bluuebunny/crossref_metadata_2025 huggingface dataset:
Structural basis for regiospecific midazolam oxidation by human cytochrome P450 3A4
Authors: Sevrioukova Irina F. , Poulos Thomas L.
Published: December 2016

Significance

Human cytochromes P450 (CYPs) play a leading role in detoxication by metabolizing drugs and other foreign compounds. CYP3A4 is the most important CYP because it oxidizes the majority of administered therapeutics and is implicated in drug–drug interactions, drug toxicity, and other adverse effects. To date, little is known about how CYP3A4 adjusts and reshapes the active site to accommodate and regioselectively oxidize a wide variety of compounds. The CYP3A4–midazolam cocrystal structure reveals a profound structural reorganization triggered by the substrate, which was anticipated but never before observed, which helps us better understand and explain experimental results and, by representing a conformational snapshot, could be used for computer modeling and molecular dynamics simulations to improve the outcomes for drug metabolism predictions.
Does women's employment enhance women's citizenship?
Authors: Jensen Per H. , Møberg Rasmus Juul
Published: December 2016

The EU discourse on increasing female employment holds promise. The integration of women into the labour market supposedly supports economic growth, social cohesion, and citizenship. The question is, however, whether the expected consequences of female employment are consistent with reality. Using the EU discourse as a point of departure, this paper scrutinises the effects of female employment from a citizenship perspective in three European cities: Aalborg (Denmark), Leeds (England), and Bologna (Italy). Using survey data collected in the three cities, it quantitatively analyses whether employment counteracts poverty, supports social and political participation, and increases social trust. It also analyses whether there are spill-over effects from the different dimensions of citizenship; that is, whether poverty leads to social isolation, political apathy, and low levels of social trust. We find that unemployment is important for citizenship but that the differences between employed women and women outside the labour force are rather limited. We also find that the effect of a woman's position in the vertical and horizontal division of labour is rather limited, and no spill-over effects from economic hardship on other dimensions of citizenship exist. What matters for citizenship are personal and family characteristics as well as the city of residence.
Sexual pheromone modulates the frequency of cytosolic Ca2+bursts inSaccharomyces cerevisiae
Authors: Carbó Natalia , Tarkowski Nahuel , Ipiña Emiliano Perez , Dawson Silvina Ponce , Aguilar Pablo S.
Published: December 2016

Transient and highly regulated elevations of cytosolic Ca2+control a variety of cellular processes. Bulk measurements using radioactive Ca2+and the luminescent sensor aequorin have shown that in response to pheromone, budding yeast cells undergo a rise of cytosolic Ca2+that is mediated by two import systems composed of the Mid1-Cch1-Ecm7 protein complex and the Fig1 protein. Although this response has been widely studied, there is no treatment of Ca2+dynamics at the single-cell level. Here, using protein calcium indicators, we show that both vegetative and pheromone-treated yeast cells exhibit discrete and asynchronous Ca2+bursts. Most bursts reach maximal amplitude in 1–10 s, range between 7 and 30 s, and decay in a way that fits a single-exponential model. In vegetative cells, bursts are scarce but preferentially occur when cells are transitioning G1 and S phases. On pheromone presence, Ca2+burst occurrence increases dramatically, persisting during cell growth polarization. Pheromone concentration modulates burst frequency in a mechanism that depends on Mid1, Fig1, and a third, unidentified, import system. We also show that the calcineurin-responsive transcription factor Crz1 undergoes nuclear localization bursts during the pheromone response.
Drug-drug interaction discovery and demystification using Semantic Web technologies
Authors: Noor Adeeb , Assiri Abdullah , Ayvaz Serkan , Clark Connor , Dumontier Michel
Published: December 2016

Objective: To develop a novel pharmacovigilance inferential framework to infer mechanistic explanations for asserted drug-drug interactions (DDIs) and deduce potential DDIs.

Materials and Methods: A mechanism-based DDI knowledge base was constructed by integrating knowledge from several existing sources at the pharmacokinetic, pharmacodynamic, pharmacogenetic, and multipathway interaction levels. A query-based framework was then created to utilize this integrated knowledge base in conjunction with 9 inference rules to infer mechanistic explanations for asserted DDIs and deduce potential DDIs.

