years (range, 30–66 yr), mean experience of 10 years (range, 0–30 yr), were 46% female (13/28), and 96% white (27/28). A novel conceptual model emerged that related the difficulty of the decision about intracranial pressure monitor placement (y-axis) with the estimated outcome of the patient (x-axis). This model had a bimodal shape, with the most difficult decisions occurring for patients who 1) had a good opportunity for recovery but whose neurologic examination had not yet normalized or 2) had a low but uncertain likelihood of neurologically functional recovery. Emergent themes included gaps in medical knowledge and information available for decision-making, differences in perspective between clinical specialties, and ethical implications of decision-making about intracranial pressure monitoring. Experienced clinicians described less difficulty with decision-making overall. Conclusions: Children with severe traumatic brain injury near perceived transition points along a spectrum of potential for recovery present challenges for decision-making about intracranial pressure monitor placement. Clinician experience and specialty discipline further influence decision-making. These findings will contribute to the design of a multidisciplinary clinical decision support tool for intracranial pressure monitor placement in children with traumatic brain injury. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (http://journals.lww.com/pccmjournal). Dr. Bennett's institution also received funding from the National Institutes of Health (NIH) Eunice Kennedy Shriver National Institute of Child Health and Human Development and NIH/National Center for Advancing Translational Science. Drs. Bennett's and Rutebemberwa's institutions received funding from Mindsource Brain Injury Network of the Colorado Department of Human Services. Ms. Marsh's and Dr. Maertens's institutions received funding from the Colorado Department of Human Services. Dr. Hankinson's institution received funding from Colorado Traumatic Brain Injury Trust Fund. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: tell.bennett@ucdenver.edu ©2019The Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Biological Theory

Toward a Macroevolutionary Theory of Human Evolution: The Social Protocell Abstract Despite remarkable empirical and methodological advances, our theoretical understanding of the evolutionary processes that made us human remains fragmented and contentious. Here, we make the radical proposition that the cultural communities within which Homo emerged may be understood as a novel exotic form of organism. The argument begins from a deep congruence between robust features of Pan community life cycles and protocell models of the origins of life. We argue that if a cultural tradition, meeting certain requirements, arises in the context of such a "social protocell," the outcome will be an evolutionary transition in individuality whereby traditions and hominins coalesce into a macroscopic bio-socio-technical system, with an organismal organization that is culturally inherited through irreversible fission events on the community level. We refer to the resulting hypothetical evolutionary individual as a "sociont." The social protocell provides a preadapted source of alignment of fitness interests that addresses a number of open questions about the origins of shared adaptive cultural organization, and the derived genetic (and highly unusual) adaptations that support them. Also, social cooperation between hominins is no longer in exclusive focus since cooperation among traditions becomes salient in this model. This provides novel avenues for explanation. We go on to hypothesize that the fate of the hominin in such a setting would be mutualistic coadaptation into a part-whole relation with the sociont, and we propose that the unusual suite of derived features in Homo is consistent with this hypothesis.

Mating Markets: A Naturally Selected Sex Allocation Theory of Sexual Selection Abstract This article utilizes three premises. (1) There are commonly ecologically oriented, naturally selected specialized differences in frequency and/or quality as well as sexually selected differences between the sexes. (2) Sex in the sense of coming together and going apart (syngamy and meiosis in haploids) or going apart and coming together (meiosis and syngamy in diploids) is trade in these naturally selected differences, i.e., there is a mating market in sexual species. (3) While such trade is beneficial to the population as a whole, sexual competition and selection is conflict over the profits of that trade and can be detrimental to the population as a whole. These premises yield a naturally selected sex allocation theory of the possible directions and forms of sexual selection, i.e., one that includes costs as well as frequencies. This can explain conventional sex roles, the sex-role reversed, inter- as well as intrasexual selection, and passive as well as active choice. Any of these alternatives may be over mates, over gametes, or both. A hypothetical example based on density dependence relative to resources is provided, one that suggests that centrioles may be a cytoplasmic resource in males in multicellular animals, and which are the target of active choice and the mechanism of manipulation in passive female choice. As a whole, the approach yields a truly general theory of sexual selection, provides an alternative to the mechanism for Fisher's principle, and gives a theoretical explanation for Mayr's biological species definition.

