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Objectives: Research has shown that analyzing intrusion errors generated on verbal learning and memory measures is helpful for distinguishing between the memory disorders associated with Alzheimer’s disease (AD) and other neurological disorders, including Huntington’s disease (HD). Moreover, preliminary evidence suggests that certain clinical populations may be prone to exhibit different types of intrusion errors. Methods: We examined the prevalence of two new California Verbal Learning Test-3 (CVLT-3) intrusion subtypes – across-trial novel intrusions and across/within trial repeated intrusions – in individuals with AD or HD. We hypothesized that the encoding/storage impairment associated with medial-temporal involvement in AD would result in a greater number of novel intrusions on the delayed recall trials of the CVLT-3, whereas the executive dysfunction associated with subcortical-frontal involvement in HD would result in a greater number of repeated intrusions across trials. Results: The AD group generated significantly more across-trial novel intrusions than across/within trial repeated intrusions on the delayed cued-recall trials, whereas the HD group showed the opposite pattern on the delayed free-recall trials. Conclusions: These new intrusion subtypes, combined with traditional memory analyses (e.g., recall versus recognition performance), promise to enhance our ability to distinguish between the memory disorders associated with primarily medial-temporal versus subcortical-frontal involvement.
Surgery for CHD has been slow to develop in parts of the former Soviet Union. The impact of an 8-year surgical assistance programme between an emerging centre and a multi-disciplinary international team that comprised healthcare professionals from developed cardiac programmes is analysed and presented.
Material and methods
The international paediatric assistance programme included five main components – intermittent clinical visits to the site annually, medical education, biomedical engineering support, nurse empowerment, and team-based practice development. Data were analysed from visiting teams and local databases before and since commencement of assistance in 2007 (era A: 2000–2007; era B: 2008–2015). The following variables were compared between periods: annual case volume, operative mortality, case complexity based on Risk Adjustment for Congenital Heart Surgery (RACHS-1), and RACHS-adjusted standardised mortality ratio.
A total of 154 RACHS-classifiable operations were performed during era A, with a mean annual case volume by local surgeons of 19.3 at 95% confidence interval 14.3–24.2, with an operative mortality of 4.6% and a standardised mortality ratio of 2.1. In era B, surgical volume increased to a mean of 103.1 annual cases (95% confidence interval 69.1–137.2, p<0.0001). There was a non-significant (p=0.84) increase in operative mortality (5.7%), but a decrease in standardised mortality ratio (1.2) owing to an increase in case complexity. In era B, the proportion of local surgeon-led surgeries during visits from the international team increased from 0% (0/27) in 2008 to 98% (58/59) in the final year of analysis.
The model of assistance described in this report led to improved adjusted mortality, increased case volume, complexity, and independent operating skills.
Major depressive disorder (MDD) is a leading cause of disease burden worldwide, with lifetime prevalence in the United States of 17%. Here we present the results of the first prospective, large-scale, patient- and rater-blind, randomized controlled trial evaluating the clinical importance of achieving congruence between combinatorial pharmacogenomic (PGx) testing and medication selection for MDD.
1,167 outpatients diagnosed with MDD and an inadequate response to ≥1 psychotropic medications were enrolled and randomized 1:1 to a Treatment as Usual (TAU) arm or PGx-guided care arm. Combinatorial PGx testing categorized medications in three groups based on the level of gene-drug interactions: use as directed, use with caution, or use with increased caution and more frequent monitoring. Patient assessments were performed at weeks 0 (baseline), 4, 8, 12 and 24. Patients, site raters, and central raters were blinded in both arms until after week 8. In the guided-care arm, physicians had access to the combinatorial PGx test result to guide medication selection. Primary outcomes utilized the Hamilton Depression Rating Scale (HAM-D17) and included symptom improvement (percent change in HAM-D17 from baseline), response (50% decrease in HAM-D17 from baseline), and remission (HAM-D17<7) at the fully blinded week 8 time point. The durability of patient outcomes was assessed at week 24. Medications were considered congruent with PGx test results if they were in the ‘use as directed’ or ‘use with caution’ report categories while medications in the ‘use with increased caution and more frequent monitoring’ were considered incongruent. Patients who started on incongruent medications were analyzed separately according to whether they changed to congruent medications by week8.
