Individual Variation In Response Research Articles

Signaling differences in peripheral blood mononuclear cells of high and low vaccine responders prior to, and following, vaccination in piglets

Individual variability in responses to vaccination can result in vaccinated subjects failing to develop a protective immune response. Vaccine non-responders can remain susceptible to infection and may compromise efforts to achieve herd immunity. Biomarkers of vaccine unresponsiveness could aid vaccine research and development as well as strategically improve vaccine administration programs. We previously vaccinated piglets (n = 117) against a commercial Mycoplasma hyopneumoniae vaccine (RespiSure-One) and observed in low vaccine responder piglets, as defined by serum IgG antibody titers, differential phosphorylation of peptides involved in pro-inflammatory cytokine signaling within peripheral blood mononuclear cells (PBMCs) prior to vaccination, elevated plasma interferon-gamma concentrations, and lower birth weight compared to high vaccine responder piglets. In the current study, we use kinome analysis to investigate signaling events within PBMCs collected from the same high and low vaccine responders at 2 and 6 days post-vaccination. Furthermore, we evaluate the use of inflammatory plasma cytokines, birthweight, and signaling events as biomarkers of vaccine unresponsiveness in a validation cohort of high and low vaccine responders. Differential phosphorylation events (FDR < 0.05) within PBMCs are established between high and low responders at the time of vaccination and at six days post-vaccination. A subset of these phosphorylation events were determined to be consistently differentially phosphorylated (p < 0.05) in the validation cohort of high and low vaccine responders. In contrast, there were no differences in birth weight (p > 0.5) and plasma IFNγ concentrations at the time of vaccination (p > 0.6) between high and low responders within the validation cohort. The results in this study suggest, at least within this study population, phosphorylation biomarkers are more robust predictors of vaccine responsiveness than other physiological markers.

Individual Variation in Response to Novel Food in Captive Capuchin Monkeys (Sapajus spp.)

How animals respond to novelty may have important outcomes in terms of fitness. On the one hand, aversion to novel stimuli may reduce the risks of consuming potentially toxic food or encountering predators. On the other hand, the propensity to approach novel stimuli may allow individuals to explore novel food sources and more flexibly adapt to novel challenges. Different species and individuals may find different ways to balance the costs and benefits that novelty posits. To date, however, little is known on how response to novel food varies across individuals of the same species depending on their previous experience with novelty, risk attitude and presence of higher-ranking conspecifics. In this study, we assessed individual variation in response to novel food by testing captive capuchin monkeys (Sapajus spp.) in an unconstrained social context, where all individuals in a group were able to access the testing area on a voluntary basis. We provided familiar and novel food to 23 study subjects belonging to four social groups differing in (i) previous experience with novel food, (ii) risk attitude (as assessed by a previous risky decision-making task), and (iii) dominance rank. We predicted that, as individuals may generalize their previous experience to novel contexts, those with more previous experience with novel food would be less neophobic than those with less experience. Moreover, if neophobia is a facet of the individual’s risk attitude, we predicted that more risk-prone individuals would be less neophobic than less risk-prone ones. Finally, individuals might flexibly modify their food choices according to the presence of conspecifics; in this respect, we predicted that, in response to monopolization of preferred resources by higher-ranking individuals, lower-ranking individuals would prefer familiar over novel food in the absence of higher-ranking individuals, but would modify their preference in favor of novel food in the presence of higher-ranking individuals. None of these predictions were supported by our results. We observed, however, that neophobia, measured as the latency to retrieve a food item, was more pronounced in lower-ranking than higher-ranking individuals, and that males showed a generally stronger bias than females toward a quicker retrieval of familiar food.

The Impact of COVID Vaccination on Symptoms of Long COVID: An International Survey of People with Lived Experience of Long COVID.