Social-Ecological Theory of Maximization: Basic Concepts and Two Initial Models Abstract Efforts have been dedicated to the understanding of social-ecological systems, an important focus in ethnobiological studies. In particular, ethnobiological investigations have found evidence and tested hypotheses over the last 30 years on the interactions between human groups and their environments, generating the need to formulate a theory for such systems. In this article, we propose the social-ecological theory of maximization to explain the construction and functioning of these systems over time, encompassing hypotheses and evidence from previous ethnobiological studies. In proposing the theory, we present definitions and two conceptual models, an environmental maximization model and a redundancy generation model. The first model seeks to address biota selection and its use by human populations. The second emphasizes how the system organizes itself from the elements that were incorporated into it. Furthermore, we provide the theoretical scenario of plant selection and use from an evolutionary perspective, which explicitly integrates the phylogenetic relationships of plants (or other living resources) and human beings.

Why is There No Successful Whole Brain Simulation (Yet)? Abstract With the advent of powerful parallel computers, efforts have commenced to simulate complete mammalian brains. However, so far none of these efforts has produced outcomes close to explaining even the behavioral complexities of animals. In this article, we suggest four challenges that ground this shortcoming. First, we discuss the connection between hypothesis testing and simulations. Typically, efforts to simulate complete mammalian brains lack a clear hypothesis. Second, we treat complications related to a lack of parameter constraints for large-scale simulations. To demonstrate the severity of this issue, we review work on two small-scale neural systems, the crustacean stomatogastric ganglion and the Caenorhabditis elegans nervous system. Both of these small nervous systems are very thoroughly, but not completely understood, mainly due to issues with variable and plastic parameters. Third, we discuss the hierarchical structure of neural systems as a principled obstacle to whole-brain simulations. Different organizational levels imply qualitative differences not only in structure, but in choice and appropriateness of investigative technique and perspective. The challenge of reconciling different levels also undergirds the challenge of simulating and hypothesis testing, as modeling a system is not the same thing as simulating it. Fourth, we point out that animal brains are information processing systems tailored very specifically for the ecological niches the respective animals live in.

The Role of Assessor Teaching in Human Culture Abstract According to the dual inheritance theory, cultural learning in our species is a biased and highly efficient process of transmitting cultural traits. Here we define a model of cultural learning where social learning is integrated as a complementary element that facilitates the discovery of a specific behavior by an apprentice, and not as a mechanism that works in opposition to individual learning. In that context, we propose that the emergence of the ability to approve or disapprove of offspring behavior, orienting their learning (a process we call assessor teaching), transformed primate social learning into a cultural transmission system, like that which characterizes our species. Assessor teaching facilitates the replication and/or reconstruction of behaviors that are difficult to imitate and helps to determine which behaviors should be imitated. We also explore the form in which assessor teaching has conditioned the evolution of our abilities to develop cultures in the hominin line, converting us into individuals equipped with what we call a suadens psychology. Our main point is to defend the hypothesis that suadens psychology determines the stability and dynamics that affect the trajectories of many cultural characters. We compare our proposal with other theories about cultural evolution, specifically with dual inheritance theory and cultural attraction theory.

Multicellular Individuality: The Case of Bacteria Abstract Recent attention to complex group-level behavior amongst bacteria has led some to conceive of multicellular clusters of bacteria as individuals. In this article, I assess these recent claims by first drawing a distinction between two concepts of individuality: physiological and evolutionary. I then survey cases that are representative of three different modes of growth: myxobacteria (surface-attached agglomerative growth), Bacillus subtilis(agglomerative growth not attached to a surface), and cyanobacteria (filamentous growth). A closer look at these cases indicates that multicellular individuality among bacteria is remarkably complex. Physiologically, the three cases of multicellular clusters do not form physiological individuals. But matters are different when it comes to evolutionary individuality; although multicellular clusters that grow by agglomeration are not highly individuated, filament-forming groups achieve a relatively high degree of individuality. I also suggest that debates about bacterial multicellular individuality may have been obscured by a failure to see that selection on highly individuated groups is by no means the only mechanism to bring about the complex group-level behaviors that have led some to view bacteria as multicellular individuals.