Results: The drug-drug interactions discovery and demystification (D3) system achieved an overall 85% recall rate in terms of inferring mechanistic explanations for the DDIs integrated into its knowledge base, while demonstrating a 61% precision rate in terms of the inference or lack of inference of mechanistic explanations for a balanced, randomly selected collection of interacting and noninteracting drug pairs.

Discussion: The successful demonstration of the D3 system’s ability to confirm interactions involving well-studied drugs enhances confidence in its ability to deduce interactions involving less-studied drugs. In its demonstration, the D3 system infers putative explanations for most of its integrated DDIs. Further enhancements to this work in the future might include ranking interaction mechanisms based on likelihood of applicability, determining the likelihood of deduced DDIs, and making the framework publicly available.

Conclusion: The D3 system provides an early-warning framework for augmenting knowledge of known DDIs and deducing unknown DDIs. It shows promise in suggesting interaction pathways of research and evaluation interest and aiding clinicians in evaluating and adjusting courses of drug therapy.
Microbes, allergic sensitization, and the natural history of asthma
Authors: Anderson Halie M. , Jackson Daniel J.
Published: December 2016

Purpose of review

Understanding factors that lead to asthma development in early life is essential to developing strategies aimed at primary or secondary prevention.

Recent findings

This article will review current evidence addressing the development of early life allergic sensitization in relation to microbes and the gut and airway microbiome. Wheezing illnesses, particularly viral, remain a significant risk factor for asthma inception; however, bacterial pathogens have recently emerged as an additional important contributor to asthma risk, either alone or as cofactors with viral infections. The combined influence and interaction of early life viral wheezing and aeroallergen sensitization is important, with allergic sensitization preceding the onset of viral wheeze. Lastly, we review recent data from longitudinal studies regarding the development of irreversible airway obstruction and its impact on the natural history of asthma.

The development of asthma remains complex and incompletely understood. There is interplay between genetic predisposition and environmental exposures, including allergens and microbes. Interventions aimed at these risk factors during the preschool years may prevent the longitudinal course of asthma progression to irreversible airway obstruction.
Measuring Glutamate Levels in the Brains of Fibromyalgia Patients and a Potential Role for Glutamate in the Pathophysiology of Fibromyalgia Symptoms
Authors: Pyke Tahni L. , Osmotherly Peter G. , Baines Surinder
Published: December 2016

Objectives:

The aim of this study was to systematically review the literature concerning proton magnetic resonance spectroscopy (H-MRS) measured glutamate levels in specific brain regions of fibromyalgia (FM) patients to determine if there is a correlation between raised glutamate levels and the presentation of FM.

Materials and Methods:

The electronic databases—MEDLINE, EMBASE Classic+Embase, PsychINFO, Cochrane Database of Systematic Reviews, Cochrane Database of Abstracts of Reviews of Effect, Cochrane Central Register of Controlled Trials—were searched to find original studies that used H-MRS to measure glutamate concentrations in the brains of FM patients.

Results:

Nine studies with a total of 482 participants were selected for inclusion in the review. Seven of the 8 studies that investigated an association between cerebral glutamate levels and FM, showed a positive association. Brain regions identified as having increased glutamate levels include the posterior cingulate gyrus, posterior insula, ventrolateral prefrontal cortex, and amygdala. One study reported a decrease in glutamate levels in the hippocampus of FM patients compared with healthy controls. Seven of the 8 studies that analyzed the correlations between cerebral glutamate levels and FM symptoms, found a significant positive correlation.

Discussion:

Although the cause of FM remains inconclusive, there is converging data in favor of a dysregulation of pain processing in the central nervous system of FM patients, particularly associated with an increase in cerebral glutamate levels. Furthermore, there is evidence to support an association between increased glutamate levels and an increase in FM symptoms.
Safe zones of pin insertion in the pelvis and acetabulum: a cadaver study
Authors: Meselhy Mohammed Anter , Essmat Emad Eldin , Ali Ali Mohamed , Singer Mohamed Salah
Published: December 2016

Background:

The external fixator is used in emergency stabilization of unstable pelvic fractures; however, its role as a definitive fixation device remains unestablished. The main problem is the risk of injury to surrounding neurovascular structures with no definite safe corridors for pin insertion. The purpose of the current cadaver study is to outline safe corridors in the pelvis and acetabulum and directions for pin insertion.