Long COVID is a multi-system syndrome following SARS-CoV-2 infection with persistent symptoms of at least 4 weeks, and frequently for several months. It has been suggested that there may be an autoimmune component. There has been an understandable caution amongst some people experiencing long COVID that, by boosting their immune response, a COVID vaccine may exacerbate their symptoms. We aimed to survey people living with long COVID, evaluating the impact of their first COVID vaccination on their symptoms. Methods: Patients with long COVID were invited to complete a web-based questionnaire through postings on social media and direct mailing from support groups. Basic demographics, range and severity of long COVID symptoms, before and after their vaccine, were surveyed. Results: 900 people participated in the questionnaire, of whom 45 had pre-existing myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS) but no evidence of COVID infection, and a further 43 did not complete the survey in full. The demographics and symptomology of the remaining 812 people were similar to those recorded by the UK Office of National Statistics. Following vaccination, 57.9% of participants reported improvements in symptoms, 17.9% reported deterioration and the remainder no change. There was considerable individual variation in responses. Larger improvements in symptom severity scores were seen in those receiving the mRNA vaccines compared to adenoviral vector vaccines. Conclusions: Our survey suggests COVID-19 vaccination may improve long COVID patients, on average. The observational nature of the survey limits drawing direct causal inference, but requires validation with a randomised controlled trial.

Influence of anesthesia on hemodynamic assessment of mitral stenosis severity.

BackgroundThe treatment of choice for severe rheumatic mitral stenosis (MS) is balloon mitral valvuloplasty (BMV). Assessment of MS severity is usually performed by echocardiography. Before performing BMV, invasive hemodynamic assessment is also performed. The effect of anesthesia on the invasive assessment of MS severity has not been studied. The purpose of the present study was to assess changes in invasive hemodynamic measurement of MS severity before and after induction of general anesthesia.MethodsThe medical files of 22 patients who underwent BMV between 2014 and 2020 were reviewed. Medical history, laboratory, echocardiographic and invasive measurements were collected. Anesthesia induction was performed with etomidate or propofol. Pre-procedural echocardiographic measurements of valve area using pressure half time, and continuity correlated well with invasive measurements using the Gorlin formula.ResultsAfter induction of anesthesia the mean mitral valve gradient dropped by 2.4 mmHg (p = 0.153) and calculated mitral valve area (MVA) increased by 0.2 cm2 (p = 0.011). A wide variability in individual response was observed. While a drop in gradient was noted in 14 patients, it increased in 7. Gorlin derived MVA rose in most patients but dropped in 4. Assuming a calculated MVA of 1.5 cm2 and below to define clinically significant MS, 4 patients with pre-induction MVA of 1.5 cm2 or below had calculated MVA above 1.5 cm2 after induction.ConclusionsThe impact of general anesthesia on the hemodynamic assessment of MS is heterogeneous and may lead to misclassification of MS severity.

Functional and Structural Brain Connectivity in Children With Bilateral Cerebral Palsy Compared to Age-Related Controls and in Response to Intensive Rapid-Reciprocal Leg Training.

BackgroundCompared to unilateral cerebral palsy (CP), less is known about brain reorganization and plasticity in bilateral CP especially in relation or response to motor training. The few trials that reported brain imaging results alongside functional outcomes include a handful of studies in unilateral CP, and one pilot trial of three children with bilateral CP. This study is the first locomotor training randomized controlled trial (RCT) in bilateral CP to our knowledge reporting brain imaging outcomes.MethodsObjective was to compare MRI brain volumes, resting state connectivity and white matter integrity using DTI in children with bilateral CP with PVL and preterm birth history (<34 weeks), to age-related controls, and from an RCT of intensive 12 week rapid-reciprocal locomotor training using an elliptical or motor-assisted cycle. We hypothesized that connectivity in CP compared to controls would be greater across sensorimotor-related brain regions and that functional (resting state) and structural (fractional anisotropy) connectivity would improve post intervention. We further anticipated that baseline and post-intervention imaging and functional measures would correlate.ResultsImages were acquired with a 3T MRI scanner for 16/27 children with CP in the trial, and 18 controls. No conclusive evidence of training-induced neuroplastic effects were seen. However, analysis of shared variance revealed that greater increases in precentral gyrus connectivity with the thalamus and pons may be associated with larger improvements in the trained device speed. Exploratory analyses also revealed interesting potential relationships between brain integrity and multiple functional outcomes in CP, with functional connectivity between the motor cortex and midbrain showing the strongest potential relationship with mobility. Decreased posterior white matter, corpus callosum and thalamic volumes, and FA in the posterior thalamic radiation were the most prominent group differences with corticospinal tract differences notably not found.ConclusionsResults reinforce the involvement of sensory-related brain areas in bilateral CP. Given the wide individual variability in imaging results and clinical responses to training, a greater focus on neural and other mechanisms related to better or worse outcomes is recommended to enhance rehabilitation results on a patient vs. group level.