Are Verbal-Narrative Models More Suitable than Mathematical Models as Information Processing Devices for Some Behavioral (Biosemiotic) Problems? Abstract This article argues that many, if not most, behavior descriptions and sequencing are in essence an interpretation of signs, and are evaluated as sequences of signs by researchers. Thus, narrative analysis, as developed by Barthes and others, seems best suited to be used in behavioral/biosemiotic studies rather than mathematical modeling, and is very similar to some classic ethology methods. As our brain interprets behaviors as signs and attributes meaning to them, narrative analysis seems more suitable than mathematical modeling to describe and study behavior. Mathematical models are, on many occasions, extremely reductionist and simplifying because of computational and/or numerical representation limitations that lead to errors and straitjacketing interpretations of reality. Since actual animals (and our analysis of their behavior) are not as optimal in real life as our mathematical models, here it is proposed that we should consider logical/verbal models and semantic interpretations as equally or even better suited for behavioral analysis, and refrain from enforcing mathematical modeling as the only (right) way to study and understand biological problems, especially those of a behavioral and biosemiotic nature.

Criteria for Holobionts from Community Genetics Abstract We address the controversy in the literature concerning the definition of holobionts and the apparent constraints on their evolution using concepts from community population genetics. The genetics of holobionts, consisting of a host and diverse microbial symbionts, has been neglected in many discussions of the topic, and, where it has been discussed, a gene-centric, species-centric view, based in genomic conflict, has been predominant. Because coevolution takes place between traits or genes in two or more species and not, strictly speaking, between species, it may affect some traits but not others in either host or symbiont. Moreover, when interacting species pairs are embedded in a larger community, indirect ecological effects can alter the expected pairwise dynamics. Mode of symbiont transmission and the degree of host inbreeding both affect the extent of microbial mixing across host lineages and thereby the degree to which selection on one trait of either partner affects other aspects of a holobiont phenotype. We discuss several potential defining criteria for holobionts using community genetics and population genetics models, suggesting their application and limitations. Using community genetics models, we show how conflict between genomes can be self-limiting, while cooperation and mutualism tend to be self-accelerating. It is likely that this bias in the evolutionary dynamics of interaction between hosts and symbionts is an important feature of holobionts. This bias in the evolutionary dynamic could contribute to explaining the absence of cheaters from natural mutualisms, although cheaters are predicted by gene-centered conflict theory to cause the evolutionary instability of mutualisms. Additionally, it may help explain the more frequent origin of mutualisms from parasitic than from free-living systems, an evolutionary trajectory opposite to that predicted by genome conflict theory.

Reflections on a Biometrics of Organismal Form Abstract Back in 1987 the physicist/theoretical biologist Walter Elsasser reviewed a range of philosophical issues at the foundation of organismal biology above the molecular level. Two of these are particularly relevant to quantifications of form: the concept of ordered heterogeneity and the principle of nonstructural memory, the truism that typically the forms of organisms substantially resemble the forms of their ancestors. This essay attempts to weave Elsasser's principles together with morphometrics (the biometrics of organismal form) for one prominent data type, the representation of animal forms by positions of landmark points. I introduce a new spectrum of pattern descriptors of the shape variation of landmark configurations, ranging from the most homogeneous (uniform shears) through growth gradients and focal features to a model of totally disordered heterogeneity incompatible with the rhetoric of functional explanation. An investigation may end up reporting its findings by one of these descriptors or by several. These descriptors all derive from one shared diagrammatic device: a log–log plot of sample variance against one standard formalism of today's geometric morphometrics, the bending energies of the principal warps that represent all the scales of variability around the sample average shape. The new descriptors, which I demonstrate over a variety of contemporary morphometric examples, may help build the bridge we urgently need between the arithmetic of today's burgeoning image-based data resources and the rhetoric of biological explanations aligned with the principles of Elsasser along with an even earlier philosopher of biology, the Viennese visionary Hans Przibram.

