bluuebunny/crossref_metadata_2025 huggingface dataset:
In Silico Modeling of Minimal Effective Insulin Doses Using the UVA/PADOVA Type 1 Diabetes Simulator
Authors: Campos-Náñez Enrique , Layne Jennifer E. , Zisser Howard C.
Published: September 2017

Background:

The objective of this study was to identify the minimum basal insulin infusion rates and bolus insulin doses that would result in clinically relevant changes in blood glucose levels in the most insulin sensitive subjects with type 1 diabetes.

Methods:

The UVA/PADOVA Type 1 Diabetes Simulator in silico population of children, adolescents, and adults was administered a basal insulin infusion rate to maintain blood glucose concentrations at 120 mg/dL (6.7 mmol/L). Two scenarios were modeled independently after 1 hour of simulated time: (1) basal insulin infusion rates in increments of 0.01 U/h were administered and (2) bolus doses in increments of 0.01 U were injected. Subjects were observed for 4 hours to determine insulin delivery required to change blood glucose by 12.5 mg/dL (0.7 mmol/L) and 25 mg/dL (1.4 mmol/L) in only 5% of the in silico population.

Results:

The basal insulin infusion rates required to change blood glucose by 12.5 mg/dL and 25 mg/dL in 5% of children, adolescents, and adults were 0.03, 0.11, and 0.10 U/h and 0.06, 0.21, and 0.19 U/h, respectively. The bolus insulin doses required to change blood glucose by the target amounts in the respective populations were 0.10, 0.28, and 0.30 U and 0.19, 0.55, and 0.60 U.

Conclusions:

In silico modeling suggests that only a very small percentage of individuals with type 1 diabetes, corresponding to children with high insulin sensitivity and low body weight, will exhibit a clinically relevant change in blood glucose with very low basal insulin rate changes or bolus doses.
Beyond ADA Accessibility Requirements: Meeting Seniors’ Needs for Toilet Transfers
Authors: Lee Su Jin , Sanford Jon , Calkins Margaret , Melgen Sarah , Endicott Sarah , Phillips Anjanette
Published: September 2017

Purpose:

To identify the optimal spatial and dimensional requirements of grab bars that support independent and assisted transfers by older adults and their care providers.

Background:

Although research has demonstrated that toilet grab bars based on the Americans with Disabilities Act (ADA) Accessibility Standards do not meet the needs of older adults, the specific dimensional requirements for alternative configurations are unknown.

Methods:

A two-phased study with older adults and care providers in residential facilities was conducted to determine the optimal requirements for grab bars. Seniors and caregivers in skilled nursing facilities performed transfers using a mock-up toilet. In Phase 1, participants evaluated three grab bar configurations to identify optimal characteristics for safety, ease of use, comfort, and helpfulness. These characteristics were then validated for using ability-matched samples in Phase 2.

Results:

The optimal configuration derived in Phase 1 included fold-down grab bars on both sides of the toilet (14" from centerline [CL] of toilet, 32" above the floor, and extended a minimum of 6" in front of the toilet) with one side open and a sidewall 24" from CL of toilet on the other. Phase 2 feedback was significantly positive for independent and one-person transfers and somewhat lower, albeit still positive, for two-person transfers.

Conclusion:

The study provides substantial evidence that bilateral grab bars are significantly more effective than those that comply with current ADA Accessibility Standards. Findings provide specific spatial and dimensional attributes for grab bar configurations that would be most effective in senior facilities.
Management of a Tibial Plafond Lung Cancer Metastasis Using an Intramedullary Hindfoot Fusion Nail
Authors: Hsu Andrew R. , Lindsay Adam D.
Published: September 2017

Metastatic disease to the tibial plafond is rare with few reports in the literature. No consensus exists regarding surgical reconstruction of large structural defects of the ankle due to these lesions, as each treatment must be tailored to the individual patient’s goals and prognosis. Cancer metastases pose a unique challenge to limb salvage as there is often bone loss and poor soft tissue quality combined with the need for postoperative adjuvant therapy. The goal of surgery is to obtain early weightbearing, pain relief, and a durable reconstruction that will outlive the patient. In this report, we present the case of an intraarticular fracture of the tibial plafond with severe bone loss due to a lung carcinoma metastasis. The patient was successfully treated with en bloc tumor excision, curettage, argon beam coagulation, tibiotalocalcaneal arthrodesis using an intramedullary hindfoot fusion nail, and bone cementation with postoperative chemotherapy and radiation. One year after surgery, the patient was able to bear full weight on the extremity without a brace or assistive device and had no pain in the ankle with no local tumor recurrence.

Levels of Evidence: Level V: Expert opinion
Comparison of Ankle Joint Visualization Between the 70° and 30° Arthroscopes: A Cadaveric Study
Authors: Tonogai Ichiro , Hayashi Fumio , Tsuruo Yoshihiro , Sairyo Koichi
Published: September 2017

Ankle arthroscopy is an important diagnostic and therapeutic tool. Arthroscopic ankle surgery for anterior ankle impingement or osteochondral lesions (OCLs) is mostly performed with a 30° arthroscope; however, visualization of lesions is sometimes difficult. This study sought to compare ankle joint visualization between 70° and 30° arthroscopes and clarify the effectiveness of 70° arthroscopy. Standard anterolateral and anteromedial portals were placed with 4-mm 70° or 30° angled arthroscopes in a fresh 77-year-old male cadaveric ankle. The medial ligament and surrounding tissue were dissected via a medial malleolar skin incision. Kirschner wires were inserted into the distal tibia anterior edge; 5-mm diameter OCLs were created on the medial talar gutter anteriorly, midway, and posteriorly. The talar dome and distal tibia anterior edge were visualized using both arthroscopes. The 70° arthroscope displayed the anterior edge of the distal tibia immediately in front of the arthroscope, allowing full visualization of the posterior OCL of the medial talar gutter more clearly than the 30° arthroscope. This study revealed better ankle joint visualization with the 70° arthroscope, and may enable accurate, safe, and complete debridement, especially in treatment of medial talar gutter posterior OCLs and removal of anterior distal tibial edge bony impediments.

