bluuebunny/crossref_metadata_2025 huggingface dataset:
Intrahepatic cholestasis of pregnancy and comorbidity: A 44‐year follow‐up study
Authors: Hämäläinen Suvi‐Tuulia , Turunen Kaisa , Mattila Kari J. , Kosunen Elise , Sumanen Markku
Published: July 2019

Introduction

Intrahepatic cholestasis of pregnancy (ICP) is a reversible liver disorder occurring during pregnancy. It has a typical genetic background with known genetic mutations and can be considered an expression of this genetic predisposition. The objective of this study was to determine whether ICP is associated with specific long‐term comorbidity.

Material and methods

The study population comprised 571 women with ICP in at least one pregnancy who were compared with 1333 pregnant women without ICP during 1969‐1988 at Tampere University Hospital, Finland. The cohort's follow‐up time was 44 years. All ICD‐10 classification discharge diagnoses were examined for the women in the ICP group from 1998 to 2013 and ICD‐10 diagnoses from outpatient care from 1969 to 2013.

Results

At least one disease of the digestive system had been diagnosed in 50.4% (288/571) of the ICP mothers compared with 34.4% (459/1333) of the reference group (P < 0.001). In a more detailed analysis, women with a history of ICP had an increased risk for cholelithiasis and/or cholecystitis (odds ratio [OR] 2.88, 95% confidence interval [CI] 2.17 to 3.84), diseases of the pancreas (OR 2.26, 95% CI 1.20 to 4.27) and hypothyroidism (OR 2.38, 95% CI 1.27 to 4.46) compared with the reference group. Arterial diseases were less common in the ICP mothers than in the reference group (OR 0.38, 95% CI .15 to .99). Regarding other diseases, there were no statistically significant differences between the ICP mothers and reference group.

Conclusions

Half of the women with a history of ICP were diagnosed with at least one disease of the digestive system compared with a third in the reference group. The risk of cholelithiasis, cholecystitis, diseases of the pancreas and hypothyroidism was increased compared with the reference group. These are important facts when counseling women after a pregnancy with ICP. Also, this is of importance for the general practitioners and other physicians who take care of these women.
A Theory of Planned Behavior‐Based Program to Increase Physical Activity in Overweight/Obese Military Personnel: A Randomised Controlled Trial
Authors: Sanaeinasab Hormoz , Saffari Mohsen , Dashtaki Mohammad‐ali , Pakpour Amir H. , Karimi Zarchi Aliakbar , O'Garo Keisha‐Gaye N. , Koenig Harold G.
Published: July 2019

Background

Designing a health promotion program to increase physical activity may contribute to weight management. The purpose of this study was to investigate a theory of planned behavior (TPB) program to address this problem in military people.

Methods

Eighty‐four obese/overweight military personnel were randomised into the intervention or control group. A questionnaire assessed demographics, aspects of the TPB program, and physical activity levels. Also assessed were blood glucose and lipid levels. The intervention consisted of seven educational sessions based on TPB. Data were collected at baseline and 3 months after the intervention.

Results

All constructs of the TPB improved between baseline and follow‐up in the intervention group (p < .001), while there were no significant changes in the control group (within‐group comparisons). Between‐group comparisons on TPB measures revealed differences in all domains when results were controlled for baseline covariates. Greater light and moderate physical activity was observed in the intervention group. Body mass index decreased significantly within the intervention group (p < .001). Changes in triglyceride and high‐density lipoprotein also favored the intervention over the control group.

Conclusion

An intervention based on the TPB may be effective in promoting physical activity and decreasing weight in military personnel who are obese or overweight.
Identifying an optimal lymph node yield for penile squamous cell carcinoma: prognostic impact of surgical dissection
Authors: Chipollini Juan , Azizi Mounsif , Lo Vullo Salvatore , Mariani Luigi , Zhu Yao , Ye Ding W. , Ornellas Antonio Augusto , Watkin Nick , Ager Michael , Hakenberg Oliver , Heidenreich Axel , Raggi Daniele , Catanzaro Mario , Ornellas Paulo , Salvioni Roberto , Cheriyan Salim K. , Necchi Andrea , Spiess Phillippe E.
Published: July 2019

Objective

To evaluate the prognostic impact of lymph node yield (LNY) on survival outcomes for penile squamous cell carcinoma (SCC).

Patients and methods

In all, 532 patients who underwent inguinal LN dissection (ILND) across tertiary referral centres from Europe, China, Brazil and North America were retrospectively evaluated. From this cohort, 198 patients received pelvic LND (PLND).We identified threshold values for ILND and PLND using receiver operating characteristic curves. We tested prognostic value of LNY for recurrence‐free survival (RFS), disease‐specific survival (DSS), and overall survival (OS) using the Kaplan–Meir method and Cox proportional hazard regression models.

Results

The median (interquartile [IQR]) age was 59 (49–68) years and the median (IQR) follow‐up after ILND was 28 (12–68.2) months. Overall, 85% of the patients had bilateral dissections. The median (IQR) number of inguinal LNs removed was 15 (10–22). Of those receiving PLND, The median (IQR) number of LNs was 13 (8–19). A LNY of ≥15 was used for dichotomisation of ILND patients, and a LNY of ≥9 was used in the PLND cohort. Patients with a LNY ≥15 had significantly better 5‐year OS vs patients with a LNY <15 (70.1% vs 58.7%). On multivariable analyses, a LNY ≥15 was a predictor of OS (hazard ratio [HR] 0.68, P = 0.029). For cN0 patients, a LNY ≥15 was an independent predictor of RFS (HR 0.52, P = 0.043) and OS (HR 0.53, P = 0.021). In the PLND cohort, a LNY ≥9 was a predictor of RFS (HR 0.53, P = 0.032).