Epigenetics in Precision Nutrition.

Precision nutrition is an emerging area of nutrition research, with primary focus on the individual variability in response to dietary and lifestyle factors, which are mainly determined by an individual’s intrinsic variations, such as those in genome, epigenome, and gut microbiome. The current research on precision nutrition is heavily focused on genome and gut microbiome, while epigenome (DNA methylation, non-coding RNAs, and histone modification) is largely neglected. The epigenome acts as the interface between the human genome and environmental stressors, including diets and lifestyle. Increasing evidence has suggested that epigenetic modifications, particularly DNA methylation, may determine the individual variability in metabolic health and response to dietary and lifestyle factors and, therefore, hold great promise in discovering novel markers for precision nutrition and potential targets for precision interventions. This review summarized recent studies on DNA methylation with obesity, diabetes, and cardiovascular disease, with more emphasis put in the relations of DNA methylation with nutrition and diet/lifestyle interventions. We also briefly reviewed other epigenetic events, such as non-coding RNAs, in relation to human health and nutrition, and discussed the potential role of epigenetics in the precision nutrition research.

Same Space, Different Standards: A Review of Cumulative Effects Assessment Practice for Marine Mammals

Marine mammals are vulnerable to a variety of acute and chronic anthropogenic stressors, potentially experiencing these in isolation, successively and/or simultaneously. Formal assessment of the likely impact(s) of the cumulative effects of multiple stressors on a defined population is carried out through a Cumulative Effects Assessment (CEA), which is a mandatory component of the Environmental Impact Assessment (EIA) process in many countries. However, for marine mammals, the information required to feed into CEA, such as thresholds for disturbance, frequency of multiple (and simultaneous) exposures, interactions between stressors, and individual variation in response, is extremely limited, though our understanding is slowly improving. The gaps in knowledge make it challenging to effectively quantify and subsequently assess the risk of individual and population consequences of multiple disturbances in the form of a CEA. To assess the current state of practice for assessing cumulative effects on marine mammals within UK waters, 93 CEAs were reviewed across eleven maritime industries. An objective framework of thirteen evaluative criteria was used to score each assessment on a scale of 13-52 (weak - strong). Scores varied significantly by industry. On average, the aquaculture industry produced the lowest scoring CEAs, whilst the large offshore windfarm industry (≥ 20 turbines) scored highest, according to the scoring criteria used. There was a significant increase in scores over the sample period (2009-2019), though this was mostly attributed to five industries (cable, large and small offshore wind farms, tidal and wave energy). There was inconsistency in the language used to define and describe cumulative effects and a lack of routinely applied methodology. We use the findings presented here, along with a wider review of the literature, to provide recommendations and discussion points aimed at supporting the standardisation and improvement of CEA practice. Although this research focused on how marine mammals were considered within UK CEAs, recommendations made are broadly applicable to assessments conducted for other receptors, countries and/or environments. Adoption of these proposals would help to ensure a more consistent approach, and would aid decision-makers and practitioners in mitigating any potential impacts, to ensure conservation objectives of marine mammal populations are not compromised.

Evaluation of the genetic risk for COVID-19 outcomes in COPD and differences among worldwide populations.