Levels of evidence: Level IV, Anatomic study
Three Decades of Antillean Manatee (Trichechus manatus manatus) Stranding Along the Brazilian Coast
Authors: Balensiefer Deisi Cristiane , Attademo Fernanda Loffler Niemeyer , Sousa Gláucia Pereira , Freire Augusto Carlos da Bôaviagem , da Cunha Fábio Adônis Gouveia Carneiro , Alencar Ana Emília Barboza , Silva Flávio José de Lima , Luna Fábia de Oliveira
Published: September 2017

Alive Antillean manatee stranding is one of the main challenges for the conservation of the species in Brazil. In the present study, data on Antillean manatee stranding recorded by the CMA/ICMBio’s Wild Animals Rehabilitation Center from 1987 to 2015 were analyzed. The CMA and the REMANE’s (Northeastern Aquatic Mammal Stranding Network’s) institutions have rescued on average five Antillean manatees per year. Approximately 56% of the animals were alive when rescued, and 43.7% were found dead. The states of Ceará and Rio Grande do Norte have the highest records of stranding, rescue, and assistance of alive calves. Stranding of alive specimens is more frequent during the austral summer, especially in January, February, and March. In the North region, the main threat to the Antillean manatee population seems to be interaction with fishing activities. Studies on the causes of dependent calf stranding in northeast Brazil are urgently needed to promote the development of public policies for the conservation of the species. Brazil’s manatee rehabilitation centers must undergo improvements to better assist stranded calves, which need special care to survive.
Gastrointestinal Prophylaxis in Sports Medicine
Authors: Patel Akash R. , Oheb Daniel , Zaslow Tracy L.
Published: September 2017

Context:

Because sports participation at all levels often requires international travel, coaches, athletic trainers, and team physicians must effectively protect athletes from gastrointestinal infections. Traveler’s diarrhea is the most common travel-related illness and can significantly interfere with training and performance.

Evidence Acquisition:

A review of relevant publications was completed using PubMed and Google Scholar.

Study Design:

Clinical review.

Level of Evidence:

Level 5

Results:

Enterotoxigenic and enteroaggregative Escherichia coli are the most common bacterial causes of traveler’s diarrhea. Traveler’s diarrhea generally occurs within 4 days of arrival, and symptoms tend to resolve within 5 days of onset. There are several prophylactic agents that physicians can recommend to athletes, including antibiotics, bismuth subsalicylate, and probiotics; however, each has its own unique limitations. Decision-making should be based on the athlete’s destination, length of stay, and intent of travel.

Conclusion:

Prophylaxis with antibiotics is highly effective; however, physicians should be hesitant to prescribe medication due to the side effects and risks for creating antibiotic-resistant bacterial strains. Antibiotics may be indicated for high-risk groups, such as those with a baseline disease or travelers who have little flexible time. Since most cases of traveler’s diarrhea are caused by food and/or water contamination, all athletes should be educated on the appropriate food and water consumption safety measures prior to travel.
Learning in the age of algorithmic cultures
Authors: Jandrić Petar , Knox Jeremy , Macleod Hamish , Sinclair Christine
Published: September 2017

This Editorial describes the main challenges at the intersections between algorithmic cultures and human learning. It briefly analyses papers in this Special Issue of E-learning and Digital Media ‘Learning in the age of algorithmic cultures’ and shows that researchers in the field are still struggling with grand ideas and questions. It suggests that studies of algorithms and learning are in their infancy and emphasizes that they carry potentials to confirm our existing ideas and surprise us with fresh insights.
Social construction and social critique: Haslanger, race, and the study of religion
Authors: Lynch Thomas
Published: September 2017

Recent critiques of the category religion discuss the category as socially constructed, but the nature of this social construction remains underdeveloped. The work of Sally Haslanger can supplement existing discussions of “religion” while also offering a new perspective on the connection between social construction and social critique. Her analysis of race provides resources for developing a philosophical account of the social construction of religion and can help scholars of religion conceptualize racialized religious identities. I offer an example of this approach by using Haslanger’s work on race to consider historical and contemporary intersections of race and Muslim identity. I conclude that the ongoing ideological work of “religion” means that the concept remains an analytically useful term, but that scholars should aim at the gradual abolition of “religion.”
Gastrointestinal endoscopy under sedation is associated with pneumonia in older inpatients—results of a retrospective case-control study
Authors: Kollmann Christopher M , Schmiegel Wolff , Brechmann Thorsten
Published: September 2017

Background and aims

Apparent aspiration is a notable adverse event during gastrointestinal endoscopy under sedation (GIES), but data about inapparent aspiration are scarce. Generally, particularly older patients are at higher risk of suffering from adverse events.

Objective

The objective of this article is to determine the risk of pneumonia, lower respiratory tract infection (LRI) and systemic inflammatory activation after GIES, especially in patients of at least 65 years.