Conclusions

Using one of the largest LND datasets to date, we found LNY to be a significant predictor of outcomes after lymphatic staging for penile SCC. Prospective validation is warranted.
Interdomain twists of human thymidine phosphorylase and its active–inactive conformations: Binding of 5‐FU and its analogues to human thymidine phosphorylase versus dihydropyrimidine dehydrogenase
Authors: Tozer Tiffany , Heale Kali , Manto Chagas Caroline , de Barros Andre Luis Branco , Alisaraie Laleh
Published: July 2019

5‐fluorouracil (5‐FU) is an anticancer drug, which inhibits human thymidine phosphorylase (hTP) and plays a key role in maintaining the process of DNA replication and repair. It is involved in regulating pyrimidine nucleotide production, by which it inhibits the mechanism of cell proliferation and cancerous tumor growth. However, up to 80% of the administered drug is metabolized by dihydropyrimidine dehydrogenase (DPD). This work compares binding of 5‐FU and its analogues to hTP and DPD, and suggests strategies to reduce drug binding to DPD to decrease the required dose of 5‐FU. An important feature between the proteins studied here was the difference of charge distribution in their binding sites, which can be exploited for designing drugs to selectively bind to the hTP. The 5‐FU presence was thought to be required for a closed conformation. Comparison of the calculation results pertaining to unliganded and liganded protein showed that hTP could still undergo open–closed conformations in the absence of the ligand; however, the presence of a positively charged ligand better stabilizes the closed conformation and rigidifies the core region of the protein more than unliganded or neutral liganded system. The study has also shown that one of the three hinge segments linking the two major α and α/β domains of the hTP is an important contributing factor to the enzyme's open–close conformational twist during its inactivation–activation process. In addition, the angle between the α/β‐domain and the α‐domain has shown to undergo wide rotations over the course of MD simulation in the absence of a phosphate, suggesting that it contributes to the stabilization of the closed conformation of the hTP.
Troubling Discourses of Poverty in Early Childhood in the UK
Authors: Lyndon Sandra
Published: July 2019

Poverty in early childhood is pervasive, affecting every aspect of children’s lives. Under current government policies child poverty in the UK is predicted to rise to 40 per cent by 2022. Dominant discourses of poverty have historically focussed on an over‐arching discourse of moral responsibility, essentially relating to notions of deserving and underserving poor. This paper examines how government policy continues to significantly impact on young children and families on low incomes in early childhood and how stigmatised discourses about welfare, work are pervasive. It is argued that discourses of redistribution and children’s rights deserve greater recognition if poverty is to be addressed.
Quantitative clinical adjustment analysis of posterior single implant crown in a chairside digital workflow: A randomized controlled trial
Authors: Zhang Yifan , Tian Jiehua , Wei Donghao , Di Ping , Lin Ye
Published: July 2019

Objectives

To compare the three‐dimensional changes in quantity and morphology following clinical adjustment of a posterior single implant crown between chairside digital workflow (test) and hybrid digital workflow (control).

Materials and Methods

A total of 33 participants were included for single‐tooth replacement with screw‐retained crowns in posterior sites of either the maxillary or mandible. A total of 17 participants were carried to a chairside digital workflow, receiving monolithic lithium disilicate (LS2)‐crowns (test), while the remaining 16 participants were fitted with CAD/CAM‐fabricated zirconia superstructures and hand‐layered ceramic veneering crowns (control). As each crown underwent intraoral scanning (3Shape TRIOS Color, 3Shape), 3D digital models were rendered. These scans were taken both before and after try‐in. Clinical adjustment dimensional changes were measured by superimposing the optical scans of models within a reverse software (Geomagic Control 2014). Adjustment counts and amounts (from vertical dimension) between two workflows were assessed and compared. Time consumption was recorded for efficiency analysis.

Results

All patients were successfully treated in both groups. The median maximum vertical adjustment (taking both occlusal and interproximal surfaces into consideration) was 237 μm ± 112 in the test group and 485 μm ± 195 in the control group (p < .0001), respectively. The median adjustment count was 2.00 ± 1.09 in test group and 3.00 ± 1.05 in control group (p = .001), respectively. The total active working time/ total time for two workflows was 92.3/113.7 min for the test group and 146.3/676.3 min for the control group, respectively.

Conclusion

The test group showed fewer adjustments and apparent precision on the occlusal surface compared with the control group with only a fifth of the consumption of a hybrid workflow.
The Sound of the Past: Sound in the Exhibition at the Danish Museum Mosede Fort, Denmark 1914–18
Authors: Hjortkjær Kamilla
Published: July 2019

Part of our cultural heritage is the sound that surrounds us. Is there a particular sound for a particular historical period? How can a curator in a historical museum use sound in the exhibition for the purpose of enhancing the experience of a particular historical period, event or place? This case study includes contemporary examples from the Danish museum Mosede Fort, Denmark 1914–18. The museum have deliberately chosen to use sound and soundscapes in the permanent exhibition. Through the use of diverse sound installations, the museum have achieved working with audience immersion and discovery. With the help of sounds, the museum’s rooms and the stories from the past are experienced, rather than simply exhibited using original objects. The exhibition rooms become spaces where museum visitors experience history through all their senses, thus becoming immersed in a journey of discovery.
Physical, occupational, and speech therapy for children with cerebral palsy
Authors: McCoy Sarah Westcott , Palisano Robert , Avery Lisa , Jeffries Lynn , Laforme Fiss Alyssa , Chiarello Lisa , Hanna Steve
Published: July 2019

Aim

To explore the relationship between rehabilitation therapies and development in children with cerebral palsy (CP).