Methods:

A cadaver study using two bony and three cadaver pelves was undertaken. Half pins were inserted in specific demarcated sites and tested for resistance to pullout and safety of nearby neurovascular structures.

Results:

The iliac crest, anterior inferior iliac spine, anterior superior iliac spine, posterior inferior iliac spine, and posterior superior iliac spine, supraacetabular region, ischial tuberosity both triangular and quadrangular areas, anterior column of the acetabulum lateral to the anterior superior iliac spine, and the lateral 1 cm of ala of the sacrum are safe pin insertion sites, while the area 1 cm medial to both the anterior inferior iliac spine and the anterior superior iliac spine, and the rest of the ala of the sacrum are unsafe.

Conclusions:

There are many safe areas for half pin insertion in pelvic and acetabular fractures, while there are other unsafe areas. Adequate knowledge of the safe sites and direction of pin insertion decreases the risks of neurovascular injury and allows a wider use of external fixators in pelvic and acetabular fractures.
Factors Associated With Patient-Initiated Telephone Calls After Orthopaedic Trauma Surgery
Authors: Hadeed Michael M. , Kandil Abdurrahman , Patel Vandan , Morrison Avery , Novicoff Wendy M. , Yarboro Seth R.
Published: December 2016

Objectives:

The primary aim of this study is to investigate the incidence of early patient-initiated postoperative telephone calls and reasons for those calls. Secondary goals are to determine perioperative predictive factors for calls including the procedures most frequently associated with them.

Design:

Retrospective chart review.

Setting:

Academic Level-1 Trauma Center.

Patients/Participants:

Six hundred eighty-four patients who underwent surgical treatment by our orthopaedic trauma division between 01/01/2014 and 31/12/2014.

Main Outcome Measurements:

Patient-initiated telephone call documented within 14 days after discharge.

Results:

Twenty-nine percent (n = 199) of patients initiated a telephone call within 14 days after discharge. The most common reasons for telephone calls were pain control (22%), bathing/dressing/wound questions (16%), and questions regarding discharge medications (8%). The procedures associated with the highest percentage of telephone calls were tibial shaft intramedullary nailing (36.0%), calcaneus open reduction internal fixation (31.3%), and cephalomedullary nailing for proximal femur fractures (29.3%). Perioperative factors predictive of an increase in phone calls included discharge directly to home, higher baseline level of health of the patient (based on comorbidities and the American Society for Anesthesiologists score), and a more robust support network (based on marital and employment status).

Conclusions:

This study identifies the incidence and common reasons for patient-initiated calls after orthopaedic trauma surgery and an analysis of perioperative factors predictive of increased phone calls. These data give direction for communication at the time of discharge to improve efficiency, patient care, and patient satisfaction.

Level of Evidence:

Prognostic Level IV. See Instructions for Authors for a complete description of levels of evidence.
Gradual Deformity Correction in Blount Disease
Authors: Mayer Stephanie W. , Hubbard Elizabeth W. , Sun Dan , Lark Robert K. , Fitch Robert D.
Published: December 2016

Background:

Blount disease is a disorder of the posteromedial proximal tibial physis which causes a progressive varus, procurvatum, and internal rotation deformity of the tibia. Untreated, it can cause significant limb malalignment. The goal of this study is to evaluate the results of correction of Blount disease using types of external fixation.

Methods:

We conducted a retrospective review of 41 patients (51 limbs) who underwent correction of Blount disease with an Ilizarov external fixator or a Taylor spatial frame (TSF) by a single surgeon. The medial proximal tibial angle (MPTA), mean axis deviation (MAD), posterior proximal tibial angle, and joint line congruence angle (JLCA) were measured on radiographs preoperatively, at frame removal and at final follow-up.

Results:

The average age at treatment was 9.6 years old, with a mean follow-up time of 34 months. Mean preoperative MPTA, MAD, and JLCA were significantly improved at the time of frame removal as well as at final follow-up with no significant changes in correction between the time of frame removal and final follow-up. There was no difference in MPTA and MAD in patients treated with an Ilizarov frame versus a TSF. MPTA, MAD, and JLCA all significantly improved regardless of the underlying diagnosis (infantile vs. adolescent Blount disease) or history of prior surgical intervention. The most common complication was superficial pin-site infection.

Conclusions:

Both Iliazarov and TSF are viable treatment options for infantile and adolescent Blount disease, with the ability to significantly improve both the limb mechanical axis and the mechanical axis of the affected tibia. Correction can be attained regardless of whether patients have previously failed surgical intervention.