Methods

The retrospective case-control study included 250 patients undergoing GIES and assigned age-, gender- and time of performance-matched controls without invasive procedure or sedation (ratio 1:1).

Results

On day 3 patients of advanced age presented with both pneumonia and LRI more often (2.6 vs. 0.0%, p = 0.041 and 7.8 vs. 2.5%, p = 0.034, respectively). In general, several inflammatory parameters increased significantly after GIES (i.e. white blood cell count (increase of ≥ 25%) 18.6 vs. 6.9%, p < 0.001), leading to more frequent antibiotic treatment (6.8 vs. 1.6%, p = 0.004). The effects were less pronounced on day 7.

Conclusions

Patients of advanced age carry an increased risk of pneumonia and LRI after GIES. Patients are generally more likely to feature inflammation and to receive antibiotic treatment.
Are emergency department clinical pathway interventions adequately described, and are they delivered as intended? A systematic review
Authors: Adjemian Raffi , Moradi Zirkohi Atbin , Coombs Robin , Mickan Sharon , Vaillancourt Christian
Published: September 2017

Introduction

The accurate reproduction of clinical interventions and the evaluation of provider adherence in research publications improve the evaluation and implementation of research findings into clinical practice. We sought to examine the proportion of clinical pathway publications in an emergency department setting that adequately reported the following: (1) the exact reproduction of the clinical pathway that was implemented in the study, (2) the adherence to and correct execution of the clinical pathway intervention, and (3) the presence of a pre-implementation education phase.

Methods

We performed a descriptive systematic review of the literature from 2006 to 2015 using MEDLINE, EMBASE, CENTRAL, and CINAHL. All types of prospective trial designs were eligible. Validated clinical pathway criteria were used to identify relevant publications. Two reviewers independently collected data using a piloted data abstraction tool. Risk of bias was assessed using the Cochrane Effective Practice and Organization of Care Group Risk of Bias Tool and the Newcastle-Ottawa Scale.

Results

We identified 5947 publications, 44 of which met our inclusion criteria. The formal clinical pathway was fully reproduced in 27 (61%) publications, partially reproduced in 9 (21%), and not reproduced in 8 (18%). Only 14 (32%) studies reported whether at least one decision step was executed correctly. The presence of a pre-implementation education phase was reported in 33 (75%) studies.

Conclusion

The underreporting of intervention elements may present a barrier to both the evaluation and accurate replication of clinical pathway interventions. These finding may be useful for the elaboration of complex intervention reporting guidelines, improved reporting in future clinical pathway publications, and improved knowledge translation and exchange of clinical pathway interventions.
A comparison of multiple sclerosis disease activity after discontinuation of fingolimod and placebo
Authors: Vermersch Patrick , Radue Ernst-Wilhelm , Putzki Norman , Ritter Shannon , Merschhemke Martin , Freedman Mark S
Published: September 2017

Background

Cases of higher-than-expected disease activity have been reported following fingolimod discontinuation.

Objective

The objective of this paper is to assess the risk of substantially higher-than-expected disease activity post-study drug discontinuation (SDD) at the individual patient level using data from the Phase III, placebo-controlled FREEDOMS and FREEDOMS II trials.

Methods

Baseline gadolinium-enhancing T1-lesion volumes were used to statistically model the expected level of MRI disease activity post-SDD. Patients exceeding this level were classed as “MRI outliers.” Patients with an unusually high increase in Expanded Disability Status Scale score, hospitalization for relapse, severe relapse, or relapse with incomplete recovery post-SDD were classed as “clinical outliers.”

Results

In FREEDOMS, the number of MRI outliers post-SDD was 2/69 (2.9%), 1/65 (1.5%) and 7/83 (8.4%) for the placebo, fingolimod 0.5 mg, and fingolimod 1.25 mg groups, respectively. In FREEDOMS II, the corresponding numbers were 4/72 (5.6%), 6/79 (7.6%) and 3/73 (4.1%). The number of clinical outliers across both trials was low. No consistent evidence of placebo vs fingolimod, dose-related or inter-trial patterns was discernable.

Conclusion

The low number of clinical and MRI outliers and lack of any discernible pattern within and between trials, including between placebo and fingolimod, argues against a systematic risk of higher-than-expected recurrence of disease activity following discontinuation of fingolimod.
How to train radiology residents to diagnose pulmonary embolism using a dedicated MRI protocol
Authors: Nordgren Rogberg Anna , Nyrén Sven , Westerlund Eli , Lindholm Peter
Published: September 2017

Background

In recent years, magnetic resonance imaging (MRI) has been suggested as an alternative to computed tomography angiography (CTA) to diagnose pulmonary embolism (PE). In previous studies, only senior radiologists have been evaluated as reviewers.

Purpose

To investigate if radiology residents can be trained to review MRI regarding PE and to determine the learning curve effects.

Material and Methods

Four residents independently went through a training program consisting of 70 participants that had undergone steady-state free precession MRI. The individuals were randomized into ten training sessions. For each exam, the review time and presence or absence of embolus was recorded. After completing each session, the residents received feedback on diagnostic accuracy compared to a consensus reading by two specialists. The residents were also presented with the corresponding CTA.

Results

The review time was nearly halved ( P = 0.0002) during the training program. Comparing the first three sessions with the last three sessions for all residents, the review time decreased from 5:22 min to 2:51 min. The inter-reader agreement improved for all residents during the training program reaching a clinically acceptable level after seven sessions.