Method

We conducted a prospective, longitudinal study involving 656 children with CP (mean age [SD] 6y [2y 8mo] at study entry; 1y 6mo–11y 11mo; 287 females, 369 males), and their parents. Children were assessed two to five times over 2 years by therapists using standardized measures of balance and walking endurance. Parents completed questionnaires on demographics, rehabilitation therapies, and their children’s performance in self‐care and participation in recreation. Therapists and parents collaboratively classified children’s Gross Motor Function Classification System (GMFCS) levels. We created longitudinal graphs for each GMFCS level, depicting change across time using centiles. Using multinomial models, we analyzed the relationship between therapies (amount, focus, family‐centeredness, and the extent therapies met children’s needs) and whether change in balance, walking endurance, and participation was ‘more than’ and ‘less than’ the reference of ‘as expected’.

Results

Children were more likely to progress ‘more than expected’ when participating in recreation when therapies were family‐centered, met children’s needs, and focused on structured play/recreation. A focus on health and well‐being was positively associated with participation and self‐care. The amount of therapy did not predict outcomes.

Interpretation

Therapy services that are family‐centered, consider the needs of the child, and focus on structured play/recreational activities and health/well‐being may enhance the development of children with CP.

What this paper adds

Family‐centered rehabilitation therapies were positively associated with greater participation in family/recreation activities and walking endurance.

Parental perception that rehabilitation therapies met children’s needs was associated with greater participation in family/recreation activities.

Structured play, recreational activities, and health/well‐being are important for self‐care and participation when planning rehabilitation therapy.

The amount of rehabilitation therapy was not related to developmental outcomes.
Historical and philosophical perspectives on the study of developmental bias
Authors: Brigandt Ingo
Published: July 2019

Throughout the recent history of research at the intersection of evolution and development, notions such as developmental constraint, evolutionary novelty, and evolvability have been prominent, but the term “developmental bias” has scarcely been used. And one may even doubt whether a unique and principled definition of bias is possible. I argue that the concept of developmental bias can still play a vital scientific role by means of setting an explanatory agenda that motivates investigation and guides the formulation of integrative explanatory frameworks. Less crucial is a definition that would classify patterns of phenotypic variation and unify variational patterns involving different traits and taxa as all being “bias.” Instead, what we should want is a concept that generates intellectual identity across various researchers, and that unites the diverse fields and approaches relevant to the study of developmental bias, from paleontology to behavioral biology. I point to some advantages of conducting research specifically under the label of “developmental bias,” compared with employing other, more common terms such as “evolvability.”
Postmetamorphic ontogenetic allometry and the evolution of skull shape in Nest‐building frogs Leptodactylus (Anura: Leptodactylidae)
Authors: Duport‐Bru Ana S. , Ponssa María L. , Vera Candioti Florencia
Published: July 2019

Allometry constitutes an important source of morphological variation. However, its influence in head development in anurans has been poorly explored. By using geometric morphometrics followed by statistical and comparative methods we analyzed patterns of allometric change during cranial postmetamorphic ontogeny in species of Nest‐building frogs Leptodactylus (Leptodactylidae). We found that the anuran skull is not a static structure, and allometry plays an important role in defining its shape in this group. Similar to other groups with biphasic life‐cycle, and following a general trend in vertebrates, ontogenetic changes mostly involve rearrangement in rostral, otoccipital, and suspensorium regions. Ontogenetic transformations are paralleled by shape changes associated with evolutionary change in size, such that the skulls of species of different intrageneric groups are scaled to each other, and small and large species show patterns of paedomorphic/peramorphic features, respectively. Allometric trajectories producing those phenotypes are highly evolvable though, with shape change direction and magnitude varying widely among clades, and irrespective of changes in absolute body size. These results reinforce the importance of large‐scale comparisons of growth patterns to understand the plasticity, evolution, and polarity of morphological changes in different clades.
Developmental noise and ecological opportunity across space can release constraints on the evolution of plasticity
Authors: Draghi Jeremy
Published: July 2019

Phenotypic plasticity is a potentially definitive solution to environment heterogeneity, driving biologists to understand why it is not ubiquitous in nature. While costs and constraints may limit the success of plasticity, we are still far from a complete theory of when these limitations actually proscribe adaptive plasticity. Here I use a simple model of plasticity incorporating developmental noise to explore the competitive and evolutionary relationships of specialist and generalist genotypes spreading across a heterogeneous landscape. Results show that plasticity can arise in the context of specialism, preadapting genotypes to later evolve toward plastic generalism. Developmental noise helps a mutant with imperfect plasticity successfully compete against its ancestor, providing an evolutionary path by which subsequent mutations can refine plasticity toward its optimum. These results address how the complex selection pressures across a heterogeneous environment can help evolution find paths around constraints arising from developmental mechanisms.
Spiders, microbes and sex: Bacterial exposure on copulatory organs alters mating behaviour in funnel‐web spiders
Authors: Spicer Michelle Elise , Pruitt Jonathan N. , Keiser Carl N.
Published: July 2019