At week 8, symptom improvement for individuals in the guided-care arm was not significantly different than TAU (27.2% versus 24.4%, p=0.11). However, individuals in the guided-care arm were more likely than those in TAU to achieve remission (15% versus 10%; p<0.01) and response (26% versus 20%; p=0.01). Remission rates, response rates, and symptom reductions continued to improve in the guided-treatment arm until the 24week time point. Congruent prescribing increased to 91% in the guided-care arm by week 8. Among patients who were taking one or more incongruent medication at baseline, those who changed to congruent medications by week 8 demonstrated significantly greater symptom improvement (p<0.01), response (p=0.04), and remission rates (p<0.01) compared to those who persisted on incongruent medications.
Combinatorial PGx testing improves short- and long-term response and remission rates for MDD compared to standard of care. In addition, prescribing congruency with PGx-guided medication recommendations is important for achieving symptom improvement, response, and remission for MDD patients.
Funding Acknowledgements: This study was supported by Assurex Health, Inc.
Objectives: The third edition of the California Verbal Learning Test (CVLT-3) includes a new index termed List A versus Novel/Unrelated recognition discriminability (RD) on the Yes/No Recognition trial. Whereas the Total RD index incorporates false positive (FP) errors associated with all distractors (including List B and semantically related items), the new List A versus Novel/Unrelated RD index incorporates only FP errors associated with novel, semantically unrelated distractors. Thus, in minimizing levels of source and semantic interference, the List A versus Novel/Unrelated RD index may yield purer assessments of yes/no recognition memory independent of vulnerability to source memory difficulties or semantic confusion, both of which are often seen in individuals with primarily frontal-system dysfunction (e.g., early Huntington’s disease [HD]). Methods: We compared the performance of individuals with Alzheimer’s disease (AD) and HD in mild and moderate stages of dementia on CVLT-3 indices of Total RD and List A versus Novel/Unrelated RD. Results: Although AD and HD subgroups exhibited deficits on both RD indices relative to healthy comparison groups, those with HD generally outperformed those with AD, and group differences were more robust on List A versus Novel/Unrelated RD than on Total RD. Conclusions: Our findings highlight the clinical utility of the new CVLT-3 List A versus Novel/Unrelated RD index, which (a) maximally assesses yes/no recognition memory independent of source and semantic interference; and (b) provides a greater differentiation between individuals whose memory disorder is primarily at the encoding/storage level (e.g., as in AD) versus at the retrieval level (e.g., as in early HD). (JINS, 2018, 24, 833–841)
The impact of a deep-water plunging breaker on a finite height two-dimensional structure with a vertical front face is studied experimentally. The structure is located at a fixed horizontal position relative to a wave maker and the structure’s bottom surface is located at a range of vertical positions close to the undisturbed water surface. Measurements of the water surface profile history and the pressure distribution on the front surface of the structure are performed. As the vertical position,
axis is positive up and
is the mean water level), of the structure’s bottom surface is varied from one experimental run to another, the water surface evolution during impact can be categorized into three classes of behaviour. In class I, with
in a range of values near
is the nominal wavelength of the breaker, the behaviour of the water surface is similar to the flip-through phenomena first described in studies with shallow water and a structure mounted on the sea bed. In the present work, it is found that the water surface between the front face of the structure and the wave crest is well fitted by arcs of circles with a decreasing radius and downward moving centre as the impact proceeds. A spatially and temporally localized high-pressure region was found on the impact surface of the structure and existing theory is used to explore the physics of this phenomenon. In class II, with
in a range of values near the mean water level, the bottom of the structure exits and re-enters the water phase at least once during the impact process. These air–water transitions generate large-amplitude ripple packets that propagate to the wave crest and modify its behaviour significantly. At
, all sensors submerged during the impact record a nearly in-phase high-frequency pressure oscillation indicating possible air entrainment. In class III, with
in a range of values near
, the bottom of the structure remains in air before the main crest hits the bottom corner of the structure. The subsequent free surface behaviour is strongly influenced by the instantaneous momentum of the local flow just before impact and the highest wall pressures of all experimental conditions are found.