Populations seem to respond differently to the global pandemic of severe acute respiratory syndrome coronavirus 2. Recent studies show individual variability in both susceptibility and clinical response to COVID-19 infection. People with chronic obstructive pulmonary disease (COPD) constitute one of COVID-19 risk groups, being already associated with a poor prognosis upon infection. This study aims contributing to unveil the underlying reasons for such prognosis in people with COPD and the variability in the response observed across worldwide populations, by looking at the genetic background as a possible answer to COVID-19 infection response heterogeneity. SNPs already associated with susceptibility to COVID-19 infection (rs286914 and rs12329760) and severe COVID-19 with respiratory failure (rs657152 and rs11385942) were assessed and their allelic frequencies used to calculate the probability of having multiple risk alleles. This was performed on a Portuguese case-control COPD cohort, previously clinically characterized and genotyped from saliva samples, and also on worldwide populations (European, Spanish, Italian, African, American and Asian), using publicly available frequencies data. A polygenic risk analysis was also conducted on the Portuguese COPD cohort for the two mentioned phenotypes, and also for hospitalization and survival to COVID-19 infection. No differences in genetic risk for COVID-19 susceptibility, hospitalization, severity or survival were found between people with COPD and the control group (all p-values > 0.01), either considering risk alleles individually, allelic combinations or polygenic risk scores. All populations, even those with European ancestry (Portuguese, Spanish and Italian), showed significant differences from the European population in genetic risk for both COVID-19 susceptibility and severity (all p-values < 0.0001). Our results indicate a low genetic contribution for COVID-19 infection predisposition or worse outcomes observed in people with COPD. Also, our study unveiled a high genetic heterogeneity across major world populations for the same alleles, even within European sub-populations, demonstrating the need to build a higher resolution European genetic map, so that differences in the distribution of relevant alleles can be easily accessed and used to better manage diseases, ultimately, safeguarding populations with higher genetic predisposition to such diseases.

Whole and segmental body composition changes during mid-follicular and mid-luteal phases of the menstrual cycle in recreationally active young women

Background Changes in oestradiol and progesterone hormones and associated fluid retention during the menstrual cycle phases might affect body composition (BC) in women. Aim The main objectives of this study were to determine the changes in whole and segmental BC by dual-energy x-ray absorptiometry (DXA) and bioelectrical impedance (BIA) during the mid-follicular (MFP) and mid-luteal (MLP) phases. Subjects and methods Thirty recreationally active young women participated in this study. BC was measured by DXA and BIA during MFP and MLP. A mixed linear model for repeated measures analysis was used to determine the differences between the two phases. Results Body mass was higher during MLP than MFP, while total body water, total and segmental fat mass and fat percentages measured by both BIA and DXA were similar during the two phases. DXA-derived fat-free mass and soft lean mass in the android region were higher during MLP than MFP. Large variability in individual responses was evident. Conclusion On average, whole and segmental BC variables do not change significantly between MFP and MLP. However, given the large variability among the individual responses, it is suggested to perform repeated BC measurements during the same phase of the menstrual cycle.

Changes in discourse informativeness and efficiency following communication-based group treatment for chronic aphasia

ABSTRACT Background Evidence regarding the effect of conversationally based communication group treatment on discourse production in aphasia is limited. Given the rich, complex communication experiences provided in these groups, it seemed plausible that participation in them could result in improvement of simpler aspects of discourse production. Aims To examine the effects of group communication treatment on the informativeness and efficiency of structured and conversational discourse tasks in adults with chronic aphasia. Methods & Procedures The data for this study were discourses elicited prospectively from 23 adults with chronic aphasia by Elman & Bernstein-Ellis (1999a) as part of their randomised controlled trial, but never previously transcribed or analyzed. We evaluated changes in discourse informativeness and efficiency at treatment exit and follow-up with Bayesian generalised linear mixed-effects models. Individual effect sizes at exit and follow-up were estimated and a region-of-practical-equivalence approach was used to evaluate whether the posterior distributions at each timepoint for each participant were clinically meaningful. Outcomes & Results Results at the group level revealed that structured discourses became more informative and efficient after treatment, and that this improvement was at least maintained at follow-up. Informativeness of conversational discourse did not change from treatment entry to exit, but there was modest evidence of improvement at follow-up. There was no evidence of change to the efficiency of conversational discourse at either timepoint. There was wide variability in individual response to the treatment. Conclusions Participation in conversation-based communication group treatment was associated with more informative and efficient structured discourse production and modestly improved informativeness in conversational discourse. Examining individual responses to treatment provided additional insight about the group-level outcomes and provided some clues about factors that might have influenced performance for some of the participants.