Conclusion

Our study suggests that radiology residents can be trained to independently review MRI investigations regarding PE within a short training program. Similar training programs could be more extensively used as effective teaching method for residents.
The optimal protocol to reduce blood loss and blood transfusion after unilateral total knee replacement: Low-dose IA-TXA plus 30-min drain clamping versus drainage clamping for the first 3 h without IA-TXA
Authors: Park Joo Hyun , Choi Sung Wook , Shin Eun Ho , Park Myung Hoon , Kim Myung Ku
Published: September 2017

Introduction:

Although intraarticular tranexamic acid (IA-TXA) administration or drainage clamping are popular methods used to reduce blood loss after total knee replacement (TKR), the protocol remains controversial. We aimed (1) to establish new protocols through investigating whether two methods, that is, low-dose (500 mg) IA-TXA plus 30-min drain clamping and drainage clamping for the first 3 h without IA-TXA, can reduce blood loss and blood transfusion after unilateral TKR and (2) to make recommendations related to clinical application.

Materials and Methods:

This study, conducted from September 2014 to June 2016 related to enrolled 95 patients with primary osteoarthritis who were to have a unilateral cemented TKR, was nonrandomized and retrospective. In group A, the drain was released following tourniquet deflation. In group B, 500-mg TXA was injected into the knee joint via a drain tube after fascia closure and the drain was clamped for the first 30 min to prevent leakage. In group C, the drain was clamped for the first 3-h postoperation. Demographic characteristics and clinical data were collected, including the levels of hematocrit (Hct), the total blood loss (TBL), drained blood volume (BV), the amount of blood transfused, and any complications that developed.

Results:

We found a significantly lower postoperative TBL, drained BV, decreasing Hct level, and less transfused BV in the IA-TXA injection group (group B) and the 3-h drainage clamping group (group C) compared to the conventional negative drainage group (group A; p < 0.001). There was no significant difference between groups B and C ( p = 0.99).

Conclusions:

The drainage clamping method can be safer than IA-TXA administration in patients with risk factor of venous thromboembolic complication. Furthermore, the IA-TXA administration can be more optimal than drainage clamping in patients with high bleeding tendency or lateral retinacular release during TKR, who would be concerned about postoperative wound complication.
TG02 inhibits proteasome inhibitor–induced HSF1 serine 326 phosphorylation and heat shock response in multiple myeloma
Authors: Shah Shardule P. , Nooka Ajay K. , Lonial Sagar , Boise Lawrence H.
Published: September 2017

Key Points

Proteasome inhibition activates multiple kinases in myeloma cells resulting in the phosphorylation of p53, HSP27, c-JUN, and HSF1. TG02 inhibits proteasome inhibitor (PI)–induced HSF1 pS326, representing a novel mechanism for a TG02 and PI combination.
Differential T cell homing to colon vs. small intestine is imprinted by local CD11c+ APCs that determine homing receptors
Authors: Dzutsev Amiran , Hogg Alison , Sui Yongjun , Solaymani-Mohammadi Shahram , Yu Huifeng , Frey Blake , Wang Yichuan , Berzofsky Jay A
Published: September 2017

Mechanisms that imprint T cell homing to the small intestine have been well studied; however, those for homing to the colon are poorly understood. Recently, we found that these are distinct subcompartments of the gut mucosal immune system, which implies differential homing. Here, we show that colonic CD11c+ APCs imprint CD8+ T cell preferential homing to the colon, in contrast to those from the small intestine that imprint CD8+ T cell homing to the small intestine, and that the differences are related to the variable ability of APCs to induce α4β7-integrin and CCR9 expression on T cells. Colon APCs also expressed lower levels of retinoic acid–producing enzymes that are known to control the mucosal homing of T cells. These findings are the first to our knowledge to directly demonstrate that colon APCs imprint T cells to selectively home to the large bowel, which is critical for the design of successful T cell–based therapies and vaccines, such as colon cancer immunotherapy and HIV vaccines.
Potential contribution of tumor-associated slan+ cells as anti-CSF-1R targets in human carcinoma
Authors: Lonardi Silvia , Licini Sara , Micheletti Alessandra , Finotti Giulia , Vermi William , Cassatella Marco A
Published: September 2017

The precise identification of the types and respective roles of the tumor-associated myeloid cells, which include tumor-associated Mϕs (TAMs), neutrophils, dendritic cells, and myeloid-derived suppressor cells, is under intensive investigation. Although tumor-associated myeloid cells may contribute to tumor cell eradication by virtue of their effector functions, they are retained to fulfill predominantly protumorigenic roles. It follows that depletion of tumor-associated myeloid cells represents one of the currently pursued therapeutic options in advanced malignancies. In that regard, RG7155/emactuzumab, a specific anti-CSF-1R humanized Ab, has been reported recently to deplete CSF-1R+ TAMs, in association with objective clinical responses in patients with advanced cancer. Because RG7155/emactuzumab has also been shown to deplete blood non-classic CD14dim/−CD16++ monocytes, which in large part include the CD16++slan+ monocytes, we asked whether RG7155/emactuzumab could target tumor-associated slan+ cells. In this study, we confirmed that slan+ cells localize only to metastatic tumor-draining lymph nodes, not to primary tumors or distant metastases in patients with different types of carcinoma. Notably, by cell scoring on serial sections, we found that slan+ cells represent a minor fraction of the total CSF-1R+ cell pool, suggesting that slan+ cells potentially represent minor targets of anti-CSF-1R therapy. Therefore, a protumorigenic role for slan+ cells, such as that of CSF-1R+TAMs, based on our current data, remains questionable.
Hematopoietic MyD88 and IL-18 are essential for IFN-γ–dependent restriction of type A Francisella tularensis infection
Authors: Skyberg Jerod A , Lacey Carolyn A
Published: September 2017