Environmental microbes have the potential to be involved in nearly all behavioural processes. For example, mating systems where males use intromittent organs to transfer sperm to females represent a means by which environmental microbes collected by males can breach entry into females' body cavities during mating. However, the degree to which the acquisition of environmental microbes onto important sex structures alters courtship behaviours remains unknown. Here, we collected bacteria from the copulatory organs of Agelenopsis pennsylvanica funnel‐weaving spiders in situ to test whether exposure to bacteria on copulatory organs can alter hosts' courtship behaviour, reproductive success and survival. We used a standardized assay to repeatedly measure each spider's aggressiveness, a behavioural component of both male courtship and female sexual receptivity. Then, we experimentally altered the bacteria present on male and female spiders' copulatory organs with an application of either (a) a mixture of bacteria collected from conspecifics to increase bacterial presence, (b) an antibiotic to reduce bacterial presence or (c) a procedural control. Each spider was paired with a size‐matched spider of the opposite sex whose copulatory organs were unaltered, and we measured the latency until the onset and the duration of courtship. Spiders were then isolated, and we measured each individual's time until death and female fecundity over the next 40 days. We found that female exposure to bacteria had multiple effects on mating dynamics. Males took over four times longer to begin courting females that had been exposed to bacteria compared to unexposed and antibiotic‐treated females. Only when courting these bacteria‐exposed females, males began courtship sooner when females were more aggressive. Lastly, females whose mate had been exposed to bacteria experienced reduced survival. These data suggest that bacteria present on animals' copulatory organs can alter courtship behaviours, female survivorship, and may potentially play a role in mating dynamics.
Perioperative haemostasis with full‐length, PEGylated, recombinant factor VIII with extended half‐life (rurioctocog alfa pegol) in patients with haemophilia A: Final results of a multicentre, single‐arm phase III trial
Authors: Gruppo Ralph , López‐Fernández Maria‐Fernanda , Wynn Tung T. , Engl Werner , Sharkhawy Marlies , Tangada Srilatha
Published: July 2019

Introduction

Rurioctocog alfa pegol (BAX 855, TAK‐660) is a PEGylated, full‐length, recombinant factor VIII (rFVIII) with extended half‐life developed from unmodified rFVIII (antihaemophilic factor [recombinant]).

Aim

To determine the perioperative haemostatic efficacy and safety of rurioctocog alfa pegol in male previously treated patients (PTPs) with severe haemophilia A.

Methods

This multicentre, single‐arm, phase III study included PTPs who were to undergo major or minor elective or minor emergency surgical, dental or other invasive procedures. Rurioctocog alfa pegol dose and frequency were individualized based on patients’ pharmacokinetic profiles for major surgeries and by rurioctocog alfa pegol incremental recovery for minor surgeries. Haemostatic efficacy was assessed using the Global Haemostatic Efficacy Assessment score.

Results

Twenty‐one patients aged 16‐61 years underwent 21 major and five minor surgeries. For all 24 evaluable surgeries, overall haemostatic efficacy was rated as excellent and blood loss comparable to that expected in non‐haemophilic patients. No blood transfusions were required intraoperatively but were administered postoperatively for four surgeries in three patients. Five injury‐related postoperative bleeding episodes occurred in five patients, of which two required additional rurioctocog alfa pegol treatment. Two non‐serious adverse events of mild severity (increased ALT level and headache) were considered possibly related to rurioctocog alfa pegol. There were no deaths or treatment‐related serious adverse events. No patients developed inhibitory antibodies to FVIII or persistent IgG‐ or IgM‐binding antibodies to FVIII, PEG‐FVIII or PEG.

Conclusion

Rurioctocog alfa pegol was well tolerated and effective for perioperative use in patients with haemophilia A and showed no signs of immunogenicity.
C‐C chemokine receptor 4 expression in CD8+ cutaneous T‐cell lymphomas and lymphoproliferative disorders, and its implications for diagnosis and treatment
Authors: Geller Shamir , Hollmann Travis J , Horwitz Steven M , Myskowski Patricia L , Pulitzer Melissa
Published: July 2019

Aims

Patients with aggressive CD8+ cutaneous T‐cell lymphomas (CTCLs) progress rapidly and respond poorly to therapy. Confounding treatment planning, there is clinicopathological overlap between aggressive CD8+ CTCLs and other lymphoproliferative disorders (LPDs). Hence, improved diagnostic methods and therapeutic options are needed. The aim of this study was to examine C‐C chemokine receptor 4 (CCR4) expression as a diagnostic and therapeutic biomarker in CD8+ CTCLs/LPDs.

Methods and results

Forty‐nine cases (41 patients) with CD8+ CTCLs/LPDs were examined, including CD8+ mycosis fungoides (MF) (n = 14), aggressive epidermotropic CD8+ cytotoxic T‐cell lymphoma (AETCL) (n = 8), subcutaneous panniculitis‐like T‐cell lymphoma (SPTCL) (n = 7), CD30+ LPDs (n = 6), primary cutaneous γδ T‐cell lymphoma (GDTCL) (n = 6), and others (n = 8). Immunohistochemical tissue staining was performed with a CCR4 monoclonal antibody on formalin‐fixed paraffin‐embedded tissue sections. CCR4 immunostaining was graded as percentage infiltrate, i.e. high (>25%) and low (≤25%), and the results were correlated with clinicopathological diagnoses. CCR4 expression was seen in 69% of the studied cases. Any CCR4 positivity was seen in all CD8+ MF cases, in 83% of CD30+ LPD cases, in 75% of AETCL cases, in 33% of GDTCL cases, and in none of the SPTCL cases. High CCR4 expression was seen in 79% of CD8+ MF cases versus 33% of CD30+ LPD cases, in 17% of GDTCL cases, and in 12.5% of AETCL cases. Patients with more advanced MF stage had higher CCR4 expression.