Induced Hypothermia as Cold as 3°C in Humans: Forgotten Cases Rediscovered.

Zafren, Ken, Raimund Lechner, Peter Paal, Hermann Brugger, Giles Peek, and Tomasz Darocha. Induced hypothermia as cold as 3°C in humans: Forgotten cases rediscovered. High Alt Med Biol. 23:105-113.-The lowest temperature from which humans can be successfully rewarmed from accidental hypothermia is unknown. The lowest published core temperature with survival from accidental hypothermia is 11.8°C. We recently reported a rediscovered case series of patients in whom profound hypothermia was induced for surgery. The patient in this case series with the lowest core temperature, 4.2°C, survived neurologically intact. We subsequently rediscovered several additional case series of induced hypothermia to core temperatures below 11.8°C. In one case series, at least one patient was cooled to 3°C. We do not know if any patient survived cooling to 3°C. As in the previous case series, the authors of the additional reports presented physiological data at various core temperatures, showing wide variations in individual responses to hypothermia. These data add to our understanding of the physiology of profound hypothermia. Although induced hypothermia for surgery differs from accidental hypothermia, survival from very low temperatures in induced hypothermia provides evidence that humans with accidental hypothermia can be resuscitated successfully from temperatures much lower than 11.8°C. We continue to advise against using core temperature alone to decide if a hypothermic patient in cardiac arrest has a chance of survival.

Complete nutrition drink with retrograded starch is low glycemic, and the individual glucose response to the low glycemic complete nutrition drink depends on fasting insulin levels and HOMA-IR in a randomized cross-over control trial.

Complete nutrition drinks with a low glycemic index (GI) provide nutritional support and prevent hyperglycaemia. The present study identified GI and factors predicting individual glucose response to a new complete nutrition drink. A randomised cross-over controlled trial was conducted in eighteen healthy volunteers (FPG < 100 mg/dl). Complete nutrition drinks containing retrograded starch, glucose solution and white bread were assigned in a random sequence with 14-day wash-out intervals. Plasma glucose and insulin levels were measured from baseline to 180 min after consuming each food. Results show the adjusted GIs of the drink was 48.2 ± 10.4 and 46.7 ± 12.7 with glucose and white bread as the reference, respectively. While the drink has low GI (<55), the individual glucose responses varied (GI: 7-149). Comparing characters in individual GI < 55 (n = 12) and GI ≥ 55 (n = 6) groups revealed significantly higher baseline insulin in the low GI group (14.86 ± 16.51 μIU/ml v. 4.9 ± 3.4 μIU/ml, P < 0·05). The correlation matrix confirms only two predictive factors for having individual GI <55 were baseline insulin (r = 0·5, P = 0·03) and HOMA-IR (r = 0·55, P = 0·02). ROC curve reveals fasting insulin above 1.6 μIU/ml and HOMA-IR above 1.05 as the cut-off values. The findings suggest that the complete nutrition drink has a low GI, but there was wide variability in individual responses partly explained by fasting insulin levels and HOMA-IR. Screening for fasting insulin and HOMA-IR may be encouraged to maximise the functional benefit of the drink.

Characterizing Within-Driver Variability in Driving Dynamics During Obstacle Avoidance Maneuvers

Variability in human response creates non-trivial challenges for modeling and control of human-automation systems. As autonomy becomes pervasive, methods that can accommodate human variability will become paramount, to ensure efficiency, safety, and high levels of performance. We propose an easily computable modeling framework which takes advantage of a metric to assess variability in individual human response in a dynamic task that participants repeat over several trials. Our approach is based in a transformation of observed trajectories to a reproducing kernel Hilbert space, which captures variability in human response as a distribution embedded within the Hilbert space. We evaluate the similarity across responses via the maximum mean discrepancy, which measures the distance between distributions within the Hilbert space. We apply this metric to a difficult driving task designed to elucidate differences across participants. We conducted a pilot study with 6 participants in an advanced driving simulator, in which participants were tasked with collision avoidance of an obstacle in the middle of the road, around a blind corner, in a nighttime scenario, while steering only with the non-dominant hand.

