bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of inflammatory bowel disease treatment on the risk of nonalcoholic fatty liver disease: a meta-analysis
Authors: Lapumnuaypol Kamolyut , Kanjanahattakij Napatt , Pisarcik David , Thongprayoon Charat , Wijarnpreecha Karn , Cheungpasitporn Wisit
Published: April 2018

Background

Epidemiological studies have demonstrated an association between inflammatory bowel disease (IBD) and an increased risk for the development of nonalcoholic fatty liver disease (NAFLD). However, the risk of NAFLD in IBD patients who receive different medical treatments including glucocorticoids, immunomodulators, and tumor necrosis factor-α inhibitors remains unclear. We aimed to assess whether the use of certain IBD medications is associated with the development of NAFLD.

Materials and methods

A systematic review was carried out in Medline, Embase, and Cochrane databases from inception through October 2017 to identify studies that assessed the association between the use of IBD medications and the risk of developing NAFLD. Effect estimates from the individual study were derived and combined using random-effect, generic inverse variance method of DerSimonian and Laird.

Results

Seven observational studies with a total of 1610 patients were enrolled. There was no significant association between the use of IBD medications and the incidence of NAFLD. The pooled odds ratios of NAFLD in patients who use biological agents, immunomodulators, methotrexate, and steroids were 0.85 [95% confidence interval (CI): 0.49–1.46], 1.19 (95% CI: 0.70–2.01), 3.62 (95% CI: 0.48–27.39), and 1.24 (95% CI: 0.85–1.82), respectively. Egger’s regression asymmetry test was performed and showed no publication bias.

Conclusion

Our study demonstrates no significant association between medications used in the treatment of IBD and the risk of developing NAFLD. The findings of our study suggest a complex, multifactorial relationship between IBD and the development of NAFLD beyond the scope of current pharmacological intervention.
Advances in the role of the aryl hydrocarbon receptor to regulate early hematopoietic development
Authors: Angelos Mathew G. , Kaufman Dan S.
Published: April 2018

Purpose of review

We summarize current advances to define the role the aryl hydrocarbon receptor (AHR) plays in mammalian hematopoiesis. We emphasize approaches to modulate AHR throughout human hematopoietic development in vitro to support the production of clinically relevant blood products suitable for patient care.

Recent findings

Initial data demonstrate that both pharmacologic AHR inhibition and genetic deletion from human pluripotent stem cells provide useful strategies to enhance the yield of hematopoietic stem and progenitor cells. AHR hyperactivation following the induction of CD34+ megakaryocyte–erythroid progenitors skews developed toward erythroid lineages, whereas AHR inhibition supports platelet production. At the level of lymphoid specification, AHR inhibition enhances the proliferation and differentiation of functional human natural killer cells, whereas hyperactivation leads to production of Group 3 innate lymphoid cells and provides a novel platform for studying human innate lymphoid cell development.

Modulation of AHR in human hematopoietic cells in vitro is a promising tool to mediate development of terminal hematopoietic cell populations with significant clinical implications to generate cells suitable for antitumor immunotherapy and bone marrow transplantation.
A sustainable model for cochlear implantation in the developing world: perspectives from the Indian subcontinent
Authors: Sampath Kumar Raghunandhan , Kameswaran Mohan
Published: April 2018

Purpose of review

The overall prevalence of deafness in India is 0.2%, but the prevalence in the southern state of Tamil Nadu is much higher (around 0.6%) because of consanguinity. Especially in India, establishing cochlear implantation as a treatment modality for hearing loss has been a daunting task, but in the last decade, the cochlear implantation program has emerged as an unqualified success in many states, with over 20 000 cochlear implantations done till date. Several states are sponsoring free implants to children under the age of 6 years and below poverty line.

Recent findings

Nearly 3000 cochlear implantations have been performed in Tamil Nadu under the Chief Minister's Comprehensive Health Insurance Scheme, with the goal to have a ‘deafness free Tamil Nadu’ by 2025. This scheme covers nearly 40 million people in rural areas. Valuable lessons have been learnt from this social experiment. One of the cornerstones of this scheme is the method to deliver habilitation via satellite centers in rural areas at the doorstep of the patient. The outcomes in peripheral centers were found to be statistically similar to those in the main center and correlated well with duration of habilitation.

Opening up satellite centers for habilitation across the state of Tamil Nadu has greatly helped to improve the attendance and outcomes. The Indian model has been hugely successful and has helped start similar cochlear implantation programs in neighboring countries such as Nepal, Sri Lanka and Bangladesh.
An Unlikely Cause of a Blunt Pancreatic Injury
Authors: Cully Matthew , Perry Jonathan , Titus M. Olivia
Published: April 2018

We report the case of a 17-year-old male football player with blunt abdominal trauma. Careful evaluation, including computed tomography and laboratory, revealed a pancreatic body laceration. Pancreatic injuries are relatively uncommon and associated with significant morbidity and mortality and require early diagnosis for optimal management and outcome.
Early Hospital Discharge After Helicopter Transport of Pediatric Trauma Patients
Authors: Fahy Aodhnait S. , Polites Stephanie F. , Thiels Cornelius A. , Parker Maile , Ishitani Michael B. , Moir Christopher R. , Berns Kathleen , Zietlow Scott P. , Jenkins Donald H. , Zielinski Martin D.
Published: April 2018

Objectives

Helicopter air ambulance (HAA) of pediatric trauma patients is a life-saving intervention. Triage remains a challenge for both scene transport and interhospital transfer of injured children. We aimed to understand whether overtriage or undertriage was a feature of scene or interhospital transfer and how in or out of state transfers affected these rates.