Conclusions

CCR4 immunohistochemistry may be an adjunct in distinguishing advanced CD8+ MF from other CD8+ CTCLs/LPDs. Although CCR4 expression may justify therapeutic targeting of this receptor in CD8+ MF, the role of such therapies in other CD8+ CTCLs/LPDs is not yet clear.
Systemic administration of probiotics reduces the severity of apical periodontitis
Authors: Cosme‐Silva L. , Dal‐Fabbro R. , Cintra L. T. A. , dos Santos V. R. , Duque C. , Ervolino E. , Mogami Bomfim S. , Gomes‐Filho J. E.
Published: July 2019

Aim

To evaluate the effect of systemic administration of probiotics on the severity of apical periodontitis (AP).

Methodology

Twenty‐four male Wistar rats were used. AP was induced in the maxillary left/right first molars. The animals were arranged into groups: Control, Lactobacillus rhamnosus, and Lactobacillus acidophilus. Probiotics were administered orally for gavage (109 colony‐forming units diluted in 5 mL of water for 30 days) during the development of AP. After 30 days, cardiac puncture was performed to analyse the complete blood count. Moreover, microbiological analysis of the root canal contents and saliva was performed. Then, the animals were euthanized and the jaw removed for histopathological and IL‐10, IL‐1β and IL‐6 immunolabeling analyses. After the Shapiro–Wilk test of normality, the Kruskal–Wallis followed by Dunn's test was performed for nonparametric data, and analysis of variance followed by the Tukey test was performed for parametric data (P < 0.05).

Results

No significance difference was observed in the blood profiles and in the counts of microorganisms from the saliva samples among the groups (P > 0.05). Total microorganism counts in the root canal, the inflammatory infiltrate and the immunostaining for IL‐1β and IL‐6 in AP were significantly lower in the probiotic groups when compared with the control group (P < 0.05). IL‐10 was significantly more immunolabled in the probiotic groups than in the control group (P < 0.05).

Conclusion

Supplementation with probiotics (Lactobacillus rhamnosus and Lactobacillus acidophilus) had a significant effect on the severity of apical periodontitis in rats, demonstrating the anti‐inflammatory effect of probiotics on the development of apical periodontitis.
Optimal monetary and fiscal policy with social status seeking and liquidity constraints
Authors: Chang Juin‐Jen , Lin Hsieh‐Yu , Shieh Jhy‐Yuan
Published: July 2019

We study the optimal monetary (nominal interest rate) and fiscal (income tax) policy with both consumption‐ and wealth‐induced status seeking under a generalized liquidity constraint on consumption and investment. Our results suggest that monetary policy, in general, has an advantage in correcting status‐seeking‐induced distortions. A simple policy mix is incapable of leading the optimal allocation to be decentralized in the presence of wealth‐based (consumption‐based) status seeking under the cash constraint on consumption (investment) only. As for sub‐optimal policies, the monetary policy follows Friedman's rule while the optimal income tax corrects the consumption‐induced externality, leaving the wealth‐induced externality uncorrected.
Updates on CAR T‐cell therapy in B‐cell malignancies
Authors: Jacoby Elad , Shahani Shilpa A. , Shah Nirali N.
Published: July 2019

By increasing disease‐free survival and offering the potential for long‐term cure, chimeric antigen receptor (CAR) T‐cell therapy has dramatically expanded therapeutic options among those with high‐risk B‐cell malignancies. As CAR T‐cell utilization evolves however, novel challenges are generated. These include determining how to optimally integrate CAR T cells into standard of care and overcoming mechanisms of resistance to CAR T‐cell therapy, such as evolutionary stress induced on cancer cells leading to immunophenotypic changes that allow leukemia to evade this targeted therapy. Compounding these challenges are the limited ability to determine differences between various CAR T‐cell constructs, understanding the generalizability of trial outcomes from multiple sites utilizing unique CAR manufacturing strategies, and comparing distinct criteria for toxicity grading while defining optimal management. Additionally, as understanding of CAR behavior in humans has developed, strategies have appropriately evolved to proactively mitigate toxicities. These challenges offer complimentary insights and guide next steps to enhance the efficacy of this novel therapeutic modality. With a focus on B‐cell malignancies as the paradigm for effective CAR T‐cell therapy, this review describes advances in the field as well as current challenges and future directions.
Cellular therapy: Adoptive immunotherapy with expanded natural killer cells
Authors: Lee Dean A.
Published: July 2019