Level of Evidence:

Level III—retrospective comparative study.
What’s New in Congenital Scoliosis?
Authors: Pahys Joshua M. , Guille James T.
Published: December 2016

Background:

Congenital scoliosis is a failure of vertebral formation, segmentation, or a combination of the 2 arising from abnormal vertebral development during weeks 4 to 6 of gestation. The associated spinal deformity can be of varying severity and result in a stable or progressive deformity based on the type and location of the anomalous vertebra(e). Bracing for congenital scoliosis is rarely indicated, while recent reports have demonstrated the utility of serial derotational casting for longer curves with multiple anomalous vertebrae as an effective “time buying strategy” to delay the need for surgery. Earlier hemivertebra excision and short-segment posterior spinal fusion have been advocated to prevent future curve progression of the deformity and/or the development of large compensatory curves. It has been shown in recent long-term follow-up studies that growth rates of the vertebral body and spinal canal are not as dramatically affected by pedicle screw instrumentation at a young age as once thought. Growth friendly surgery with either spine-based or rib-based anchors has demonstrated good results with curve correction while maintaining spinal growth. Rib-based anchors are typically more commonly indicated in the setting of chest wall abnormalities and/or when spinal anatomy precludes placement of spinal instrumentation. Recently, magnetically controlled growing rods have shown promising results in several studies that include a small subset of congenital scoliosis cases.

Methods:

A literature search was performed to identify existing studies related to the treatment of congenital scoliosis published from January 1, 2005 to June 1, 2016. Databases included PubMed, Medline, and the Cochrane Library. The search was limited to English articles and yielded 36 papers. This project was initiated by the Pediatric Orthopaedic Society of North America Publications Committee and was reviewed and approved by the Pediatric Orthopaedic Society of North America Presidential Line.

Results:

A total of 36 papers were selected for review based upon new findings. Classic manuscripts on congenital scoliosis are also included to provide sufficient background information.

Conclusions:

Congenital scoliosis represents a wide range of pathology from the simple, stable hemivertebra to the complex, progressive spinal deformity with chest wall abnormalities and associated cardiac, renal, and neural axis anomalies. This paper reviews the natural history and associated anomalies with congenital scoliosis as well as the most up-to-date classification schemes and various treatment options for the care of this challenging patient population.

Level of Evidence:

Level 5.
Volar, Dorsal, and Lateral Locking Plate Fixation for Pilon Fractures
Authors: Henry Mark
Published: December 2016

The more common dorsal fracture subluxations at the base of the middle phalanx have an intact dorsal buttress of articular surface in continuity with the shaft. Capitalizing on this foundation, various fixation methods have met with relatively equivalent success including Kirschner wires, screws only, nonlocking plate and screws, and external fixation. Pilon fractures are complete articular fractures, where the comminuted articular fragments lack any structural connection to the more distal shaft of the middle phalanx, and have largely relied upon external fixation traction systems. The theoretical concept is that axial distraction prevents articular collapse and that the surrounding soft tissue envelope acts to gather the articular fragments; the term “ligamentotaxis” is often applied. Most constructs are founded on a transverse wire through the axis of rotation in the head of the proximal phalanx with the idea that patients will pursue active motion, termed “dynamic fixation.” In practice, patients find it difficult to move well while the construct is in place and have rarely achieved much range by the time of removal. These cases are prone to loss of articular reduction leading to posttraumatic arthritis, substantial proximal interphalangeal joint stiffness, and pin-tract infection. Such problems are solved with locking plates that support the articular reduction throughout healing and permit immediate range of motion while avoiding other complications such as pin-tract infection. Outcomes are reported for 40 patients treated with locking plates applied from volar, dorsal, and lateral to treat pilon fractures.
Concurrent driver mutations/rearrangements in non-small-cell lung cancer
Authors: Tabchi Samer , Kourie Hampig R. , Klastersky Jean
Published: December 2016

Purpose of review

The concept of mutually exclusive oncogenic driver alterations has prevailed over the past decade, but recent reports have stressed the possible occurrence of dual-positive non-small-cell lung cancer (NSCLC) and even triple-positive disease for these oncogenes. This entity presents novel prognostic and therapeutic challenges. The present review highlights the available data in an effort to clarify the clinical and pathological significance of coexisting mutations as well as the subsequent therapeutic consequences.