Methods

Children (<18 years) who underwent trauma activation at a level I trauma center between 2011 and 2013 were identified and reviewed. Patients transported by HAA were compared with those transported by ground ambulance (GA).

Results

Of 399 pediatric patients (median age, 10.4 years; range, 0.1–17 years; 264 male [66%]), 71 (18%) were transported by HAA. Seventy-two percent of HAA patients went to the intensive care unit or the operating room from the trauma bay or suffered in-hospital mortality (vs 42% GA, P < 0.001). More patients were overtriaged (HAA with injury severity score [ISS] of <15) from interhospital transfers than from the scene (25% vs 3%, P = 0.002). Undertriage (GA with ISS >15) was acceptable at 5% from the scene and 14% from interhospital transfers (P = 0.08). Overtriage of patients with ISS less than 15 to HAA was significantly lower from in-state hospitals (22%) than out-of-state hospitals (45%) (P = 0.02). Undertriage of patients with ISS greater than 15 to GA was also lower from in-state hospitals (20%) versus out-of-state hospitals (38%) (P = 0.03).

Conclusions

Triage of pediatric trauma patients to HAA remains difficult. There remains potential for improvement, particularly as regards interhospital HAA overtriage, but well developed transfer protocols (such in-state protocols) may help.
Accuracy of Bedside Ultrasound for the Diagnosis of Skull Fractures in Children Aged 0 to 4 Years
Authors: Choi Jea Yeon , Lim Yong Su , Jang Jae Ho , Park Won Bin , Hyun Soung Youl , Cho Jin Seong
Published: April 2018

Objectives

The aim of this study was to investigate the accuracy of bedside ultrasound (US) performed by emergency physicians for diagnosing skull fractures in children 0 to 4 years old compared with the accuracy of head computed tomography (CT). We also sought to investigate characteristics and precautions associated with US.

Methods

This single-center prospective study involved children 0 to 4 years old who had a history of head trauma. Bedside US was performed by emergency medicine physicians, and the results were compared with CT scan interpretations provided by attending radiologists. The accuracy of US for the diagnosis of skull fractures was calculated, and the errors were reviewed.

Results

A total of 87 patients were enrolled. Skull fracture was present in 13 patients (14.9%), according to CT. Bedside US had a sensitivity and specificity of 76.9% (95% confidence interval [CI], 46.0%–93.8%) and 100% (95% CI, 93.9%–100%), respectively. Overall positive predictive value was 100% (95% CI, 65.5%–100%), and negative predictive value was 96.1% (95% CI, 88.3%–99.0%). Three false-negative cases were observed.

Conclusions

Bedside US performed by emergency medicine physicians with short focused US training is a useful tool for diagnosing skull fractures in children 0 to 4 years of age. However, there were 3 false-negative cases. A meticulous examination is needed in the area adjacent to the orbital wall and skull base.
Disparities in Adherence to Pediatric Diabetic Ketoacidosis Management Guidelines Across a Spectrum of Emergency Departments in the State of Indiana
Authors: Abulebda Kamal , Abu-Sultaneh Samer , White Erin E. , Kirby Michele L. , Phillips Brian C. , Frye Courtney T. , Murphy Lee D. , Lutfi Riad
Published: April 2018

Background

Diabetic ketoacidosis (DKA) is a common presentation to an emergency department (ED), with the majority presenting to community EDs. Adherence to clinical guidelines in these EDs can reduce morbidity and mortality. Few methods to describe practice gaps for DKA management have been reported.

Objectives

We hypothesized that high-fidelity in situ simulation can be used to measure and compare the quality of the care provided to pediatric patients with DKA presenting to community EDs in the state of Indiana.

Methods

This observational study examined multiprofessional teams caring for a simulated pediatric patient who presented with DKA to community EDs. The primary outcome was overall adherence to pediatric DKA guidelines as measured by a validated performance checklist. A composite adherence score (CAS) was calculated using the sum of 9 checklist performance parameters. Multivariable logistic regression was used to examine the impact of ED volume and characteristics on the scores.

Results

A 49 multiprofessional teams from 13 sites were enrolled. Of the 252 participants, 26 (10.3%) were physicians, 143 (56.7%) registered nurses, 25 (9.9%) respiratory therapists, and 58 (23.0%) were other. The overall CAS for all sites was 55.6% (25th, 75th interquartile range, 44.4%, 66.7%). Excessive intravenous fluid boluses were given by 53.1%, whereas 30.6% and 26.5% incorrectly administered insulin and sodium bicarbonate boluses, respectively. Only 10.2% used an appropriate intravenous fluid rate, and 57.1% performed an hourly glucose. No significant difference in the CAS was found due to pediatric ED volume or presence of an inpatient pediatric service.