The absence of a dedicated transport for disaccharides in the intestine implicates that the metabolic use of dietary lactose relies on its prior hydrolysis at the intestinal brush border. Consequently, lactose in blood or urine has mostly been associated with specific cases in which the gastrointestinal barrier is damaged. On the other hand, lactose appears in the blood of lactating women and has been detected in the blood and urine of healthy men, indicating that the presence of lactose in the circulation of healthy subjects is not incompatible with normal physiology. In this cross-over study we have characterised the postprandial kinetics of lactose, and its major constituent, galactose, in the serum of fourteen healthy men who consumed a unique dose of 800 g milk or yogurt. Genetic testing for lactase persistence and microbiota profiling of the subjects were also performed. Data revealed that lactose does appear in serum after dairy intake, although with delayed kinetics compared with galactose. Median serum concentrations of approximately 0·02 mmol/l lactose and approximately 0·2 mmol/l galactose were observed after the ingestion of milk and yogurt respectively. The serum concentrations of lactose were inversely correlated with the concentrations of galactose, and the variability observed between the subjects’ responses could not be explained by the presence of the lactase persistence allele. Finally, lactose levels have been associated with the abundance of the Veillonella genus in faecal microbiota. The measurement of systemic lactose following dietary intake could provide information about lactose metabolism and nutrient transport processes under normal or pathological conditions.
Probiotic yogurt and milk supplemented with probiotics have been investigated for their role in ‘low-grade’ inflammation but evidence for their efficacy is inconclusive. This study explores the impact of probiotic yogurt on metabolic and inflammatory biomarkers, with a parallel study of gut microbiota dynamics. The randomised cross-over study was conducted in fourteen healthy, young men to test probiotic yogurt compared with milk acidified with 2 % d-(+)-glucono-δ-lactone during a 2-week intervention (400 g/d). Fasting assessments, a high-fat meal test (HFM) and microbiota analyses were used to assess the intervention effects. Baseline assessments for the HFM were carried out after a run-in during which normal milk was provided. No significant differences in the inflammatory response to the HFM were observed after probiotic yogurt compared with acidified milk intake; however, both products were associated with significant reductions in the inflammatory response to the HFM compared with the baseline tests (assessed by IL6, TNFα and chemokine ligand 5) (P<0·001). These observations were accompanied by significant changes in microbiota taxa, including decreased abundance of Bilophila wadsworthia after acidified milk (log 2-fold-change (FC)=–1·5, Padj=0·05) and probiotic yogurt intake (FC=–1·3, Padj=0·03), increased abundance of Bifidobacterium species after acidified milk intake (FC=1·4, Padj=0·04) and detection of Lactobacillus delbrueckii spp. bulgaricus (FC=7·0, Padj<0·01) and Streptococcus salivarius spp. thermophilus (FC=6·0, Padj<0·01) after probiotic yogurt intake. Probiotic yogurt and acidified milk similarly reduce postprandial inflammation that is associated with a HFM while inducing distinct changes in the gut microbiota of healthy men. These observations could be relevant for dietary treatments that target ‘low-grade’ inflammation.