Recent findings

Patients with a known driver oncogene can be successfully treated with the appropriate tyrosine kinase inhibitor, which will provide them with significant responses and lesser toxicities compared with cytotoxic therapy. Unfortunately, most patients will eventually progress. Although some resistance mechanisms have been identified, others remain to be determined but the emergence of secondary oncogenes could be part of the answer.

Approximately 20–25% of NSCLC harbor treatable driver mutations/rearrangements; epidermal growth factor receptor mutation, anaplastic lymphoma kinase and ROS-1 gene rearrangements are the main alterations for which a Food and Drug Administration-approved tyrosine kinase inhibitor can be used.

Because of recent technological advances, high sensitivity assays with a broad range of genomic targets have become more easily accessible in clinical practice, which has led to an increased detection of coexisting driver alterations in patients with advanced NSCLC. The prognostic/predictive and therapeutic implications of this novel entity are still unsettled for the time being. Randomized trials specifically designed to address this subset of patients will soon be necessary to help determine the optimal therapeutic agent to administer.
Critical aspects to achieve a high-quality melanoma clinic
Authors: Dummer Reinhard , Ramelyte Egle , Levesque Mitch , Goldinger Simone M. , Braun Ralph P.
Published: December 2016

Purpose of review

With incidence of melanoma growing worldwide and new therapies prolonging the survival of patients with advanced disease, complex medical care is needed.

Recent findings

Best care of complicated melanoma cases is achieved in specialized referral centers. Aims to provide optimized melanoma therapy, best patient-reported treatment outcome, and successful clinical and translational research, necessitate a dedicated interdisciplinary team.

We report on critical aspects of the interaction between patients, medical care givers, clinical trial and biobanking teams, and emphasize the importance of interdisciplinary tumor boards. Specialized skin cancer nurses and local patient advocacy groups should be involved in patient care and could be the binding link between the patients and the treatment team.
Treatment of Acne Scars on Darker Skin Types Using a Noninsulated Smooth Motion, Electronically Controlled Radiofrequency Microneedles Treatment System
Authors: Pudukadan David
Published: December 2016

BACKGROUND

Noninvasive technologies for treating acne scars use radiofrequency (RF)-emitting microneedles for both mechanical disruption of fibrotic strands and heat-mediated collagen remodeling.

OBJECTIVE

Efficacy and safety evaluation of electronically controlled noninsulated RF microneedling system on acne scars in patients with dark skin.

METHODS

Nineteen patients, 24 to 51 years old, skin types III to V, with acne scars were enrolled in the study. Each patient had 3 treatment sessions at monthly intervals using a multisource RF treatment platform with a microneedle RF applicator. Efficacy was evaluated by the Goodman and Barron's Global Qualitative Acne Scarring System.

RESULTS

No bleeding points occurred during treatments. Post-treatment erythema was observed immediately after the treatment and lasted up to 10 hours after the treatment. Improvement of at least 1 acne scar grade was noted in 11 of 19 patients (57.9%) after 1 month and in 9 of 9 patients (100%) after 3 months.

CONCLUSION

The tested noninsulated electronically controlled RF microneedles were found to be safe and efficient in the treatment of atrophic acne scars in skin types III to V with minimal pain or downtime.
Fractional Erbium-Doped Yttrium Aluminum Garnet Laser Versus Microneedling in Treatment of Atrophic Acne Scars: A Randomized Split-Face Clinical Study
Authors: Osman Mai Abdel Raouf , Shokeir Hisham Ali , Fawzy Marwa M.
Published: December 2016

BACKGROUND

Ablative fractional erbium-doped yttrium aluminum garnet (Er:YAG) laser and microneedling have been popularized in recent years and their effectiveness and side effects individually reported. No previous study, however, has directly compared the efficacy and safety between the 2 different treatments.

OBJECTIVE

To compare the efficacy and safety of the ablative fractional Er:YAG laser and microneedling for the treatment of atrophic acne scars.

MATERIALS AND METHODS

Thirty patients with atrophic acne scars were randomly treated in a split-face manner with a fractional Er:YAG laser on one side and microneedling on the other side. All patients received 5 treatments with a 1-month interval. Objective and subjective assessments were obtained at baseline and at 3 months after the final treatment.