Conclusions

Using validated in situ simulation; we revealed high variability in adherence to the pediatric DKA management guidelines at a wide range of community EDs. A statewide education initiative focused on decreasing variation and improving adherence to pediatric DKA guidelines is necessary for patient safety.
Long-term Outcomes of Laparoscopic Versus Open Surgery for Clinical Stage II/III Gastric Cancer
Authors: Kinoshita Takahiro , Uyama Ichiro , Terashima Masanori , Noshiro Hirokazu , Nagai Eishi , Obama Kazutaka , Tamamori Yutaka , Nabae Toshinaga , Honda Michitaka , Abe Takayuki
Published: April 2018

Objective:

A large-scale multicenter historical cohort study was conducted to investigate the efficacy of laparoscopic gastrectomy (LG) in comparison to open gastrectomy (OG) for locally advanced gastric cancer.

Background:

LG is now practiced widely, but its applicability for advanced gastric cancer is still controversial. As oncologic outcomes of randomized trials are still pending, there is an urgent need for information that would be relevant to current practice.

Methods:

Through a consensus meeting involving surgeons and biostatisticians, 30 preoperative variables possibly influencing the choice of surgical approach and associated with outcome were identified to enable rigorous estimation of propensity scores. A total of 1948 consecutive patients who underwent gastrectomy for clinical stage II/III gastric adenocarcinoma between 2008 and 2014 were identified, and their clinical data were collected from 8 participating hospitals. After propensity score matching, 610 cases (OG = 305, LG = 305) were finally selected for comparison of long-term outcomes.

Results:

In the propensity-matched OG and LG populations, the mean observation period was 3.5 and 3.4 years, and the 5-year overall survival was 53.0% and 54.2%, respectively. The hazard ratio (LG/OG) for overall survival was 1.01 (95% confidence interval, 0.80–1.29), and noninferiority of LG was demonstrated statistically as the upper 95% confidence limit was less than the prespecified margin (1.33). The recurrence rate was 30.8% and 29.8% for OG and LG, respectively, and the hazard ratio for recurrence was 0.98 (95% confidence interval, 0.74–1.31). The patterns of recurrence in the 2 groups were similar.

Conclusions:

This observational study strictly adjusted for confounding factors has provided evidence to suggest that LG is oncologically comparable to OG for locally advanced gastric cancer. The validity of this result will be examined in ongoing randomized trials.
Injury Characteristics and von Willebrand Factor for the Prediction of Acute Respiratory Distress Syndrome in Patients With Burn Injury
Authors: Afshar Majid , Burnham Ellen L. , Joyce Cara , Gagnon Robin , Dunn Robert , Albright Joslyn M. , Ramirez Luis , Repine John E. , Netzer Giora , Kovacs Elizabeth J.
Published: April 2018

Objective:

To derive and validate a prediction model for the development of ARDS in burn-injured patients.

Summary Background Data:

Burn injury carries the highest incidence of acute respiratory distress syndrome (ARDS) among all predisposing conditions, but few studies exist on risk factors in these patients. Studies employing biomarkers and clinical risk factors for predicting ARDS mortality have recently been examined but none exist for onset of ARDS nor in patients with burn injury.

Methods:

This was a prospective multicenter study of 113 patients with isolated burn injury or inhalation injury. Clinical variables and plasma biomarkers representative of endothelial injury, epithelial injury, or inflammation were collected within 24 hours of admission. The most parsimonious model was chosen by considering discrimination, calibration, and model fit.

Results:

Among the biomarkers measured in patients with burn injuries, a one-standard deviation increase in log-transformed levels of the A2 domain of von Willebrand factor in the first 24 hours was most strongly associated with the development of ARDS (OR 7.72; 95% CI: 1.64–36.28, P = 0.03). Of candidate models, a 3-variable model with %TBSA, inhalation injury, and von Willebrand factor-A2 had comparable discrimination to more complex models (area under the curve: 0.90; 95% CI 0.85–0.96). The 3-variable model had good model fit by Hosmer–Lemeshow test (P = 0.74) and maintained similar discrimination after accounting for performance optimism (Bootstrapped area under the curve: 0.90; 95% CI: 0.84–0.95).

Conclusions:

The 3-variable model with %TBSA, inhalation injury, and von Willebrand factor could be used to better identify at-risk patients for both the study and prevention of ARDS in patients with burn injury.
Vaginal Myomectomy to Resolve Bladder Outlet Obstruction 50 Years After Hysterectomy
Authors: Johansson Shorty , Walters Rustin , Mayer Kaitlyn , Shippey Stuart
Published: April 2018

Background

Leiomyomas can develop after hysterectomy and, when located in the bladder, can result in voiding dysfunction and incontinence.

Case

Fifty years after a hysterectomy, a 77-year-old woman presented with a 1-year history of urinary retention requiring self-catheterization and bothersome urinary incontinence. Multiple imaging modalities demonstrated a well-circumscribed 2-cm mass abutting the bladder beneath the trigone. After ureteral stent placement, we excised the nonpalpable mass using ultrasound guidance. We identified a 1.5-cm incidental cystomy and repaired it in layers. After the repair, we placed a suprapubic catheter. Pathologic examination of the mass revealed a leiomyoma. Postoperatively, we confirmed the integrity of the bladder, removed the ureteral stents, and reviewed postvoid residuals, which were minimal before removing the suprapubic catheter. Six weeks after her operation, the patient voided spontaneously with significant improvement of her urinary incontinence.