Adoptive immunotherapy with natural killer cells was pioneered 30 years ago in human clinical trials with the development of cytokine‐induced killer cells—unfractionated peripheral blood mononuclear cell (PBMC) populations activated overnight with IL‐2. Higher doses were subsequently made possible through the advent of steady‐state apheresis, allowing the collection of PBMC numbers equivalent to an entire adult blood volume, and increased purity made feasible through magnetic CD3‐depletion and/or CD56‐selection methods. Still, these approaches rarely achieved clinical dosing above a single infusion of 108 NK cells/kg, except with substantial donor‐recipient size mismatch (eg, parents donating cells to children). To address this shortcoming, leukemia cell lines with NK cell‐like function or ex vivo expansion approaches centered on the homeostatic cytokine IL‐15 were developed. Here, we describe the development of an ex vivo expansion system based on a feeder cell expressing membrane‐bound IL‐21 that enables log‐phase growth of primary NK cells for many weeks without inducing senescence, and describe the biology, correlative science, and translation to clinical trials for patients with leukemia, brain tumors, and solid tumors.
Morphology, Morphogenesis, and Molecular Phylogeny of Neobakuella aenigmatica n. sp. (Ciliophora, Spirotrichea, Bakuellidae)
Authors: Moon Ji Hye , Kim Ji Hye , Quintela‐Alonso Pablo , Jung Jae‐Ho
Published: July 2019

The morphology and morphogenesis of a new ciliate species, Neobakuella aenigmatica n. sp., which was discovered in an estuary in Korea, were investigated, using live observation, protargol impregnation, and scanning electron microscopy. This new species is characterized by a large (185–300 × 55–105 μm in vivo), elongate‐ellipsoidal, flexible but not contractile body. It has ellipsoidal, yellowish cortical granules, 1.3 × 1.0 μm in size. The species has invariably 3 frontal and 2 frontoterminal cirri, about 5–10 buccal and 1–6 parabuccal cirri, 7 midventral rows, and 1 right and 2–4 left marginal rows. The outer left marginal row(s) consists of 1–7 short rows of cirri. The nuclear apparatus comprises 130 macronuclear nodules and 2 spherical micronuclei on average. The dorsal ciliature consists of 3 dorsal kineties. The leftmost left marginal row(s) likely develops from anlagen originating from both the rightmost and leftmost left marginal row(s). The molecular phylogenetic tree based on SSU rDNA suggests the nonmonophyly of the genus Neobakuella.
Patient and Caregiver Benefit From a Comprehensive Dementia Care Program: 1‐Year Results From the UCLA Alzheimer's and Dementia Care Program
Authors: Reuben David B. , Tan Zaldy S. , Romero Tahmineh , Wenger Neil S. , Keeler Emmett , Jennings Lee A.
Published: July 2019

BACKGROUND/OBJECTIVES

Persons with Alzheimer disease and related dementias (ADRDs) require comprehensive care that spans health systems and community‐based organizations. This study examined the clinical outcomes of a comprehensive dementia care program and identified subgroups who were more likely to benefit.

DESIGN

Observational, baseline and 1 year after intervention.

SETTING

Urban, academic medical center.

PARTICIPANTS

A total of 554 persons with dementia and their caregivers who had 1‐year follow‐up evaluations and data on clinical outcomes.

INTERVENTION

Health system‐based comprehensive dementia care management program using nurse practitioner dementia care managers.

MEASUREMENTS

Patient measures included the Mini‐Mental State Examination (MMSE), the Functional Activities Questionnaire, Basic and Instrumental Activities of Daily Living scales, the Cornell Scale for Depression in Dementia, and the Neuropsychiatric Inventory Questionnaire (NPI‐Q) Severity. Caregiver measures included the Modified Caregiver Strain Index, the Patient Health Questionnaire‐9, NPI‐Q Distress, and the Dementia Burden Scale‐Caregiver). We used established minimal clinically important differences and lowest tertiles of baseline symptoms to define improving symptoms and maintaining low symptoms as clinical benefit for patients and caregivers.

RESULTS

At year 1, persons with ADRD improved on all scales, except MMSE and functional status measures; caregivers improved on all scales. Using validated instruments, 314/543 (58%) of patients, 282/447 (63%) of caregivers, and 376/501 (75%) of patients or caregivers demonstrated clinical benefit. In adjusted multivariate models, at year 1, more behavioral symptoms and fewer depression symptoms at baseline were associated with patient improvement; and fewer baseline depression symptoms were associated with maintaining low behavioral symptoms. Male caregiver sex, higher baseline caregiver burden, and caring for patients with fewer baseline depression symptoms were associated with caregiver improvement. Male caregiver sex and patients with fewer depression symptoms, fewer behavioral symptoms, and more functional impairment at baseline were associated with caregivers maintaining low burden at 1 year.

CONCLUSIONS

Health system‐based comprehensive dementia care management is a promising approach to improving clinical outcomes, with benefits for both patients and caregivers. J Am Geriatr Soc 67:2267–2273, 2019
Predictive Ability of a Serious Game to Identify Emergency Patients With Unrecognized Delirium
Authors: Lee Jacques S. , Tong Tiffany , Tierney Mary C. , Kiss Alex , Chignell Mark
Published: July 2019

OBJECTIVES

Recognition of delirium in the emergency department (ED) is poor. Our objectives were to assess: (1) the diagnostic accuracy of the Predicting Emergency department Delirium with an Interactive Computer Tablet (PrEDICT) “serious game” to identify older ED patients with delirium compared to clinical recognition and (2) the feasibility of the PrEDICT application compared to existing tests of attention.

DESIGN

Prospective observational study.

SETTING

ED of a Canadian tertiary care center.

PARTICIPANTS

We included ED patients, aged 70 years and older, with a minimum 4‐hour stay. We excluded anyone with critical illness, communication barriers, and visual impairment or those unable to use a computer tablet. None had prevalent delirium by ED clinicians' routine clinical assessment.