This review summarizes the results from the INRA (Institut National de la Recherche Agronomique) divergent selection experiment on residual feed intake (RFI) in growing Large White pigs during nine generations of selection. It discusses the remaining challenges and perspectives for the improvement of feed efficiency in growing pigs. The impacts on growing pigs raised under standard conditions and in alternative situations such as heat stress, inflammatory challenges or lactation have been studied. After nine generations of selection, the divergent selection for RFI led to highly significant (P<0.001) line differences for RFI (−165 g/day in the low RFI (LRFI) line compared with high RFI line) and daily feed intake (−270 g/day). Low responses were observed on growth rate (−12.8 g/day, P<0.05) and body composition (+0.9 mm backfat thickness, P=0.57; −2.64% lean meat content, P<0.001) with a marked response on feed conversion ratio (−0.32 kg feed/kg gain, P<0.001). Reduced ultimate pH and increased lightness of the meat (P<0.001) were observed in LRFI pigs with minor impact on the sensory quality of the meat. These changes in meat quality were associated with changes of the muscular energy metabolism. Reduced maintenance energy requirements (−10% after five generations of selection) and activity (−21% of time standing after six generations of selection) of LRFI pigs greatly contributed to the gain in energy efficiency. However, the impact of selection for RFI on the protein metabolism of the pig remains unclear. Digestibility of energy and nutrients was not affected by selection, neither for pigs fed conventional diets nor for pigs fed high-fibre diets. A significant improvement of digestive efficiency could likely be achieved by selecting pigs on fibre diets. No convincing genetic or blood biomarker has been identified for explaining the differences in RFI, suggesting that pigs have various ways to achieve an efficient use of feed. No deleterious impact of the selection on the sow reproduction performance was observed. The resource allocation theory states that low RFI may reduce the ability to cope with stressors, via the reduction of a buffer compartment dedicated to responses to stress. None of the experiments focussed on the response of pigs to stress or challenges could confirm this theory. Understanding the relationships between RFI and responses to stress and energy demanding processes, as such immunity and lactation, remains a major challenge for a better understanding of the underlying biological mechanisms of the trait and to reconcile the experimental results with the resource allocation theory.
The chromosphere is a complex region that acts as an intermediary between the magnetic flux emergence in the photosphere and the magnetic features seen in the corona. Large eruptions in the chromosphere of flares and filaments are often accompanied by ejections of coronal mass off the sun. Several studies have observed fast-moving progressive trains of compact bright points (called Sequential Chromospheric Brightenings or SCBs) streaming away from chromospheric flares that also produce a coronal mass ejection (CME). In this work, we review studies of SCBs and search for commonalties between them. We place these findings into a larger context with contemporary chromospheric and coronal observations. SCBs are fleeting indicators of the solar atmospheric environment as it existed before their associated eruption. Since they appear at the very outset of a flare eruption, SCBs are good early indication of a CME measured in the chromosphere.
The epidemiology of laboratory-confirmed respiratory syncytial virus (RSV) infections in young children has not recently been described in England, and is an essential step in identifying optimal target groups for future licensed RSV vaccines. We used two laboratory surveillance systems to examine the total number and number of positive RSV tests in children aged <5 years in England from 2010 to 2014. We derived odds ratios (ORs) with 95% confidence intervals (CIs) comparing children by birth month, using multivariable logistic regression models adjusted for age, season and sex. Forty-seven percent of RSV tests (29 851/63 827) and 57% (7405/13 034) of positive results in children aged <5 years were in infants aged <6 months. Moreover, 38% (4982/13 034) of positive results were in infants aged <3 months. Infants born in September, October and November had the highest odds of a positive RSV test during their first year of life compared to infants born in January (OR 2·1, 95% CI 1·7–2·7; OR 2·4, 95% CI 2·1–2·8; and OR 2·4, 95% CI 2·1–2·7, respectively). Our results highlight the importance of young age and birth month near the beginning of the RSV season to the risk of laboratory-confirmed RSV infection. Future control measures should consider protection for these groups.
We determined prescribing rates of neuraminidase inhibitors (NIs) for influenza in UK primary care since 2009 in relation to national prescribing guidelines. All NI prescriptions issued during the influenza seasons between October 2010 and May 2013 were extracted from The Health Improvement Network (THIN), a large UK primary-care database. We calculated NI prescribing rates per 100 000 person-weeks (pw) by age group, sex, deprivation level, influenza season and presence of chronic conditions with 95% confidence intervals (CIs), and used negative binomial regression models to determine the independent association between these variables and NI prescribing. NI prescribing was rare. The prescribing rate was 1·7/100 000 pw (95% CI 1·7–1·8) during influenza-active periods, and 0·1/100 000 (95% CI 0·1–0·1) during non-active periods. Prescribing rates were highest in 25- to 44-year-olds in 2010/2011 and in persons aged ⩾85 years in 2011/2012 and 2012/2013. Individuals with chronic conditions had significantly higher prescribing rates than persons without (rate ratio 2·62, 95% CI 2·27–3·03). GPs are more likely to prescribe NIs to high-risk individuals and during influenza active periods, as per national guidelines. We could not assess the proportion of patients with influenza-like illness who were prescribed an NI.