Conclusion

Vaginal resection with ureteral stenting represents a safe surgical approach for resection of a symptomatic, benign bladder mass.
Depression, Anxiety, and Pelvic Floor Symptoms Before and After Surgery for Pelvic Floor Dysfunction
Authors: Larouche Maryse , Brotto Lori A. , Koenig Nicole A. , Lee Terry , Cundiff Geoffrey W. , Geoffrion Roxana
Published: April 2018

Objectives

We aimed to explore the correlation between perioperative symptoms of depression and anxiety with pelvic floor symptoms after urogynecologic surgery. Postoperative pain, goal attainment, quality of life, and satisfaction were assessed.

Methods

A prospective cohort study of women undergoing inpatient urogynecologic surgery was conducted. Preoperative questionnaires included Beck Depression and Beck Anxiety Inventories, Pain Catastrophizing Scale, Pelvic Floor Distress Inventory, Pelvic Floor Impact Questionnaire, and a detailed goals and perioperative supports questionnaire. Postoperative pain was assessed via the Short-Form McGill Pain Questionnaire. Questionnaires were readministered 6 weeks postoperatively. Descriptive statistics were obtained. Spearman correlation determined the relationship between preoperative and postoperative questionnaire scores. Quantile regression assessed the potential moderating effect of patient characteristics on these relationships.

Results

Sixty women (mean age, 58.5 years) were recruited. Fifty-seven (95%) completed follow-up. Most common surgical indication was pelvic organ prolapse (59/60; 98%). Depression and anxiety symptoms were minimal in most women. There was significant median change in preoperative to postoperative scores for Beck Anxiety Inventory (−2.0, P = 0.011), Pelvic Floor Distress Inventory-20 (−69.4, P < 0.001), and Pelvic Floor Impact Questionnaire-7 (−23.8, P = 0.001). Baseline depression and anxiety symptoms were correlated with higher immediate postoperative pain, but not other outcomes. The most common goal, achieved by 47 (92%) of 51, was to reduce condition-specific symptoms. Postoperative depression and anxiety symptoms, and pelvic floor distress and impact were significantly correlated.

Conclusions

Baseline depression and anxiety symptoms were not significantly associated with postoperative pelvic floor symptom burden or surgical satisfaction. Bothersome postoperative pelvic floor symptoms were associated with postoperative depressive symptoms.
Catecholamine Challenge Uncovers Distinct Mechanisms for Direct Versus Indirect, but Not Social Versus Non-Social, Learning
Authors: Cook Jennifer L. , Swart Jennifer C. , Froböse Monja I. , Diaconescu Andreea , Geurts Dirk E. M. , den Ouden Hanneke E. M. , Cools Roshan
Published: April 2018

Evidence that social and individual learning are at least partially dissociable sustains the belief that humans possess adaptive specialisations for social learning. However, in most extant paradigms, social information comprises an indirect source that can be used to supplement one’s own, direct, experience. Thus, social and individual learning differ both in terms of social nature (social versus non-social) and directness (indirect versus direct). To test whether the dissociation between social and individual learning is best explained in terms of social nature or directness, we used a catecholaminergic challenge known to modulate learning. Two groups completed a decision-making task which required direct learning, from own experience, and indirect learning from an additional source. The groups differed in terms of whether the indirect source was social or non-social. The catecholamine transporter blocker, methylphenidate, affected direct learning by improving adaptation to changes in the volatility of the environment but there was no effect of methylphenidate on learning from the social or non-social indirect source. Thus, we report positive evidence for a dissociable effect of methylphenidate on direct and indirect learning, but no evidence for a distinction between social and non-social. These data fail to support the adaptive specialisation view, instead providing evidence for distinct mechanisms for direct versus indirect learning.
Dynamic linear models guide design and analysis of microbiota studies within artificial human guts
Authors: Silverman Justin D , Durand Heather , Bloom Rachael J. , Mukherjee Sayan , David Lawrence A
Published: April 2018

Artificial gut models provide unique opportunities to study human-associated microbiota. Outstanding questions for these models’ fundamental biology include the timescales on which microbiota vary and the factors that drive such change. Answering these questions though requires overcoming analytical obstacles like estimating the effects of technical variation on observed microbiota dynamics, as well as the lack of appropriate benchmark datasets. To address these obstacles, we created a modeling framework based on multinomial logistic-normal dynamic linear models (MALLARDs) and performed dense longitudinal sampling of replicate artificial human guts over the course of 1 month. The resulting analyses revealed that when observed on an hourly basis, 76% of community variation could be ascribed to technical noise from sample processing, which could also skew the observed covariation between taxa. Our analyses also supported hypotheses that human gut microbiota fluctuate on sub-daily timescales in the absence of a host and that microbiota can follow replicable trajectories in the presence of environmental driving forces. Finally, multiple aspects of our approach are generalizable and could ultimately be used to facilitate the design and analysis of longitudinal microbiota studies in vivo.
Vacuolar iron stores gated by NRAMP3 and NRAMP4 are the primary source of iron in germinating seeds
Authors: Bastow Emma L , Torre Vanesa S Garcia de la , Maclean Andrew E , Green Robert T , Merlot Sylvain , Thomine Sebastien , Balk Janneke
Published: April 2018