How Did Language Evolve? Some Reflections on the Language Parasite Debate Abstract The language parasite approach (LPA) refers to the view that language, like a parasite, is an adaptive system that evolves to fit its human hosts. Supported by recent computer simulations, LPA proponents claim that the reason that humans can use languages with ease is not because we have evolved with genetically specified linguistic instincts but because languages have adapted to the preexisting brain structures of humans. This article examines the LPA. It argues that, while the LPA has advantages over its rival, Chomskyan nativism, there are additional factors that may limit linguistic variety that have yet to be identified by its insightful proponents. This article suggests abandoning the search for a decisive cause of language capacity and argues that language evolution is more likely to arise from balancing multiple engineering constraints.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Cytology and Genetics

Molecular Characterization and Tissue Expression of Common Tobacco ( Nicotiana tabacum ) Cadmium Resistance Protein 2 and Metal Tolerance Protein 4 Genes Abstract The complete coding sequences of common tobacco cadmium resistance protein 2 and metal tolerance protein 4 genes were amplified by RT-PCR. The tobacco cadmium resistance protein 2 gene encodes a protein of 192 amino acids which shares high identity with the cadmium resistance protein 2 of four species—nicotiana tomentosiformis (99%), wood tobacco (97%), capsicum annuum (90%) and potato (86%). The tobacco metal tolerance protein 4 gene encodes a protein of 415 amino acids which shares high identity with the metal tolerance protein 4 of six species—nicotiana tomentosiformis (90%), wood tobacco (90%), lycopersicon esculentum(84%), potato (84%), lycopersicon pennellii (83%) and capsicum annuum (82%). Prediction of transmembrane helices showed that cadmium resistance protein 2 and metal tolerance protein 4 might be two transmembrane proteins. Phylogenetic analysis revealed that the common tobacco cadmium resistance protein 2 and metal tolerance protein 4 genes both have a closer genetic relationship with the wood tobacco cadmium resistance protein 2 and metal tolerance protein 4 genes. Computer-assisted analysis showed that cadmium resistance protein 2 gene is structured in 4 exons and 3 introns and metal tolerance protein 4 gene consists of 7 exons and 6 introns. The gene expression profile analysis indicated that the common tobacco cadmium resistance protein 2 and metal tolerance protein 4 genes were highly expressed in root.

Expression Profiles of a Tung Tree Phosphate Transporter cDNA and Structural Characteristics of the Encoded Protein Abstract— Plant phosphate transporters mediate phosphate acquisition, translocation, and recycling. A Vernicia fordii cDNA encoding a phosphate transporter was cloned using a reverse transcription polymerase chain reaction (PCR) and rapid amplification of cDNA ends. The resulting cDNA named Vernicia fordii Phosphate Transporter-1;1 (VfPht1;1) encodes a predicted protein consisting of 533 amino acids. This protein, which was predicted to contain 12 transmembrane domains, is most similar (89.9%) to a Ricinus communis predicted protein. The quantitative real-time PCR data revealed that VfPht1;1 is most highly expressed in mature leaf petioles. It is also highly expressed in seeds collected in June, when developing fruits require a large amount of phosphates. Our observations suggest that VfPht1;1 may have diverse functions related to phosphate uptake and translocation.