Heterogeneity of Hematological Response to Hypoxia and Short-Term or Medium-Term Bed Rest.

Hematological changes are commonly observed following prolonged exposure to hypoxia and bed rest. Typically, such responses have been reported as means and standard deviations, however, investigation into the responses of individuals is insufficient. Therefore, the present study retrospectively assessed individual variation in the hematological responses to severe inactivity (bed rest) and hypoxia. The data were derived from three-bed rest projects: two 10-d (LunHab project: 8 males; FemHab project: 12 females), and one 21-d (PlanHab project: 11 males). Each project comprised a normoxic bed rest (NBR; PIO2=133mmHg) and hypoxic bed rest (HBR; PIO2=91mmHg) intervention, where the subjects were confined in the Planica facility (Rateče, Slovenia). During the HBR intervention, subjects were exposed to normobaric hypoxia equivalent to an altitude of 4,000m. NBR and HBR interventions were conducted in a random order and separated by a washout period. Blood was drawn prior to (Pre), during, and post bed rest (R1, R2, R4) to analyze the individual variation in the responses of red blood cells (RBC), erythropoietin (EPO), and reticulocytes (Rct) to bed rest and hypoxia. No significant differences were found in the mean ∆(Pre-Post) values of EPO across projects (LunHab, FemHab, and PlanHab; p>0.05), however, female EPO responses to NBR (Range - 17.39, IQR – 12.97 mIU.ml−1) and HBR (Range – 49.00, IQR – 10.91 mIU.ml−1) were larger than males (LunHab NBR Range – 4.60, IQR – 2.03; HBR Range – 7.10, IQR – 2.78; PlanHab NBR Range – 7.23, IQR – 1.37; HBR Range – 9.72, IQR – 4.91 mIU.ml−1). Bed rest duration had no impact on the heterogeneity of EPO, Rct, and RBC responses (10-d v 21-d). The resultant hematological changes that occur during NBR and HBR are not proportional to the acute EPO response. The following cascade of hematological responses to NBR and HBR suggests that the source of variability in the present data is due to mechanisms related to hypoxia as opposed to inactivity alone. Studies investigating hematological changes should structure their study design to explore these mechanistic responses and elucidate the discord between the EPO response and hematological cascade to fully assess heterogeneity.

The Future of Personalized Medicine in Space: From Observations to Countermeasures.

The aim of personalized medicine is to detach from a “one-size fits all approach” and improve patient health by individualization to achieve the best outcomes in disease prevention, diagnosis and treatment. Technological advances in sequencing, improved knowledge of omics, integration with bioinformatics and new in vitro testing formats, have enabled personalized medicine to become a reality. Individual variation in response to environmental factors can affect susceptibility to disease and response to treatments. Space travel exposes humans to environmental stressors that lead to physiological adaptations, from altered cell behavior to abnormal tissue responses, including immune system impairment. In the context of human space flight research, human health studies have shown a significant inter-individual variability in response to space analogue conditions. A substantial degree of variability has been noticed in response to medications (from both an efficacy and toxicity perspective) as well as in susceptibility to damage from radiation exposure and in physiological changes such as loss of bone mineral density and muscle mass in response to deconditioning. At present, personalized medicine for astronauts is limited. With the advent of longer duration missions beyond low Earth orbit, it is imperative that space agencies adopt a personalized strategy for each astronaut, starting from pre-emptive personalized pre-clinical approaches through to individualized countermeasures to minimize harmful physiological changes and find targeted treatment for disease. Advances in space medicine can also be translated to terrestrial applications, and vice versa. This review places the astronaut at the center of personalized medicine, will appraise existing evidence and future preclinical tools as well as clinical, ethical and legal considerations for future space travel.