Paediatricians recognize that using the time-dependent community-acquired vs. hospital-acquired bloodstream infection (BSI) dichotomy to guide empirical treatment no longer distinguishes between causative pathogens due to the emergence of healthcare-associated BSIs. However, paediatric epidemiological evidence of the aetiology of BSIs in relation to hospital admission in England is lacking. For 12 common BSI-causing pathogens in England, timing of laboratory reports of positive paediatric (3 months to 5 years) bacterial blood isolates were linked to in-patient hospital data and plotted in relation to hospital admission. The majority (88·6%) of linked pathogens were isolated <2 days after hospital admission, including pathogens widely regarded as hospital acquired: Enterococcus spp. (67·2%) and Klebsiella spp. (88·9%). Neisseria meningitidis, Streptococcus pneumoniae, group A streptococcus and Salmonella spp. were unlikely to cause hospital-acquired BSI. Pathogens commonly associated with hospital-acquired BSI are being isolated <2 days after hospital admission alongside pathogens commonly associated with community-acquired BSI. We confirm that timing of blood samples alone does not differentiate between bacterial pathogens. Additional factors including clinical patient characteristics and healthcare contact should be considered to help predict the causative pathogen and guide empirical antibiotic therapy.
This introduction to the special issue on presidential disability and succession focuses on the distinctly positive contributions that invocations of the Twenty-Fifth Amendment have made to American political life since the Amendment's ratification in 1967. It also underlines the importance for Presidents, their family members and aides to understand the necessity for putting the welfare of the country first, above all else—even at times above the wishes of a disabled Chief Executive. As the articles in this special issue make clear, the Twenty-Fifth Amendment provides an effective constitutional mechanism by which the country's well-being can be maintained while simultaneously showing compassion and respect for a disabled leader. The idea for this issue emerged from a conference organized by Professor Robert E. Gilbert focusing on presidential disability and succession held on the campus of Northeastern University in April 2014. Papers from the conference assembled here clarify and add to the historical record about presidential inability while illuminating the many political, legal, and constitutional contingencies that future presidential administrators may face. Contributors to this issue have varied disciplinary and professional backgrounds, including expertise in American politics, constitutional law, the presidency and vice presidency, presidential impairment, and, of course, the Twenty-Fifth Amendment to the Constitution.
Antarctic and Southern Ocean science is vital to understanding natural variability, the processes that govern global change and the role of humans in the Earth and climate system. The potential for new knowledge to be gained from future Antarctic science is substantial. Therefore, the international Antarctic community came together to ‘scan the horizon’ to identify the highest priority scientific questions that researchers should aspire to answer in the next two decades and beyond. Wide consultation was a fundamental principle for the development of a collective, international view of the most important future directions in Antarctic science. From the many possibilities, the horizon scan identified 80 key scientific questions through structured debate, discussion, revision and voting. Questions were clustered into seven topics: i) Antarctic atmosphere and global connections, ii) Southern Ocean and sea ice in a warming world, iii) ice sheet and sea level, iv) the dynamic Earth, v) life on the precipice, vi) near-Earth space and beyond, and vii) human presence in Antarctica. Answering the questions identified by the horizon scan will require innovative experimental designs, novel applications of technology, invention of next-generation field and laboratory approaches, and expanded observing systems and networks. Unbiased, non-contaminating procedures will be required to retrieve the requisite air, biota, sediment, rock, ice and water samples. Sustained year-round access to Antarctica and the Southern Ocean will be essential to increase winter-time measurements. Improved models are needed that represent Antarctica and the Southern Ocean in the Earth System, and provide predictions at spatial and temporal resolutions useful for decision making. A co-ordinated portfolio of cross-disciplinary science, based on new models of international collaboration, will be essential as no scientist, programme or nation can realize these aspirations alone.