Development of Winter Wheat Starting Material Using Interspecific Crossing in Breeding for Increased Protein Content Abstract The results of developing new bread winter wheat starting material using interspecific crosses in breeding for increased protein content are presented. The study comprised 35 initial (2–4 crosses with modern cultivars) and 20 advanced (five and more crosses with modern cultivars) introgression lines of bread winter wheat, and nine genotypes characterized by increased relative protein content and groups of lines that combine relatively high indices of thousand grain weight or protein content with resistance to leaf or stem rust and alien glume hairiness were isolated. The significant effect of lines grouping for the number of crossings with modern cultivars on the productivity, protein content, and the sedimentation value, and the effect of cross combinations, in particular, sources of alien traits, on protein content and thousand grain weight were found. It is shown that higher protein content, observed at the backcrossing, does not always correlate with the improvement of flour quality. The improved lines showed a low frequency of combining the traits of high protein content, large grain size with high productivity, and grain quality. No correlation of the most-studied traits with protein content and weak positive correlation (r = 0.28*…0.30*) of thousand grain weight with both the quality characteristics, sedimentation and protein content, were found. The line productivity had negative correlation with protein content (r = –0.43*) in only one variant of the experiment. The lines B241_09, E2792_14, E1598_12, and Od.267b were isolated, which had relatively higher protein content and combined moderate resistance to certain diseases with relatively high indices of the productivity and sedimentation. The isolated lines are characterized by instable productivity and other properties in different environments and require improved stability of these characteristics. Created on the basis of cv. Odeska 267, the quasi-isogenic lines with resistance to leaf rust (E2363_14, E2368_14, and E2369_14) had higher productivity, protein content, and thousand grain weight than recurrent cv. Odeska 267 on a low agricultural background. Using interspecific hybridization and further complicated step crosses with the elements of recurrent breeding, it was not possible to integrate high productivity in optimal environments with tolerance to hard conditions of drought into one genotype.

New Base Number for the Chromosomally Abnormal Genus Arthraxon P. Beauv. from Rajasthan Abstract During present investigation, 4 populations covering 3 species of the genus Arthraxon P. Beauv. have been worked out cytologically from different localities of Indian hot desert, Rajasthan. Two of the three species show n = 14 (A. lanceolatus and A. lancifolius), whereas, A. hispidus show the chromosome count of n = 18. A. lanceolatus show varaiable sized bivalents i.e. two large and twelve small sized bivalents, whereas, A. lancifolius shows normal equal sized bivalents. These large sized bivalents previously might be confused with quadrivalents but during A–I it clearly indicates the chromosome count of 2n = 28. It (n = 14) is the first time reported chromosomal count for the species of the genus from the world with new proposed base number x = 7 and thus the species are considered to be tetraploid. All the three species are the first chromosome reports from Rajasthan with various meiotic abnormalities like laggards, multiple bridges, cytomixis, chromatin transfer which results in abnormal microsporogenesis and low pollen viability.

The Effect of Platelet-Rich Plasma on Morphogenesis and Expression of Chondrogenic Marker Genes by Chondrocyte-Like Cells of the Rat Nucleus Pulposus in Vitro Abstract The aim of the study was to investigate the effect of 3, 10, and 20% of platelet-rich rat plasma (PRP) on the morphological characteristics of chondrocyte-like cells of the rat nucleus pulposus (NP) and the expression of chondrogenic genes ACAN, COLII, GPC3, MGP, PTN, ANXA3, and VIM in vitro. A dose-dependent increase of NP cell viability was observed in cultures supplemented with 3, 10, and 20% PRP. Platelets showed tropicity to blast-like cells in culture and formed adhesion zones. Differentiation of blast-like cells was observed and dividing cells were identified on day 14 of cultivation with 20% PRP. PRP prevented the decrease of chondrogenic gene expression in a dose-dependent manner, with 20% PRP being the most efficient. Expression of the majority of chondrogenic genes studied was observed in these cultures: the expression of COLII increased 2.9 times (P = 0.002); that of VIM, 2.1 times (P = 0.0003); that of ANXA3, 2.3 times (P = 0.0003); that of GPC3, 1.4 times (P = 0.0011); that of PTN, 1.6 times (P = 0.0017); and that of ACAN, 1.2 times (P = 0.0606).