Francisella tularensis is a highly infectious intracellular bacterium that causes the potentially fatal disease tularemia. We used mice with conditional MyD88 deficiencies to investigate cellular and molecular mechanisms by which MyD88 restricts type A F. tularensis infection. F. tularensis–induced weight loss was predominately dependent on MyD88 signaling in nonhematopoietic cells. In contrast, MyD88 signaling in hematopoietic cells, but not in myeloid and dendritic cells, was essential for control of F. tularensis infection in tissue. Myeloid and dendritic cell MyD88 deficiency also did not markedly impair cytokine production during infection. Although the production of IL-12 or -18 was not significantly reduced in hematopoietic MyD88-deficient mice, IFN-γ production was abolished in these animals. In addition, neutralization studies revealed that control of F. tularensis infection mediated by hematopoietic MyD88 was entirely dependent on IFN-γ. Although IL-18 production was not significantly affected by MyD88 deficiency, IL-18 was essential for IFN-γ production and restricted bacterial replication in an IFN-γ–dependent manner. Caspase-1 was also found to be partially necessary for the production of IL-18 and IFN-γ and for control of F. tularensis replication. Our collective data show that the response of leukocytes to caspase-1–dependent IL-18 via MyD88 is critical, whereas MyD88 signaling in myeloid and dendritic cells is dispensable for IFN-γ–dependent control of type A F. tularensis infection.
Lamina propria group 2 innate lymphoid cells impair the antibacterial defense of burned mice to enterococcal translocation
Authors: Ito Ichiaki , Bhopale Kamlesh K , Kobayashi Makiko , Finnerty Celeste C , Herndon David N , Suzuki Fujio
Published: September 2017

Gut microbiota that invades to the defective mucosal barrier is one of the major sources of infectious complications in severely burned hosts. In this study, a role of group 2 innate lymphoid cells (ILC2) and effects of N-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}-2-thiophenesulfonamide (SR3335) on the host antibacterial resistance against infectious complications caused by Enterococcus faecalis oral infection were investigated in burned mice. Retinoic acid receptor-related orphan receptor α (RORα) is a transcription factor required for the development of ILC2, and SR3335 is an RORα-selective inverse agonist. All of burned mice died within 6 d of E. faecalis infection (5 × 106 CFU/mouse), whereas 100% of the same mice treated with SR3335 survived. The increased ILC2 and their cytokine products (IL-5 and IL-13) were detected in the lamina propria of mice, 1–7 d after burn injury. However, the number of ILC2 did not increase in the lamina propria of burned mice treated with SR3335. The antibacterial resistance of SCID-beige (SCIDbg) mice to E. faecalis infection was impaired by the inoculation of ILC2. BALB/c, SCIDbg, and polymorphonuclear leukocyte (PMN)-depleted SCIDbg mice were shown to be resistant against E. faecalis infection. However, all Mϕ depleted SCIDbg mice died after the infection. These results indicate that host antibacterial effector Mϕ against enterococcal translocation are influenced by ILC2, increased in the bacterial translocation site of burned mice, and sepsis stemming from E. faecalis oral infection was amazingly mitigated in these mice after treatment with SR3335, an inhibitor of cellular differentiation from an ILC precursor (ILCP) to ILC2.
Metabolic energy sensors as targets for designing host-directed therapies for tuberculosis
Authors: Cheng Catherine Y , Böhme Julia , Singhal Amit
Published: September 2017

A wealth of scientific and clinical evidence during the past few years has lent credence to the idea that key components of the host immune effector mechanisms can be targeted to boost current tuberculosis (TB) treatment and control patient relapse. These host-directed strategies not only accelerate the clearance of pathogens but also have the ability to limit overt inflammation and pathology, which are associated with the tissue damage. Studies have indicated that inflammatory responses are intrinsically linked to cellular metabolism and together drive the fate of many host responses, coupling host survival with the capacity to respond to infectious insult. Metabolic sensors such as mammalian target of rapamycin, AMP-activated protein kinase, and sirtuin 1 are central regulators of host metabolic alterations and play important roles in immune responses against infections. The present review discusses the functions of AMP-activated protein kinase and sirtuin 1, with a focus on their role in immune homeostasis and how manipulating the AMP-activated protein kinase–sirtuin 1 axis with drugs can modulate immunity to tuberculosis.
Group A streptococcal pharyngitis: Immune responses involved in bacterial clearance and GAS-associated immunopathologies
Authors: Soderholm Amelia T , Barnett Timothy C , Sweet Matthew J , Walker Mark J
Published: September 2017