During seed germination, iron (Fe) stored in vacuoles is exported by the redundant NRAMP3 and NRAMP4 transporter proteins. A doublenramp3 nramp4mutant is unable to mobilize Fe stores and does not develop in the absence of external Fe. We used RNA sequencing to compare gene expression innramp3 nramp4and wild type during germination and early seedling development. Even though sufficient Fe was supplied, the Fe-responsive transcription factorsbHLH38, 39, 100and101and their downstream targetsFRO2andIRT1mediating Fe uptake were strongly upregulated in thenramp3 nramp4mutant. Activation of the Fe deficiency response was confirmed by increased ferric chelate reductase activity in the mutant. At early stages, genes important for chloroplast redox control (FSD1, SAPX), Fe homeostasis(FER1, SUFB)and chlorophyll metabolism (HEMA1, NYC1) were downregulated, indicating limited Fe availability in plastids. In contrast, expression ofFRO3, encoding a ferric reductase involved in Fe import into the mitochondria, was maintained and Fe-dependent enzymes in the mitochondria were unaffected innramp3 nramp4. Together these data show that a failure to mobilize Fe stores during germination triggered Fe deficiency responses and strongly affected plastids but not mitochondria.
A rapid microwave method for isolation of genomic DNA and identification of white rot fungi
Authors: Rao Ramya G. , Ravichandran A. , Dhali A. , Kolte A.P. , Giridhar K , Manpal Sridhar
Published: April 2018

White rot fungi (WRF) produce lignolytic enzymes comprised by laccases and peroxidases responsible for mineralization of recalcitrant lignin. Because of the so-called lignin modifying enzymes(LME’s), these fungi have potential applications in biodegradation and bioremediation processes. Increased demand for lignolytic enzymes to exploit their various applications has sparked interest in identifying and characterizing new novel strains of WRF. Despite this undisputed biotechnological significance, molecular identification of WRF, remains a daunting task for researchers as genomic DNA isolation is a tedious process, unsuccessful many a times because of their rigid and resistant cell walls. A rapid, effective and efficient method to identify the innumerable fungal strains within no time is the need of the hour. The fungal mycelia of various unknown as well as know isolates of WRF, after alternative washing with TE buffer and sterile water were suspended in TE buffer. Fungi in solution were then exposed to microwave. The crude extract contained genomic DNA which was extracted and amplified using ITS primers for further identification. Based on sequencing results the identity of known cultures was confirmed, while the unknown cultures were identified asClitopilus scyphoides(AGUM004, BankIt2098576 MH172163); Ganodermarasinaceum(AGUM007, BankIt2098576 MH172163);Schizophyllum sp(KONA001BankIt2098576 MH172164;AGUM011BankIt2098576 MH172165andAGUM021BankIt2098576 MH172166respectively),Coprinellus disseminatus(BANG001, BankIt2098576 MH172167) andLentinus squarrosulus(TAMI004, BankIt2098576 MH172167). The microwave method described for isolating quality DNA of WRF without further purification steps proved a novel method requiring less than ten minutes and minimized the chances of the presence of PCR inhibitors.

IMPORTANCE

White rot fungi which decay wood, possess selective lignin degrading enzymes responsible for degrading a wide variety of environmental pollutants, xenobiotic compounds in addition to mineralizing chemicals that are insoluble and recalcitrant. Lignolytic enzymes hold potential towards replacing conventional chemical processes and their increased demand in the market has ignited interest in identifying and characterizing new strains of WRF. A rapid, efficient method capable of quickly identifying fungal isolates is a constraint. The microwave method is a novel quick method for isolating superior quality DNA. Its adoption circumvents the initial purification steps and /or interference of PCR inhibitors, which are encompassed in the use of conventional methods. The microwave method thus permits the thorough amplification of the ITS region thereby aiding in the easy identification of unknown species. Use of the microwave method will permit researchers to obtain DNA from fungi very quickly for further application in molecular studies.
Aggressive or moderate drug therapy for infectious diseases? Trade-offs between different treatment goals at the individual and population levels
Authors: Scire Jérémie , Hozé Nathanaël , Uecker Hildegard
Published: April 2018

Antimicrobial resistance is one of the major public health threats of the 21st century. There is a pressing need to adopt more efficient treatment strategies in order to prevent the emergence and spread of resistant strains. The common approach is to treat patients with high drug doses, both to clear the infection quickly and to reduce the risk of de novo resistance. Recently, several studies have argued that, at least in some cases, low-dose treatments could be more suitable to reduce the within-host emergence of antimicrobial resistance. However, the choice of a drug dose may have consequences at the population level, which has received little attention so far.

Here, we study the influence of the drug dose on resistance and disease management at the host and population levels. We develop a nested two-strain model and unravel trade-offs in treatment benefits between an individual and the community. We use several measures to evaluate the benefits of any dose choice. Two measures focus on the emergence of resistance, at the host level and at the population level. The other two focus on the overall treatment success: the outbreak probability and the disease burden. We find that different measures can suggest different dosing strategies. In particular, we identify situations where low doses minimize the risk of emergence of resistance at the individual level, while high or intermediate doses prove most beneficial to improve the treatment efficiency or even to reduce the risk of resistance in the population.