MEASUREMENTS

Participants were asked to tap targets on a tablet at four difficulty levels. Time and accuracy were automatically recorded. Other measures included the Confusion Assessment Method, the Delirium Severity Index, the Digit Vigilance Test (DVT), and the Choice Reaction Test (CRT).

RESULTS

We enrolled 203 patients. Their average age was 80.6 years, 49.8% were female, and their average ED length of stay was 15.9 hours. Sixteen subjects had clinically unrecognized delirium, and 14 of them completed the PrEDICT game (87.5%). We developed a threshold score with 100% sensitivity (95% confidence interval [CI] = 76.8%‐100.0%) and 59.7% specificity (95% CI = 52.3%‐66.6%) to identify patients with clinically unrecognized delirium. The area under the curve was 0.86 (95% CI = 0.77‐0.94). Completion rates were 196/203 (96.6%) for the PrEDICT serious game compared to 128/203 (63.1%) for the CRT and 51/203 (25.1%) for the DVT.

CONCLUSION

Older ED patients were able to use our serious game, including 87.5% of those with clinically unrecognized delirium. The PrEDICT application has potential to act as a sensitive screening tool to identify older ED patients with clinically unrecognized delirium. J Am Geriatr Soc 67:2370–2375, 2019
Sleep problems in Korean children with Down syndrome and parental quality of life
Authors: Choi E. K. , Jung E. , Van Riper M. , Lee Y. J.
Published: July 2019

Background

Sleep problems are common among children with Down syndrome (DS), and they can have a serious impact on children with DS as well as their parents and other family members. Specific aims of this study were to evaluate parent‐reported sleep problems in children with DS and to examine the relationship between the sleep behaviour of children with DS and their parents' quality of life (QOL).

Method

A cross‐sectional survey was conducted in September and October of 2017. Parents of children with DS were recruited from an online self‐support community for parents of children with DS in South Korea. The mean age of the parents and children with DS was 40.40 years (SD = 5.09) and 7.89 years (SD = 3.03), respectively. Children's sleep problems and parents' QOL were assessed using the Children's Sleep Habits Questionnaire and the abbreviated version of the World Health Organization Quality of Life scale, respectively.

Results

Results revealed that 83% of the parents reported that their child with DS experienced sleep problems. Children with DS had significantly more bedtime resistance, night waking, parasomnias and sleep‐disordered breathing than did typically developing children. In addition, their Children's Sleep Habits Questionnaire scores were higher than those of typically developing children. Moreover, being older, being male and having more severe developmental delays were significant risk factors for sleep problems among children with DS. Furthermore, sleep problems in children with DS negatively affected parents' QOL.

Conclusions

Sleep problems negatively affect children with DS as well as their parents; therefore, health care providers should be aware of these issues and help parents manage sleep problems proactively.
Ontogenetic changes of geometrical and mechanical characteristics of the avian femur: a comparison between precocial and altricial birds
Authors: Wei Xinsen , Zhang Zihui
Published: July 2019

The mechanical performance of limb bones is closely associated with an animal's locomotor capability and is thus important to our understanding of animal behaviour. This study combined a geometrical analysis and three‐point bending tests to address the question of how the mechanical performance of the femurs of Japanese quail (Coturnix coturnix japonica) and pigeon (Columba livia domestica) respond to changing functional demands during ontogeny. Results showed that hatchling quails had stiff bone tissues, and the femoral ultimate loads scaled negatively with body mass, corresponding to high functional demands during early growth. The hatchling pigeon femora had weak material properties but they showed a dramatic increase in Young's modulus during growth. Consequently, although femoral cross‐sectional geometry showed negative allometry, the ultimate loads scaled positively with body mass. Older pigeons had more circular bone cross‐sections than younger pigeons, probably due to load stimulation changes occurred shortly after the onset of locomotion. Negative allometry and isometry of the cross‐sectional geometry of hind limb bones were observed in flying birds and ground‐dwelling birds, respectively. The correspondence between geometrical change and locomotor pattern suggests that ontogenetic changes in cross‐sectional geometry may be an effective indicator of avian locomotor behaviour.
A new mineralized tissue in the early vertebrateAstraspis
Authors: Lemierre Alfred , Germain Damien
Published: July 2019

The dermoskeleton of the earliest vertebrates is well known but their endoskeleton is thought to have been largely cartilaginous until the Late Silurian. We confirm that the dermal plates ofAstraspisare three‐layered, with a superficial layer of enameloid and orthodentine, a middle layer of aspidin and a basal layer of lamellar acellular bone. This dermoskeleton is found in association with globular calcified cartilage, indicating the presence of a partially mineralized endoskeleton. In addition to the classical three‐layered organization, some dermal plates exhibit alignments of chondrocyte‐like lacunae, very similar to a pattern typical of chondroid metaplastic bone, previously unknown in early vertebrates. This discovery implies the presence of a proliferative cartilage, hitherto only known in Osteichthyans. This discovery indicates that a pattern similar to the first step of endochondral ossification was already present in the earliest vertebrates.
A potential risk factor for paraoxonase 1: in silico and in-vitro analysis of the biological activity of proton-pump inhibitors
Authors: Türkeş Cüneyt
Published: July 2019

Objectives

Proton-pump inhibitors (PPIs) are drugs commonly utilized by about 7% of adults in the world. Recent researches have shown that there are countless and severe side effects of these drugs. This situation has raised concern among clinicians and patients alike. The purpose of this study is to contribute the novel drug discovery and development technology and toxicology field by researching interactions of PPIs on paraoxonase 1.