Streptococcus pyogenes, the Group A Streptococcus (GAS), is the most common cause of bacterial pharyngitis in children and adults. Innate and adaptive host immune responses are fundamental for defense against streptococcal pharyngitis and are central to the clinical manifestation of disease. Host immune responses also contribute to the severe poststreptococcal immune diseases that constitute the major disease burden for this organism. However, until recently, little was known about the host responses elicited during infection. Cellular mediators of innate immunity used during host defense against GAS include epithelial cells, neutrophils, macrophages, and dendritic cells (DCs), which are reported to secrete a number of soluble inflammatory mediators, such as antimicrobial peptides (AMPs); eicosanoids, including PGE2 and leukotriene B4 (LTB4); chemokines; and proinflammatory cytokines. Th1 and Th17 responses play significant roles in adaptive immunity in both murine models of GAS pharyngitis and in human tonsil tissue. A number of inflammatory complications are associated with GAS pharyngitis, which can lead to chronic disease in patients. These include scarlet fever, tonsillar hypertrophy, and sleep apnea, as well as postinfectious sequelae, such as acute rheumatic fever (ARF), poststreptococcal glomerulonephritis, and guttate psoriasis (GP). This review aims to present the current state of knowledge on innate and adaptive immune responses elicited during GAS pharyngitis, mechanisms by which GAS evades these responses, the emerging role of the pharyngeal microbiota, and how the interplay among these factors can influence the outcome of infection and inflammation-related complications.
Differentiation stage-specific effect of histone deacetylase inhibitors on the expression of RORγT in human lymphocytes
Authors: Sałkowska Anna , Karaś Kaja , Walczak-Drzewiecka Aurelia , Dastych Jarosław , Ratajewski Marcin
Published: September 2017

The role of epigenetic mechanisms in the regulation of the human RORγT gene, which encodes a Th17 lymphocyte signature transcription factor, remains largely unknown. We investigated the effect of histone deacetylase (HDAC) inhibition on RORγT and RORγT-dependent gene expression in human T lymphocytes. We found that, in Jurkat T cells and in in vitro–differentiated Th17 cells, treatment with 2 HDAC inhibitors, butyrate and apicidin, led to the induction of the RORγT gene, which was associated with an increase in histone H4 acetylation near the RORγT proximal promoter. In contrast, when the same inhibitors were added to naive CD4+ cells differentiating in vitro to Th17 cells, they mediated the down-regulation of RORγT expression. In conclusion, HDAC inhibitor-mediated H4 acetylation is involved in the epigenetic regulation of RORγT expression in Th17 cells. However, that epigenetic mechanism was observed only at a specific stage of T cell differentiation, suggesting a complex interaction with additional mechanisms that sequentially regulate RORγT expression. These observations may be relevant to the development of applications for HDAC inhibitors for diseases in which Th17 cells have a role in pathogenic mechanisms, such as some types of cancer or autoimmunologic disorders, to prevent unwanted side effects.
Geochemical sedimentary evidence from core 973-2 for methane activity near the Jiulong Methane Reef in the northern South China Sea
Authors: Pan Mengdi , Wu Daidai , Yang Fei , Sun Tiantian , Wu Nengyou , Liu Lihua
Published: September 2017

The Jiulong Methane Reef, located on the northern slope of the South China Sea, is characterized by several features, such as bottom-simulating reflections and authigenic carbonates, which are indicative of methane seeps that are currently occurring as well as those that occurred in the past. However, to date, the effect that these methane seeps have on the sedimentary environment is not completely clear. To provide further insights into the biogeochemical processes involved in methane seeps, a 6.73 m piston core (973-2) was retrieved from this area in 2011 to perform an in-depth analysis. The chronology of the core has been established by [Formula: see text] dating, and sedimentary events since the last glacial period have been recorded. The results indicate abnormally low abundance and diversity, as well as high infaunal percentages of benthic foraminiferal assemblages in the lower part of the core from 673 to 350 centimeters below the sea floor (cmbsf), indicating impacts from methane activities. Major elemental barium, bromine, and titanium, which serve as proxies of the paleoproductivity, organic contents, and terrestrial supply, respectively, are found to make little contribution in [Formula: see text] content. However, regardless of the factors mentioned above, the [Formula: see text] content is still higher in the lower part of core, indicating the presence of authigenic carbonates. In addition, the total organic carbon/total sulfur ratios of less than 400 cmbsf are found to be beyond the normal range, which is [Formula: see text], reflecting the effects of methane oxidation. In one of the sections, the trace metals and molybdenum profiles show enrichments that are closely related to those of the methane seeps. The results indicate that this area experienced methane seep events in the last glacial period.
Fat–Bone Interactions in Adults With Spina Bifida
Authors: Trinh Anne , Wong Phillip , Sakthivel Anuradha , Fahey Michael C , Hennel Sabine , Brown Justin , Strauss Boyd J , Ebeling Peter R , Fuller Peter J , Milat Frances
Published: September 2017

Context

Spina bifida (SB) can lead to changes in body composition and bone mineral density (BMD) through diminished ambulation, renal impairment, and anticonvulsant medication. With increased life expectancy, diseases such as obesity and osteoporosis are emerging comorbidities in SB, with limited data to guide management.

Objective

To examine the relationship between cardiometabolic factors, body composition, BMD, and minimal trauma fractures (MTFs) in adults with SB.

Design

Retrospective cross-sectional study.

Setting and Participants

Forty-nine adults with SB (median age, 32.7 years; interquartile range, 22.6 to 39.0) who had undergone dual-energy x-ray absorptiometry imaging at a single tertiary hospital from 2004 to 2015.

Results

The mean body mass index was 31.7 ± 7.5 kg/m2; 26 (53.1%) were obese. Using age- and sex-matched fat percentiles from the National Health and Nutrition Examination Survey III, 62.5% had a total body percentage fat greater than the 95th percentile. Low bone mass (defined as a Z-score of ≤−2.0) was present in 21.9% at the L1 vertebra and in 35.1% at the femoral neck. Ten (20.4%) had a history of MTFs. A BMD or Z-score at L1, femoral neck, or total body site did not correlate with the occurrence of MTF. Fat mass was significantly and positively associated with BMD after adjustment for age, sex, and height and accounted for 18.6% of the variance in BMD (P = 0.005). The prevalence of metabolic comorbidities, such as hypertension (20.4%) and obstructive sleep apnea (16.3%), was high.