Author summary

The obvious goals of antimicrobial drug therapy are rapid patient recovery and low disease prevalence in the population. However, achieving these goals is complicated by the rapid evolution and spread of antimicrobial resistance. A sustainable treatment strategy needs to account for the risk of resistance and keep it in check. One parameter of treatment is the drug dosage, which can vary within certain limits. It has been proposed that lower doses may, in some cases, be more suitable than higher doses to reduce the risk of resistance evolution in any one patient. However, if lower doses prolong the period of infectiousness, such a strategy has consequences for the pathogen dynamics of both strains at the population level. Here, we set up a nested model of within-host and between-host dynamics for an acute self-limiting infection. We explore the consequences of drug dosing on several measures of treatment success: the risk of resistance at the individual and population levels and the outbreak probability and the disease burden of an epidemic. Our analysis shows that trade-offs may exist between optimal treatments under these various criteria. The criterion given most weight in the decision process ultimately depends on the disease and population under consideration.
Single-cell chromatin interactions reveal regulatory hubs in dynamic compartmentalized domains
Authors: Oudelaar A. Marieke , Davies James O.J. , Hanssen Lars L.P. , Telenius Jelena M. , Schwessinger Ron , Liu Yu , Brown Jill M. , Downes Damien J. , Chiariello Andrea M. , Bianco Simona , Nicodemi Mario , Buckle Veronica J. , Dekker Job , Higgs Douglas R. , Hughes Jim R.
Published: April 2018

The promoters of mammalian genes are commonly regulated by multiple distal enhancers, which physically interact within discrete chromatin domains. How such domains form and how the regulatory elements within them interact within single cells is not understood. To address this we developed Tri-C, a new Chromosome Conformation Capture (3C) approach to identify concurrent chromatin interactions at individual alleles within single cells. The heterogeneity of interactions observed between such cells shows that CTCF-mediated formation of chromatin domains and interactions within them are dynamic processes. Importantly, our analyses reveal higher-order structures involving simultaneous interactions between multiple enhancers and promoters within individual cells. This provides a structural basis for understanding how multiple cis-elements act together to establish robust regulation of gene expression.
High-speed tomography under extreme conditions at the PSICHE beamline of the SOLEIL Synchrotron
Authors: Boulard E. , King A. , Guignot N. , Deslandes J.-P. , Le Godec Y. , Perrillat J.-P. , Clark A. , Morard G. , Itié J.-P.
Published: April 2018

In situmicrotomography at high pressure and temperature has developed rapidly in the last decade, driven by the development of new high-pressure apparatus. It is now routinely possible to characterize material under high pressure with acquisition times for tomograms of the order of tens of minutes. Here, advantage was taken of the possibility to combine the use of a pink beam projected through a standard Paris–Edinburgh press in order to demonstrate the possibility to perform high-speed synchrotron X-ray tomography at high pressure and temperature allowing complete high-resolution tomograms to be acquired in about 10 s. This gives direct visualization to rapidly evolving or unstable systems, such as flowing liquids or reacting components, and avoids assumptions in the interpretation of quenched samples. Using algebraic reconstruction techniques allows the missing angle artefacts that result from the columns of the press to be minimized.
Improved protein-crystal identification by using 2,2,2-trichloroethanol as a fluorescence enhancer
Authors: Pichlo Christian , Toelzer Christine , Chojnacki Konrad , Öcal Sinan , Uthoff Matthias , Ruegenberg Sabine , Hermanns Thomas , Schacherl Magdalena , Denzel Martin S. , Hofmann Kay , Niefind Karsten , Baumann Ulrich
Published: April 2018

The identification of initial lead conditions for successful protein crystallization is crucial for structural studies using X-ray crystallography. In order to reduce the number of false-negative conditions, an emerging number of fluorescence-based methods have been developed which allow more efficient identification of protein crystals and help to distinguish them from salt crystals. Detection of the native tryptophan fluorescence of protein crystals is one of the most widely used methods. However, this method can fail owing to the properties of the crystallized protein or the chemical composition of the crystallization trials. Here, a simple, fast and cost-efficient method employing 2,2,2-trichloroethanol (TCE) has been developed. It can be performed with a standard UV-light microscope and can be applied to cases in which detection of native tryptophan fluorescence fails. In four test cases this method had no effect on the diffraction properties of the crystals and no structural changes were observed. Further evidence is provided that TCE can be added to crystallization trials during their preparation, making this method compatible with high-throughput approaches.
Structure of the tandem PX-PH domains of Bem3 fromSaccharomyces cerevisiae
Authors: Ali Imtiaz , Eu Sungmin , Koch Daniel , Bleimling Nathalie , Goody Roger S. , Müller Matthias P.
Published: April 2018

The structure of the tandem lipid-binding PX and pleckstrin-homology (PH) domains of the Cdc42 GTPase-activating protein Bem3 fromSaccharomyces cerevisiae(strain S288c) has been determined to a resolution of 2.2 Å (Rwork= 21.1%,Rfree= 23.4%). It shows that the domains adopt a relative orientation that enables them to simultaneously bind to a membrane and suggests possible cooperativity in membrane binding.
Crystal structure of tetrakis[μ-2-(methoxycarbonyl)benzoato-κ2
O
1:O
1′]bis[(N,N-dimethylformamide-κO)copper(II)](Cu—Cu) dimethylformamide disolvate
Authors: Wang Jinglin , Su Feng , Shi Lili
Published: April 2018