Categorization of Bacterial Pathogens Present in Infected Wounds and their Antibiotic Resistance Profile Recovered from Patients Attending Rizgary Hospital-Erbil

Wound infection with antibiotic-resistant bacteria can extend a patients’ debility and increase the expense of treatment in the long term; therefore, careful management of patients with wound infections is necessary to avoid complications. The usage of antimicrobial agent is a major factor in resistance development. This study aims to understand the causes of wound infections, as well as the criteria for diagnosing them for more sensible antibiotic prescribing. Samples from 269 wound patients were collected, and cultured for bacterial growth. Gram stain technique, bacterial identification via VITEK 2 compact system were investigated in this study. Gram negative bacteria accounted for 59.15% of the total isolates, while pathogenic gram positive bacteria accounted for 40.85% of total isolates. Escherichia coli and Pseudomonas aeruginosa are the dominant pathogenic gram negative bacteria in wounds, while Staphylococcus aureus, and Staphylococcus epidermidis are the dominant pathogenic gram positive bacteria. Pseudomonas aeruginosa showed 100% resistance to the majority of antibiotic tested, including Ampicillin, Amoxicillin/Clavulanic Acid, Aztreona, Ceftriaxone, and others. Staphylococcus aureus and Staphylococcus epidermidis are 100% resistant to Ampicillin, Ceftriaxone, and Cefotaxime. For more efficient antibiotic prescriptions, the causative microorganisms, and their current susceptibility patterns need to be mandated for testing before prescribing any antibiotics to patients. Prescriptions are frequently based solely on general information about the antibiotic's function, rather than on individual response variation to the pathogen and the antibiotic. Particularly when the common pathogens in this study show multidrug resistance in wounds.

Event-based analysis of wetland hydrologic response in the Prairie Pothole Region

Previous studies in the Prairie Pothole Region mainly assessed wetland hydrologic function at seasonal, annual and decadal scales. While many studies have looked at water balance dynamics and local flow generation processes in wetlands, no study looked at hydrological dynamics in response to individual rainfall events in prairie pothole wetlands (here after referred as wetlands) across a gradient of alteration. The present study aimed to investigate: (1) the most important metrics needed to characterize the spatial variability of wetland hydrologic response to rainfall-runoff events; (2)the temporal variability of individual wetland hydrologic response; (3) the spatial and temporal variability of wetland-stream interaction; and (4) the temporal persistence of various spatial controls on individual wetland hydrologic response characteristics. High-frequency water level data was collected over two years for ten intact, three consolidated, and seven drainage ditches associated with fully drained wetland(s), as well as a creek located in southwestern Manitoba, Canada. The hydrologic response of the studied wetlands to individual rainfall-runoff events was characterized using a range of metrics. Several data analysis methods were used, including principal component analysis, graphical assessments of wetland-stream hysteresis dynamics, and correlations analyses between wetland response metrics and spatial characteristics. Results suggested that wetland alteration status (i.e., drained versus intact, open-water wetlands) plays an important role in explaining differences in the event-scale hydrologic behaviour of wetlands. Climatic and antecedent storage conditions (i.e., surface and subsurface storage in wetland basin) also had a strong influence on the hydrologic responses of wetlands during individual rainfall-runoff events and appeared to override the influence of spatial controls such as wetland area, volume or catchment area. Antecedent storage also seemed to be the driving factor of wetland-stream interactions. A lack of persistent correlations between wetland spatial characteristics and response metrics was observed and suggested nonstationary wetland hydrological behaviours and controls, a conclusion that has significant implications for wetland classification and modelling.

Optimizing the Timing of Highest Hydrocortisone Dose in Children and Adolescents With 21-Hydroxylase Deficiency.

ContextHydrocortisone treatment of young patients with 21-hydroxylase deficiency (21OHD) is given thrice daily, but there is debate about the optimal timing of the highest hydrocortisone dose, either mimicking the physiological diurnal rhythm (morning), or optimally suppressing androgen activity (evening).ObjectiveWe aimed to compare 2 standard hydrocortisone timing strategies, either highest dosage in the morning or evening, with respect to hormonal status throughout the day, nocturnal blood pressure (BP), and sleep and activity scores.MethodsThis 6-week crossover study included 39 patients (aged 4-19 years) with 21OHD. Patients were treated for 3 weeks with the highest hydrocortisone dose in the morning, followed by 3 weeks with the highest dose in the evening (n = 21), or vice versa (n = 18). Androstenedione (A4) and 17-hydroxyprogesterone (17OHP) levels were quantified in saliva collected at 5 am; 7 am; 3 pm; and 11 pm during the last 2 days of each treatment period. The main outcome measure was comparison of saliva 17OHP and A4 levels between the 2 treatment strategies.ResultsAdministration of the highest dose in the evening resulted in significantly lower 17OHP levels at 5 am, whereas the highest dose in the morning resulted in significantly lower 17OHP and A4 levels in the afternoon. The 2 treatment dose regimens were comparable with respect to averaged daily hormone levels, nocturnal BP, and activity and sleep scores.ConclusionNo clear benefit for either treatment schedule was established. Given the variation in individual responses, we recommend individually optimizing dose distribution and monitoring disease control at multiple time points.