RESULTS

At the 3-month follow-up, both treatment modalities induced noticeable clinical and histological improvement, with significantly better results in fractional Er:YAG laser versus microneedling (70% vs 30%), respectively (p < .001). Fractional Er:YAG laser sides had significantly lower pain scores. Total downtime was significantly shorter in microneedling sides.

CONCLUSION

Both treatment modalities are effective and safe in the treatment of atrophic acne scars, with significantly higher scar response to the fractional Er:YAG laser treatment.
A Prospective Study of Axillary Hair Reduction in Patients Treated With Microwave Technology
Authors: Brauer Jeremy A. , Neckman Julia P. , Zelickson Brian , Vasily David B. , Geronemus Roy G.
Published: December 2016

BACKGROUND

Removing unwanted body hair is a growing trend in society today, and there are many laser-based devices for hair reduction. There are some limitations to those methods, including the lack of efficacy for lighter color hair.

OBJECTIVE

The objective was to quantify hair reduction in the axillae after treatment with a noninvasive microwave energy device.

MATERIALS AND METHODS

A prospective, multicenter study was performed at 3 private dermatology clinics. Fifty-six adult subjects seeking axillary hair reduction were enrolled and treated with the device in 1 or 2 treatment sessions 3 months apart at various energy levels, and followed for 12 months. The primary analysis was monitoring reduction of hair counts from baseline to follow-up visits. A subject assessment of overall satisfaction, odor ratings, and sweat reduction ratings was provided at follow-up visits.

RESULTS

Fifty-six subjects received treatment, with an average total underarm hair reduction of approximately 70% for both light and dark hair. Percentage of patients with hair reduction of 30% or more was significantly higher than 50% at all follow-up visits. Half of treated subjects reported expected mild transient post-treatment effects such as localized edema, discomfort, and bruising. Other reported events were mild.

CONCLUSION

This clinical study provides evidence for safe and permanent axillary hair reduction, showing stable average reduction that lasted through the year of follow-up. Most notably, the study has shown the treatment's efficacy for reduction of light-colored axillary hair.
Vulvar Varicosities: A Review
Authors: Kim Anna S. , Greyling Laura A. , Davis Loretta S.
Published: December 2016

BACKGROUND

Vulvar varicosities (VV) are dilated and tortuous veins occurring within the external female genitalia. Patients may seek treatment of these varices for both medical and cosmetic purposes. In some patients, VV may be associated with a chronic pelvic pain syndrome called pelvic congestion syndrome (PCS).

OBJECTIVE

To review the English language literature on VV in both pregnant and nonpregnant women.

MATERIALS AND METHODS

A literature search pertaining to vulvar varicosities and PCS was performed using PubMed and Google Scholar databases.

RESULTS

There is an overall paucity of literature discussing VV, particularly in nonpregnant women without PCS. Management options for VV include compression, sclerotherapy, embolization, and surgical ligation. Treatment can be dependent on the coexistence of pelvic or leg varicosities and may require referral to a vein specialist for advanced imaging techniques and procedures. Direct sclerotherapy to VV may not provide adequate treatment if pelvic or leg varices are also present.

CONCLUSION

In women with persistent VV, imaging studies should be obtained before treatment to evaluate the surrounding venous anatomy of the pelvis and leg, as the results often affect the treatment approach. Patients presenting with VV and chronic pelvic pain should be evaluated for PCS.
Single-Nucleotide Polymorphism of CYP3A5 Impacts the Exposure to Tacrolimus in Pediatric Renal Transplant Recipients: A Pharmacogenetic Substudy of the TWIST Trial
Authors: Billing Heiko , Höcker Britta , Fichtner Alexander , van Damme-Lombaerts Rita , Friman Styrbjorn , Jaray Jenö , Vondrak Karel , Sarvary Eniko , Dello Strologo Luca , Oellerich Michael , von Ahsen Nicolas , Tönshoff Burkhard
Published: December 2016

Background:

The pharmacokinetics of tacrolimus (TAC) and mycophenolic acid (MPA) are highly variable. An impact of single-nucleotide polymorphisms (SNPs) of the genes coding for enzymes and transporters involved in the pharmacokinetics of TAC and/or MPA is intuitively conceivable. Accordingly, we sought to analyze the influence of different SNPs on TAC and MPA exposure in pediatric renal transplant recipients.