The title compound, [Cu2(C9H7O4)4(C3H7NO)2]·2C3H7NO, crystallizes in the monoclinic P21/c space group, with the binuclear copper unit occupying a special position on an inversion center, i.e. the asymmetric unit of the crystal consists of one CuII ion, two 2-(methoxycarbonyl)benzoate ligands, and two DMF molecules (one coordinated and one solvate). The binuclear complex displays a paddle-wheel-shaped structure with the two copper atoms being in a Jahn–Teller-distorted octahedral coordination environment. Each 2-(methoxycarbonyl)benzoate substituent acts as a bridging ligand and links two Cu atoms with a Cu—Cu distance of 2.633 (1) Å. The carboxylate groups of the 2-(methoxycarbonyl)benzoate ligands adopt bidentate syn–syn bridging modes, with dihedral angles between the carboxylate planes and the aromatic rings of 18.427 (4) and 43.029 (6)°. In the crystal, adjacent DMF molecules coordinated to copper atoms are arranged in a mutual `head-to-tail' manner by offset face-to-face π–π stacking interactions, resulting in chains along the c-axis direction. The planes of the coordinated DMF molecules are parallel to each other, the distance between them being 3.33 (1) Å. A three-dimensional structure is assembled from the chains by weak C—H...O and C—H...π intermolecular interactions involving the DMF solvent molecules. One of the methyl ester groups is disordered over two sites with an occupancy ratio of 0.751 (12):0.249 (12).
Crystal structure of bis(acetonitrile-κN)(4,4′-di-tert-butyl-2,2′-bipyridine-κ2
N,N′)platinum(II) bis(tetrafluoridoborate) packing as head-to-head dimers
Authors: Joseph Chris , Nesterov Vladimir N. , Smucker Bradley W.
Published: April 2018

The crystal structure of a platinum(II) supramolecular building block, [Pt(dbbpy)(NCCH3)2](BF4)2 (dbbpy = 4,4′-di-tert-butyl-2,2′-bipyridine, C18H24N2) is an example of a rare head-to-head dimer, even with the bulky tert-butyl groups of the bipyridine. This packing motif still enables significant π–π interactions between two pyridyl groups, and may result from the close proximity of the tetrafluoridoborate ions to the platinum(II) complexes, resulting in intramolecular H...F distances between 2.156 and 2.573 Å.
Crystal structure of strontium and barium acesulafame (6-methyl-4-oxo-4H-1,2,3-oxathiazin-3-ide 2,2-dioxide)
Authors: Nazarenko Alexander Y.
Published: April 2018

Both strontium and barium acesulfames, namely poly[aquabis(μ3-6-methyl-2,2-dioxo-1,2λ6,3-oxathiazin-4-olato)strontium(II)], [Sr(C4H4NO4S)2(H2O)]n, and the barium(II) analogue, [Ba(C4H4NO4S)2(H2O)]n, crystallize in nearly identical isotypic forms, with barium–oxygen interatomic distances being longer due to the larger ionic radius of the barium(II) ion. The coordination number of the metal ion is 9; the coordination polyhedra can be described as distorted capped square antiprisms [Johnson solidJ10; Johnson (1966).Can. J. Math.18, 169–200]. The conformation of the acesulafame ions is a distorted envelope with an out-of-plane S atom. Metal and acesulfame ions are assembled into infinitive chains along the [100] axis. These chains are connectedviahydrogen bonds into a three-dimensional network.
Structural rearrangements occurring upon cofactor binding in the Mycobacterium smegmatis β-ketoacyl-acyl carrier protein reductase MabA
Authors: Küssau Tanja , Flipo Marion , Van Wyk Niel , Viljoen Albertus , Olieric Vincent , Kremer Laurent , Blaise Mickaël
Published: April 2018

In mycobacteria, the ketoacyl-acyl carrier protein (ACP) reductase MabA (designated FabG in other bacteria) catalyzes the NADPH-dependent reduction of β-ketoacyl-ACP substrates to β-hydroxyacyl-ACP products. This first reductive step in the fatty-acid biosynthesis elongation cycle is essential for bacteria, which makes MabA/FabG an interesting drug target. To date, however, very few molecules targeting FabG have been discovered and MabA remains the only enzyme of the mycobacterial type II fatty-acid synthase that lacks specific inhibitors. Despite the existence of several MabA/FabG crystal structures, the structural rearrangement that occurs upon cofactor binding is still not fully understood. Therefore, unlocking this knowledge gap could help in the design of new inhibitors. Here, high-resolution crystal structures of MabA from Mycobacterium smegmatis in its apo, NADP+-bound and NADPH-bound forms are reported. Comparison of these crystal structures reveals the structural reorganization of the lid region covering the active site of the enzyme. The crystal structure of the apo form revealed numerous residues that trigger steric hindrance to the binding of NADPH and substrate. Upon NADPH binding, these residues are pushed away from the active site, allowing the enzyme to adopt an open conformation. The transition from an NADPH-bound to an NADP+-bound form is likely to facilitate release of the product. These results may be useful for subsequent rational drug design and/or for in silico drug-screening approaches targeting MabA/FabG.
Microfocus diffraction from different regions of a protein crystal: structural variations and unit-cell polymorphism
Authors: Thompson Michael C. , Cascio Duilio , Yeates Todd O.
Published: April 2018