Conclusions

Obesity and low BMD are common in young adults with SB. An increased fat mass correlated significantly with BMD. The prevalence of metabolic complications in patients with SB is increased and deserves further study.
The Effect of Zinc Lozenge on Postoperative Sore Throat: A Prospective Randomized, Double-Blinded, Placebo-Controlled Study
Authors: Farhang Borzoo , Grondin Lydia
Published: September 2017

BACKGROUND:

Postoperative sore throat (POST) is commonly seen after endotracheal intubation, and oral zinc prevents oral mucositis associated with chemotherapy. This study is designed to evaluate the effects of administration of zinc lozenges on POST.

METHODS:

Seventy-nine patients undergoing low- or moderate-risk surgery with endotracheal intubation were randomly assigned into 2 groups: Control group received placebo and zinc group received 40-mg zinc lozenges 30 minutes preoperatively. Patients were assessed for incidence and severity (4-point scale, 0–3) of POST at 0, 2, 4, and 24 hours postoperatively. The primary outcome was incidence of POST at 4 hours after surgery. The secondary outcomes were the incidence of POST at 0, 2, and 24 hours and the severity of POST.

RESULTS:

At 4 hours, there was a significantly lower incidence of POST in the zinc group, 7%, than the control group, 29% (P = .046). The incidence of POST at 0 hour was 0% in zinc group and 24% in control group (P = .004). The highest incidence of POST occurred at the second hour after surgery, with the rate of 10% in the zinc group and 34% in the control group (P = .0495). The incidence of POST at 24 hours was 13% in zinc group and 24% in control group (not significant). The severity of POST was significantly lower in the zinc group for mild (P = .003) and moderate (P = .004) POST.

CONCLUSIONS:

The administration of a single dose of 40-mg zinc lozenge 30 minutes preoperatively is effective to reduce both incidence of POST in the first 4 hours and severity of mild and moderate POST in the immediate postoperative period.
The Effect of Prophylactic Phenylephrine and Ephedrine Infusions on Umbilical Artery Blood pH in Women With Preeclampsia Undergoing Cesarean Delivery With Spinal Anesthesia: A Randomized, Double-Blind Trial
Authors: Higgins Nicole , Fitzgerald Paul C. , van Dyk Dominique , Dyer Robert A. , Rodriguez Natalie , McCarthy Robert J. , Wong Cynthia A.
Published: September 2017

BACKGROUND:

Spinal anesthesia for cesarean delivery is associated with a high incidence of hypotension. Phenylephrine results in higher umbilical artery pH than ephedrine when used to prevent or treat hypotension in healthy women. We hypothesized that phenylephrine compared to ephedrine would result in higher umbilical artery pH in women with preeclampsia undergoing cesarean delivery with spinal anesthesia.

METHODS:

This study was a randomized double-blind clinical trial. Nonlaboring women with preeclampsia scheduled for cesarean delivery with spinal anesthesia at Prentice Women’s Hospital of Northwestern Medicine were randomized to receive prophylactic infusions of phenylephrine or ephedrine titrated to maintain systolic blood pressure >80% of baseline. Spinal anesthesia consisted of hyperbaric 0.75% bupivacaine 12 mg, fentanyl 15 µg, and morphine 150 µg. The primary outcome was umbilical arterial blood pH and the secondary outcome was umbilical artery base excess.

RESULTS:

One hundred ten women were enrolled in the study and 54 per group were included in the analysis. There were 74 and 72 infants delivered in the ephedrine and phenylephrine groups, respectively. The phenylephrine:ephedrine ratio for umbilical artery pH was 1.002 (95% confidence interval [CI], 0.997–1.007). Mean [standard deviation] umbilical artery pH was not different between the ephedrine 7.20 [0.10] and phenylephrine 7.22 [0.07] groups (mean difference −0.02, 95% CI of the difference −0.06 to 0.07; P = .38). Median (first, third quartiles) umbilical artery base excess was −3.4 mEq/L (−5.7 to −2.0 mEq/L) in the ephedrine group and −2.8 mEq/L (−4.6 to −2.2mEq/L) in the phenylephrine group (difference −0.6 mEq/L, 95% CI of the difference −1.6 to 0.3 mEq/L; P = .10). When adjusted for gestational age and infant gender, umbilical artery pH did not differ between groups. There were also no differences in the umbilical artery pH stratified by magnesium therapy or by the severity of preeclampsia.