Association between human paraoxonase 2 protein and efficacy of acetylcholinesterase inhibiting drugs used against Alzheimer's disease.

Serum Paraoxonase 2 (PON2) level is a potential biomarker owing to its association with a number of pathophysiological conditions such as atherosclerosis and cardiovascular disease. Since cholinergic deficiency is closely linked with Alzheimer’s disease (AD) progression, acetylcholinesterase inhibitors (AChEIs) are the treatment of choice for patients with AD. However, there is a heterogenous response to these drugs and mostly the subjects do not respond to the treatment. Gene polymorphism, the simultaneous occurrence of two or more discontinuous alleles in a population, could be one of the important factors for this. Hence, we hypothesized that PON2 and its polymorphic forms may be hydrolyzing the AChEIs differently, and thus, different patients respond differently. To investigate this, two AChEIs, donepezil hydrochloride (DHC) and pyridostigmine bromide (PB), were selected. Human PON2 wildtype gene and four mutants, two catalytic sites, and two polymorphic sites were cloned, recombinantly expressed, and purified for in vitro analysis. Enzyme activity and AChE activity were measured to quantitate the amount of DHC and PB hydrolyzed by the wildtype and the mutant proteins. Herein, PON2 esterase activity and AChE inhibitor efficiency were found to be inversely related. A significant difference in enzyme activity of the catalytic site mutants was observed as compared to the wildtype, and subsequent AChE activity showed that esterase activity of PON2 is responsible for the hydrolysis of DHC and PB. Interestingly, PON2 polymorphic site mutants showed increased esterase activity; therefore, this could be the reason for the ineffectiveness of the drugs. Thus, our data suggested that the esterase activity of PON2 was mainly responsible for the hydrolysis of AChEI, DHC, and PB, and that might be responsible for the variation in individual response to AChEI therapy.

Resource selection functions based on hierarchical generalized additive models provide new insights into individual animal variation and species distributions

Habitat selection studies are designed to generate predictions of species distributions or inference regarding general habitat associations and individual variation in habitat use. Such studies frequently involve either individually indexed locations gathered across limited spatial extents and analyzed using resource selection functions (RSFs) or spatially extensive locational data without individual resolution typically analyzed using species distribution models. Both analytical methodologies have certain desirable features, but analyses that combine individual‐ and population‐level inference with flexible non‐linear functions may provide improved predictions while accounting for individual variation. Here, we describe how RSFs can be fit using hierarchical generalized additive models (HGAMs) using widely available software, providing a means to explore individual variation in habitat associations and to generate species distribution maps. We used GPS tracking data from golden eagles Aquila chrysaetos from across eastern North America with four environmental predictors to generate monthly distribution models. We considered three model structures that assumed different amounts of individual variation in the functional relationship between predictors and habitat use and used k‐fold cross‐validation to compare model performance. Models accounting for individual variability in shape and smoothness of functional responses performed best. Eagles exhibited the least amount of individual variation in response to land cover variables during winter months, with most individuals more closely adhering to the population‐level trend. During the summer months, eagles exhibited more substantial individual variation in shape and smoothness of the functional relationships, suggesting some need to account for individual variation in eagle habitat use for both inferential and predictive purposes, during this time of year. Because they allow users to blend flexible functions with random effects structures and are well‐supported by a variety of software platforms, we believe that HGAMs provide a useful addition to the suite of analyses used for modeling habitat associations or predicting species distributions.