Methods:

A subpopulation of 37 patients (median age: 12.8 years, range 2.2–18.3 years) participating in the TWIST study was included in the analysis of SNPs of CYP3A5, ABCB1 (MDR1), ABCG2, SLCO1B3 (coding for OATP2), ABCC2 (coding for cMOAT), and UGT1/2. TAC trough concentrations and abbreviated area under the concentration–time curves (AUC) of MPA were measured on days 7, 28, 91, and 183 after transplant. Both of these were adjusted to the respective dose the patient received.

Results:

The allele frequencies of analyzed SNP's were comparable to those reported previously for white populations. Dose-adjusted trough concentrations of TAC were approximately 60% lower in patients with the CYP3A5*1/*3 allele as compared with the CYP3A5*3/*3 allele (P = 0.004). Steroid-free patients in CYP3A5*3/*3 and CYP3A5*1/*3 carrier subgroups had comparable dose-adjusted TAC concentrations to the subgroup on steroids (P = 0.13). Patients younger than 10 years had a significantly lower median dose-adjusted TAC C0 concentration than patients older than 10 years; this age effect was comparable in heterozygous and homozygous CYP3A5 carriers as well as in patients on and off steroid medication. As for MPA, the genetic variability of transporters or enzymes had no impact on dose-adjusted MPA-AUC due to the low allele frequencies. Patients off steroids had a higher dose-adjusted MPA-AUC (0.18 mg·h/L per mg/m2, 0.012–0.27) compared with patients on steroids (0.12 mg·h·L−1·mg−1, 0.09–0.19; P = 0.04).

Conclusions:

Genetic variability of CYP3A5 has an impact on TAC metabolism in pediatric renal transplant recipients, contributing partly to the variability of TAC exposure. Therefore, adjusting initial TAC dosing to the genotype of CYP3A5 might be of clinical benefit.
Cardiac Rehabilitation Leads to Improvements in Activity Limitations
Authors: Puthoff Michael L. , Youngs Brenda
Published: December 2016

Purpose:

The purposes of this study were to identify the number of participants who enter cardiac rehabilitation with an activity limitation and assess whether a cardiac rehabilitation program leads to improvements in activity, demonstrated through changes in gait speed and the 5-times-sit-to-stand test (FTSST).

Methods:

This study utilized a 1-group pretest-posttest design. Gait speed and FTSST were measured at the start and end of cardiac rehabilitation. Paired sample t tests were performed to assess changes pre- and postrehabilitation. Subgroup analysis was done on patients who presented with an activity limitation on admission (gait speed <1.0 m/s or FTSST time >12 seconds) to determine whether this subgroup experienced greater changes.

Results:

On admission, 60.2% of participants presented with an activity limitation using FTSST as the criterion. At the completion of cardiac rehabilitation, participants demonstrated improvements in gait speed and FTSST, but improvements were less than the minimal detectable change (MDC) for the outcome measures. Those who presented with an activity limitation on admission had greater improvements and surpassed the MDC. Even after cardiac rehabilitation, more than 30% of participants still had an activity limitation.

Conclusions:

Patients entering cardiac rehabilitation present with activity limitations and most, but not all, will make gains through a standard course of cardiac rehabilitation. Clinicians and researchers should consider how cardiac rehabilitation programs can be modified to assess the presence of activity limitation and maximize improvements in function to enhance participation in society.
Outcomes of Pulmonary Rehabilitation After Treatment for Non-Small Cell Lung Cancer Stages I to IIIa
Authors: Janssen Steffi M. J. , Abbink Jannie J. , Lindeboom Robert , Vliet Vlieland Thea P. M.
Published: December 2016

PURPOSE:

Although rehabilitation after treatment for non-small cell lung cancer (NSCLC) was found to have a beneficial effect on exercise capacity in a number of studies, insight into its effect on quality of life (QoL) and fatigue is limited. The aim of this study was to examine the outcome of pulmonary rehabilitation (PR) regarding fatigue, QoL, and exercise capacity in adult patients curatively treated for NSCLC stages I to IIIa.