CONCLUSIONS:

We were unable to demonstrate a beneficial effect of phenylephrine on umbilical artery pH compared with ephedrine. Our findings suggest that phenylephrine may not have a clinically important advantage compared with ephedrine with regard to improved neonatal acid-base status when used to prevent spinal anesthesia–induced hypotension in women with preeclampsia undergoing cesarean delivery.
Anteroposterior polarity and elongation in the absence of extraembryonic tissues and spatially localised signalling in Gastruloids, mammalian embryonic organoids
Authors: Turner D. A. , Girgin M. , Alonso-Crisostomo L. , Trivedi V. , Baillie-Johnson P. , Glodowski C. R. , Hayward P. C. , Collignon J. , Gustavsen C. , Serup P. , Steventon B. , Lutolf M. , Martinez Arias A.
Published: September 2017

The establishment of the anteroposterior (AP) axis is a critical step during animal embryo development. In mammals, genetic studies have shown that this process relies on signals spatiotemporally deployed in the extraembryonic tissues that locate the position of the head and the onset of gastrulation, marked by T/Brachyury (T/Bra) at the posterior of the embryo. Here, we use Gastruloids, mESC-based organoids, as a model system to study this process. We find that Gastruloids localise T/Bra expression to one end and undergo elongation similar to the posterior region of the embryo suggesting that they develop an AP axis. This process relies on precisely timed interactions between Wnt/β-Catenin and Nodal signalling, whereas BMP signalling is dispensable. Additionally, polarised T/Bra expression occurs in the absence of extraembryonic tissues or localised sources of signals. We suggest that the role of extraembryonic tissues in the mammalian embryo might not be to induce the axes but to bias an intrinsic ability of the embryo to initially break symmetry. Furthermore, we suggest that Wnt signalling has a separable activity involved in the elongation of the axis.
The Substitution Elasticity, Factor Shares, and the Low-Frequency Panel Model
Authors: Chirinko Robert S. , Mallick Debdulal
Published: September 2017

The value of the elasticity of substitution between labor and capital (σ) is a crucial assumption in understanding the secular decline in the labor share of income. This paper develops and implements a new strategy for estimating this crucial parameter by combining a low-pass filter with panel data to identify the low-frequency/long-run relations appropriate to production function estimation. Standard estimation methods, which do not filter out transitory variation, generate downwardly biased estimates of 40 percent to 70 percent relative to the benchmark value. Despite correcting for this bias, our preferred estimate of 0.40 is substantially below the Cobb-Douglas assumption of σ = 1. (JEL C51, E22, E24, E25, O41)
Why Don’t Households Smooth Consumption? Evidence from a $25 Million Experiment
Authors: Parker Jonathan A.
Published: September 2017

This paper evaluates theoretical explanations for the propensity of households to increase spending in response to the arrival of predictable, lump-sum payments, using households in the Nielsen Consumer Panel who received $25 million in randomly distributed stimulus payments. The pattern of spending is inconsistent with models in which identical households cycle rapidly through high and low- response states as they manage liquidity, but is instead highly predictable by income years before the payment. Spending responses are unrelated to expectation errors, almost unrelated to crude measures of procrastination and self-control, significantly related to sophistication and planning, and highly related to impatience. (JEL D12, D14, D91, E21, H23)
Structure and RNA recognition of ribosome assembly factor Utp30
Authors: Hu Jianfei , Zhu Xing , Ye Keqiong
Published: September 2017

The 90S preribosomes are gigantic early assembly intermediates of small ribosomal subunits. Cryo-EM structures of 90S were recently determined, but many of its components have not been accurately modeled. Here we determine the crystal structure of yeast Utp30, a ribosomal L1 domain-containing protein in 90S, at 2.65 Å resolution, revealing a classic two-domain fold. The structure of Utp30 fits well into the cryo-EM density of 90S, confirming its previously assigned location. Utp30 binds to the rearranged helix 41 of 18S rRNA and helix 4 of 5′ external transcribed spacer in 90S. Comparison of RNA-binding modes of different L1 domains illustrates that they consistently recognize a short RNA duplex with the concaved surface of domain I, but are versatile in RNA recognition outside the core interface. Cic1 is a paralog of Utp30 associating with large subunit preribosomes. Utp30 and Cic1 share similar RNA-binding modes, suggesting that their distinct functions may be executed by a single protein in other organisms. Deletion of Utp30 does not affect the composition of 90S. The nonessential role of Utp30 could be ascribed to its peripheral localization and redundant interactions in 90S.
Recent advances in the management of peptic ulcer bleeding
Authors: Beales Ian
Published: September 2017

Acute upper gastrointestinal haemorrhage due to peptic ulcer bleeding remains an important cause of emergency presentation and hospital admission. Despite advances in many aspects of management, peptic ulcer bleeding is still associated with significant morbidity, mortality, and healthcare costs. Comprehensive international guidelines have been published, but advances as well as controversies continue to evolve. Important recent advances include the evidence supporting a more restrictive transfusion strategy aiming for a target haemoglobin of 70–90 g/l. Comparative studies have confirmed that the Glasgow–Blatchford score remains the most useful score for predicting the need for intervention as well as for identifying the lowest-risk patients suitable for outpatient management. New scores, including the AIMS65 and Progetto Nazionale Emorragia Digestiva score, may be more accurate in predicting mortality. Pre-endoscopy erythromycin appears to improve outcomes and is probably underused. High-dose oral proton pump inhibition (PPI) for 11 days after PPI infusion is advantageous in those with a Rockall score of 6 or more. Oral is as effective as parenteral iron at restoring haemoglobin levels after a peptic ulcer bleed and both are superior to placebo in this respect. Within endoscopic techniques, haemostatic powders and over-the-scope clips can be used when other methods have failed. A disposable Doppler probe appears to provide more accurate determination of both rebleeding risk and the success of endoscopic therapy than purely visual guidance. Non-Helicobacter pylori, non-aspirin/non-steroidal anti-inflammatory drug ulcers contribute an increasing percentage of bleeding peptic ulcers and are associated with a poor prognosis and high rebleeding rate. The optimal management of these ulcers remains to be determined.