Improvement of feed efficiency in pigs has been achieved essentially by increasing lean growth rate, which resulted in lower feed intake (FI). The objective was to evaluate the impact of strategies for improving feed efficiency on the dynamics of FI and growth in growing pigs to revisit nutrient recommendations and strategies for feed efficiency improvement. In 2010, three BWs, at 35±2, 63±9 and 107±7 kg, and daily FI during this period were recorded in three French test stations on 379 Large White and 327 French Landrace from maternal pig populations and 215 Large White from a sire population. Individual growth and FI model parameters were obtained with the InraPorc® software and individual nutrient requirements were computed. The model parameters were explored according to feed efficiency as measured by residual feed intake (RFI) or feed conversion ratio (FCR). Animals were separated in groups of better feed efficiency (RFI− or FCR−), medium feed efficiency and poor feed efficiency. Second, genetic relationships between feed efficiency and model parameters were estimated. Despite similar average daily gains (ADG) during the test for all RFI groups, RFI− pigs had a lower initial growth rate and a higher final growth rate compared with other pigs. The same initial growth rate was found for all FCR groups, but FCR− pigs had significantly higher final growth rates than other pigs, resulting in significantly different ADG. Dynamic of FI also differed between RFI or FCR groups. The calculated digestible lysine requirements, expressed in g/MJ net energy (NE), showed the same trends for RFI or FCR groups: the average requirements for the 25% most efficient animals were 13% higher than that of the 25% least efficient animals during the whole test, reaching 0.90 to 0.95 g/MJ NE at the beginning of the test, which is slightly greater than usual feed recommendations for growing pigs. Model parameters were moderately heritable (0.30±0.13 to 0.56±0.13), except for the precocity of growth (0.06±0.08). The parameter representing the quantity of feed at 50 kg BW showed a relatively high genetic correlation with RFI (0.49±0.14), and average protein deposition between 35 and 110 kg had the highest correlation with FCR (−0.76±0.08). Thus, growth and FI dynamics may be envisaged as breeding tools to improve feed efficiency. Furthermore, improvement of feed efficiency should be envisaged jointly with new feeding strategies.
The aim of the study was to assess the impact of selection for residual feed intake (RFI) on the behavioural activity of lines divergently selected for RFI during seven generations. In all, six successive batches from the seventh generation of selection were raised in collective pens equipped with a single-place electronic feeder (SEF) from 10 weeks of age to 100 kg BW. Each batch included four groups of 12 pigs: high RFI (RFI+) castrated males, RFI+ females, low RFI (RFI−) castrated males, RFI− females. At 17 weeks of age, health criteria were evaluated using a gradient scale for increased severity of lameness, body lesions, bursae and tail biting. Individual behavioural activities were recorded by 24-h video tape on the day after health evaluation. The investigative motivation towards unfamiliar objects was quantified at 18 weeks of age. The daily individual feeding patterns were computed from SEF records during the 4 weeks surrounding 12, 17 and 22 weeks of age. All pigs spent significantly most of their time lying in diurnal (80% of total scan) and nocturnal (>89%) periods. The RFI− pigs showed a lower proportion of health problems (P<0.01) than RFI+ pigs. The RFI− pigs used the SEF less than the RFI+ pigs, in diurnal (5.3% v. 6.4% of video scans, P<0.05) and nocturnal periods (3.6% v. 4.5% of video scans, P<0.05). This was confirmed by a significantly lower daily number and duration of visits to the SEF computed from the SEF data. The feeding activity measured from the video recording was significantly correlated (R>0.34; P<0.05) with feeding patterns computed from the SEF. The RFI− pigs spent less time standing over the 24-h period (9.7% v. 12.2% of scans, i.e. 35 min/day, P<0.05). In terms of energy costs, this amounted to 14% of the line difference in terms of daily metabolizable energy intake. The castrated males used the SEF more than females, especially at night (4.7% v. 3.4% of total scans, P<0.05), whereas females displayed greater investigation of their environment (7.7±0.3% v. 6.6±0.2% of total scans, P<0.05) and the novel objects (10.7% v. 4.9% of total scans, P<0.05). In conclusion, the lower physical activity associated with reduced energy expenditure in RFI− pigs compared with RFI+ pigs contributed significantly to their improved efficiency and was not related to worsened health scores.