Real macromolecular crystals can be non-ideal in a myriad of ways. This often creates challenges for structure determination, while also offering opportunities for greater insight into the crystalline state and the dynamic behavior of macromolecules. To evaluate whether different parts of a single crystal of a dynamic protein, EutL, might be informative about crystal and protein polymorphism, a microfocus X-ray synchrotron beam was used to collect a series of 18 separate data sets from non-overlapping regions of the same crystal specimen. A principal component analysis (PCA) approach was employed to compare the structure factors and unit cells across the data sets, and it was found that the 18 data sets separated into two distinct groups, with largeRvalues (in the 40% range) and significant unit-cell variations between the members of the two groups. This categorization mapped the different data-set types to distinct regions of the crystal specimen. Atomic models of EutL were then refined against two different data sets obtained by separately merging data from the two distinct groups. A comparison of the two resulting models revealed minor but discernable differences in certain segments of the protein structure, and regions of higher deviation were found to correlate with regions where larger dynamic motions were predicted to occur by normal-mode molecular-dynamics simulations. The findings emphasize that large spatially dependent variations may be present across individual macromolecular crystals. This information can be uncovered by simultaneous analysis of multiple partial data sets and can be exploited to reveal new insights about protein dynamics, while also improving the accuracy of the structure-factor data ultimately obtained in X-ray diffraction experiments.
Job characteristics, job resources and work-related outcomes: role of person-organisation fit
Authors: Priyadarshi Pushpendra , Premchandran Rajesh
Published: April 2018

Purpose

The purpose of this paper is to examine and understand the role of person-organisation (P-O) fit in mediating the relationship between job resources and work-related outcomes. The need to study the antecedents of P-O fit, dearth of its literature in India, and growing importance of ensuring congruence between the environment and the individual in a diverse workplace, to recruit and retain the employees, underlines the significance of this research. In addition to the mediating role of P-O fit, it was hypothesised that co-worker support and decision latitude will lead to an increase in P-O fit and, in turn, be positively related to work engagement (WE), job satisfaction (JS) and organisational commitment (OC).

Design/methodology/approach

Two-phased time-lagged data were collected from a total sample of 213 middle- and senior-level executives working in India. The data consisted of a self-report questionnaire on skill discretion, decision authority and co-worker support in Phase 1 and P-O fit, WE, OC and JS scales in Phase 2.

Findings

Structural equation modelling was simultaneously used to test the hypothesised relationships. It emerged that co-worker support and skill discretion positively correlated with P-O fit. It was found that P-O fit mediated the relationship between co-worker support and JS and OC. It also established partial mediation between co-worker support and WE, and between skill discretion and JS, organisational commitment and WE. The findings of this study, therefore, have profound implications for researchers as well as for practicing managers highlighting the need for a better job design and creating a supportive work environment.

Research limitations/implications

Though the data were collected in two phases, the study design went through a time lag of four weeks, and thereby provided tests of association and not of robust causal relationships. A longitudinal design could be adopted for future research, to enable making inferences about the causal nature of these relationships. The second limitation of the study is its reliance on self- reports as the single source of data.

Originality/value

This is the first study to examine job resources as antecedents of P-O fit using a supplementary fit argument. Further, very few studies have explored P-O fit as a mediating variable and less than 2 per cent of published papers on P-O fit have been studied in the Indian context. Practitioners can employ findings to create interventions to generate more positive organisational outcomes.
Dynamic capabilities of new product development teams in performing radical innovation projects
Authors: Darawong Chonlatis
Published: April 2018

Purpose

This paper aims to examine the impact of dynamic capabilities of new product development (NPD) team on project performance, including efficiency and effectiveness.

Design/methodology/approach

Data were collected from NPD team members who have worked on radical new product projects in large manufacturing firms in Thailand. Respondents represented different departments, including research and development (R&D), quality control, production and marketing. These individuals worked in a wide range of large manufacturing industries with an average of more than 500 employees. These industries include food, automotive, auto parts and electric and electronics products.

Findings

The results indicate that NPD team with sensing, learning and integrating capabilities can increase project effectiveness. In addition, teams with high learning, integrating and coordinating capabilities will enhance project efficiency.

Research limitations/implications

First, the research findings may not be generalizable in all aspects to other industries. Second, the use of cross-sectional data in this study may not be appropriate for testing causal relationships among constructs. Third, although the samples of this study were from a wide range of functional areas, the majority were R&D personnel.

Practical implications

To improve project effectiveness, project managers should consider investing in information technologies that provide a wide range of information sources, such as business research databases and academic journals. To improve project efficiency, the managers can establish both formal and informal activities during NPD projects. These social activities can provide opportunities for team members to physically meet and adjust their personal behavior to get along with each other.

Originality/value

These findings provide a wider picture of the beneficial role of dynamic capabilities of NPD teams toward project performance, including efficiency and effectiveness.
Walk Score and tourist accommodation
Authors: Ram Yael , Hall C. Michael
Published: April 2018

Purpose

The purpose of this paper is to extend the research on tourist walkability and Walk Score® by posing the question “does tourist accommodation benefit from being located in walkable places?”.

Design/methodology/approach

Using Tel Aviv municipality as a case study, the prices and number of reviews of 81 hotels and 97 Airbnb listings were associated with their corresponding Walk Score® measures.

Findings

The relationship between Walk Score and prices and number of reviews was not linear or strong. However, the most expensive accommodation and more popular hotels were below the median Walk Score of Tel Aviv.

Research limitations/implications

The findings may reflect the specific conditions associated with Tel Aviv, such as city compactness, topography and planning regulations.

Practical implications

The study suggests that accommodation is beneficial if it is located on the margins of very walkable areas. This raises regulatory and promotion issues for accommodation, and challenges for transport and tourism planners.

Originality/value

The study adds to the limited knowledge regarding tourism-related walkability, and is the first examination of links between walkability (measured by Walk Score index) and tourist accommodation (hotels and Airbnb).