Methods

In this study, the paraoxonase 1 enzyme was purified from human serum by using rapid and straightforward chromatographic techniques. Subsequently, the inhibition effects of pantoprazole, omeprazole, and esomeprazole, PPIs, were investigated on paraoxonase 1. Besides, molecular docking studies were performed to unravel the binding mechanism between the enzyme and drugs.

Key findings

All drugs showed potent inhibitory activities. IC50 of the drugs values were 54.780 ± 0.524, 86.470 ± 0.818 and 93.390 ± 0.885 mm and Ki constants were found as 39.895 ± 0.005 mm, 70.112 ± 0.010 mm and 78.868 ± 0.008 mm, respectively. The binding scores observed in silico studies were found to agree with the obtained from in-vitro experimental results.

Conclusions

We observed that the drugs decreased PON1 activity at low concentrations. The results show that adjusting the dosages of these medications is a crucial case for each patient. The physicians should more carefully interpret whether there is an essential indication before prescribing PPIs and, if there is, to approve the proper dosing for the situation.
Pharmacokinetics of ceftriaxone in freshwater crocodiles (Crocodylus siamensis) after intramuscular administration at two dosages
Authors: Poapolathep Saranya , Giorgi Mario , Chaiyabutr Narongsak , Klangkaew Narumol , Phaochoosak Napasorn , Wongwaipairote Tara , Poapolathep Amnart
Published: July 2019

One of the major obstacles to the successful treatment of infectious disease in freshwater crocodile species is incorrect dosing of antibiotics. There are few reports on pharmacokinetics and dosage regimens of antimicrobial drugs in crocodiles. The purpose of the present study was to clarify the pharmacokinetic characteristics of ceftriaxone (CEF) in Siamese freshwater crocodiles (Crocodylus siamensis). Freshwater crocodiles, Crocodylus siamensis, in breeding farms were treated with a single intramuscular administration of CEF at two dosages, 12.5 and 25 mg/kg body weight (b.w.). Blood samples were collected at preassigned times up to 168 hr. The plasma concentrations of CEF were measured by a validated method through liquid chromatography tandem‐mass spectrometry. CEF plasma concentrations were quantified up to 72 and 96 hr after low‐ and high‐dose administration, respectively. The Cmax values of CEF were 24.61 ± 5.15 µg/ml and 26.39 ± 2.81 µg/ml at dosages of 12.5 and 25 mg/kg b.w., respectively. The AUClast values increased in a dose‐dependent fashion. The half‐life values were not statistically different between the groups (around 20 hr). The average binding percentage of CEF to plasma protein was 53.78 ± 2.11%. Based on the pharmacokinetic data, susceptibility break‐point and the surrogate PK‐PD index (T > MIC, 0.2 μg/ml), i.m. administration of CEF at a dose of 12.5 mg/kg b.w. might be appropriate for initiating treatment of susceptible bacterial infections in freshwater crocodiles.
Testing cognitive gadgets
Authors: Heyes Cecilia
Published: July 2019

Cognitive Gadgets is a book about the cultural evolution of distinctively human cognitive mechanisms. Responding to commentators with different and broader interests, I argue that intelligent design has been more important in the formation of grist (technologies, practices and ideas) than of mills (cognitive mechanisms), and that embracing genetic accommodation would leave research on the origins of human cognition empirically unconstrained. I also underline the need to assess empirical methods; query the value of theories that merely accommodate existing data; and ask whether acquiring literacy is more laborious than learning to imitate, to talk and to read minds.
CRISPR/Cas9 knockout of leghemoglobin genes in Lotus japonicus uncovers their synergistic roles in symbiotic nitrogen fixation
Authors: Wang Longlong , Rubio Maria Carmen , Xin Xian , Zhang Baoli , Fan Qiuling , Wang Qiang , Ning Guogui , Becana Manuel , Duanmu Deqiang
Published: July 2019

Legume nodules contain high concentrations of leghemoglobins (Lbs) encoded by several genes. The reason for this multiplicity is unknown.

CRISPR/Cas9 technology was used to generate stable mutants of the three Lbs of Lotus japonicus. The phenotypes were characterized at the physiological, biochemical and molecular levels. Nodules of the triple mutants were examined by electron microscopy and subjected to RNA‐sequencing (RNA‐seq) analysis.

Complementation studies revealed that Lbs function synergistically to maintain optimal N2 fixation. The nodules of the triple mutants overproduced superoxide radicals and hydrogen peroxide, which was probably linked to activation of NADPH oxidases and changes in superoxide dismutase isoforms expression. The mutant nodules showed major ultrastructural alterations, including vacuolization, accumulation of poly‐β‐hydroxybutyrate and disruption of mitochondria. RNA‐seq of c. 20 000 genes revealed significant changes in expression of carbon and nitrogen metabolism genes, transcription factors, and proteinases. Lb‐deficient nodules had c. 30–50‐fold less heme but similar transcript levels of heme biosynthetic genes, suggesting a post‐translational regulatory mechanism of heme synthesis.

We conclude that Lbs act additively in nodules and that the lack of Lbs results in early nodule senescence. Our observations also provide insight into the reprogramming of the gene expression network associated with Lb deficiency, probably as a result of uncontrolled intracellular free O2 concentration.