Calcium and Components of Lipid Signaling in Implementation of Hydrogen Sulfide Influence on the State of Stomata in Arabidopsis thaliana Abstract— A time and concentration dependence of the hydrogen sulfide donor sodium hydrosulfide (NaHS) influence on the state of stomata of Arabidopsis thaliana (Col-0) leaves, as well as the role of calcium and phospholipases in the implementation of its effects, was studied. Treatment of leaves with NaHS in the concentration range of 5–250 μM caused a decrease in the size of the stomatal aperture. The maximal effect of the stomatal closure was observed 90 min after the beginning of the treatment with H2S donor, and the stomatal aperture in NaHS variants was, on the contrary, much wider than in the control after 180 min of exposure. The effect of treatment with NaHS solutions on the stomata state was completely eliminated by hydroxylamine, the hydrogen sulfide scavenger, which indicates the specificity of NaHS effects as an H2S donor. The decrease in stomatal aperture and relative number of open stomata caused by the donor of hydrogen sulfide was almost completely leveled off by the pretreatment of leaves with the calcium channel blocker lanthanum chloride, the extracellular calcium chelator EGTA, the phospholipase C inhibitor neomycin, and the antagonist of the formation of cyclic adenosine-5'-diphosphate ribose—nicotinamide. In addition, the stomatal effect of theH2S donor was partially eliminated by the calmodulin antagonist chlorpromazine. The leveling of the hydrogen sulfide donor action on the state of stomatal apparatus of Arabidopsis leaves was also noted at the pretreatment of leaves with butanol-1, an inhibitor of phospholipase D-dependent formation of phosphatidic acid. A conclusion about the importance of calcium intake into the cytosol from various compartments, as well as lipid signaling mediators formed with the involvement of phospholipases C and D, in the implementation of hydrogen sulfide action on the state of stomata was made.

The Use of a Micronucleus Test in Pinus pallasiana D. Don and Picea abies (L.) Karst. for the Assessment of Technogenic Pollution's Influence Abstract Results of the study on the frequency of micronuclei (MN) in the meristem of Pinus pallasiana D. Don and Picea abies (L.) Karst. seedlings from natural populations and plantings of technogenically polluted territories are presented. The level of cells with MN was 0.95 ± 0.13% in the control P. pallasiana population. An increase in the level of cells with MN was observed under introduction- and technogenic-pollution conditions (2.41–3.38%). Similar results were shown for P. abies. The pathological cell contained a different amount of MN (from one to two for P. pallasiana and from one to six for P. abies). The size of MN varied from 0.13 to 14.93% of the diameter of the main nuclei in P. pallasiana cells and from 0.07 to 61.87% in P. abies cells. Multinucleated cells and cells with an irregular-shaped nucleus were observed. Correlation dependence between cytogenetic disorders and MN frequency (r = 0.98) was established. The use of MN of seedlings of studied species for the assessment of the genotoxicity of technogenically polluted areas was proposed.

The Role of HSP90 Chaperones in Stability and Plasticity of Ontogenesis of Plants under Normal and Stressful Conditions ( Arabidopsis thaliana ) Abstract The functions of HSP90 chaperones in the protein-folding system and regulation of specific substrates affecting multiple signal pathways and cellular processes were considered. The triple role of HSP90 in stress was described: binding damaged proteins and directing them for refolding or degradation, regulation of the heat-shock gene induction, and alteration in the gene expression program. Based on the results of studies of the model species Arabidopsis thaliana, the role of HSP90 in growth maintenance and morphogenesis stability, developmental plasticity, and mechanisms of stress tolerance in plants was shown. A model for the interaction of the HSP90 functions under normal and stressful conditions is presented.

CdS Quantum Dots Obtained by "Green" Synthesis: Comparative Analysis of Toxicity and Effects on the Proliferative and Adhesive Activity of Human Cells Abstract A novel alternative approach for extracellular synthesis of CdS quantum dots using Escherichia coli bacteria, the fungus Pleurotus ostreatus, and the plant Linaria maroccana as biological matrices was previously developed. The nanoparticles obtained had stable luminescent properties and diameters of 2–10 nm. This paper presents the results of MTT assay- and flow cytometry-based analysis of cytotoxic/cytostatic effects, proliferative activity, and the ability of the CdS quantum dots synthesized to adhere to HeLa cells (human cervical cancer), malignized human T- and B-lymphocytes, and tumor cells of the AGS line (stomach cancer). The toxicity of the CdS quantum dots obtained by the "green" synthesis method was lower than that of inorganic cadmium sulfide, and this makes the quantum dots attractive candidates for a new type of nontoxic luminescent probes for bioimaging in cytological studies.

Erratum to: Molecular Organization of 5S Ribosomal DNА of Deschampsia antarctica The title of the article should read as follows: Molecular Organization of 5S Ribosomal DNА of Deschampsia antarctica

Alexandros Sfakianakis
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