METHODS:

Study data were prospectively and routinely gathered in daily practice in patients taking part in an outpatient PR program after treatment for NSCLC stages I to IIIa. PR consisted of 12 weeks of supervised exercises 3 times a week, supplemented with scheduled visits with members of a multidisciplinary team. Data were gathered at initial assessment and discharge. Outcomes included fatigue (the Functional Assessment of Cancer Therapy-Fatigue and the fatigue domain of the Chronic Respiratory Disease Questionnaire); QoL (total CRQ score), Functional Assessment of Cancer Therapy-Lung, and the Short Form 36; and exercise capacity (cardiopulmonary exercise testing).

RESULTS:

Fifty patients started the program out of the 70 patients referred to PR and 43 (86%) completed the program. Significant (P ≤ .01) and clinically relevant improvements were observed for all outcome measures.

CONCLUSIONS:

Rehabilitation after treatment for NSCLC stages I to IIIa showed promising improvements regarding patient fatigue, QoL, and exercise capacity. PR should be considered for patients after treatment for NSCLC stages I to IIIa.
OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY AFTER PHOTOCOAGULATION OF TYPE 2 NEOVASCULARIZATION
Authors: Arya Malvika , Cole Emily D. , Novais Eduardo A. , Louzada Ricardo N. , Waheed Nadia K. , Duker Jay S.
Published: December 2016

Purpose:

To illustrate errors in the automated segmentation image analysis of optical coherence tomography angiography after laser photocoagulation therapy for Type 2 neovascularization.

Methods:

This case report describes a patient with extrafoveal Type 2 neovascularization treated with argon laser photocoagulation evaluated before and after treatment by optical coherence tomography angiography.

Results:

Disrupted retinal layers after laser photocoagulation therapy lead to segmentation errors.

Conclusion:

Images of optical coherence tomography angiography are prone to degradation by artifacts in cases in which there is disruption of the retinal layers. Clinicians must be aware of these errors because they can be misinterpreted as active Type 2 neovascularization. Improvement in optical coherence tomography angiography image analysis to minimize automated segmentation errors needs to be further explored.
The Influence of the Route of Antibiotic Administration, Methicillin Susceptibility, Vancomycin Duration and Serum Trough Concentration on Outcomes of Pediatric Staphylococcus aureus Bacteremic Osteoarticular Infection
Authors: McNeil J. Chase , Kaplan Sheldon L. , Vallejo Jesus G.
Published: December 2016

Background:

Bacteremia is often one factor used in deciding the need for prolonged intravenous antimicrobial therapy in osteoarticular infections (OAIs). We examined treatment practices and outcomes of Staphylococcus aureus bacteremic osteoarticular infections (BOAIs) evaluated at Texas Children’s Hospital.

Methods:

Cases of acute hematogenous OAI in children with positive blood cultures for S. aureus at Texas Children’s Hospital between 2011 and 2014 were reviewed. Orthopedic complications included chronic osteomyelitis, growth arrest, pathologic fracture, avascular necrosis and chronic dislocation. Acute kidney injury was defined as a doubling of the baseline creatinine.

Results:

One hundred and ninety-two cases of S. aureus OAI were identified with 102 cases of BOAI included [35 methicillin-resistant S. aureus (MRSA)]. Twenty-five patients were discharged home on oral antibiotics. Patients discharged on oral antibiotics had a shorter duration of fever, had a more rapid decline in C-reactive protein and were less likely to have MRSA. The frequency of orthopedic complications did not increase in patients who received early transition to oral antibiotics. For patients with MRSA bacteremia, the rates of complications between those who received ≥7 days versus <7 days of vancomycin did not differ. Vancomycin serum troughs >15 µg/mL were not associated with a decreased duration of fever, bacteremia or hospitalization, need for repeat operation or orthopedic complications but were associated with acute kidney injury.

Conclusions:

S. aureus BOAIs are associated with substantial morbidity. Early transition to oral therapy may be a safe option for select patients with S. aureus BOAI, including those due to MRSA. Prolonged courses of vancomycin and vancomycin troughs >15 μg/mL were not associated with improved outcomes for MRSA OAI.
Antiretroviral Treatment Initiated in the First Month of Life
Authors: Frigati Lisa , Wynberg Elke , Maritz Jean , Holgate Sandi , Cotton Mark F. , Rabie Helena
Published: December 2016

Background:

Earlier diagnosis of HIV-infected infants facilitates earlier access to therapy and improved clinical outcomes. The aim of this study was to describe the management of infants who started antiretroviral therapy (ART) in the first month of life.

Methods:

A retrospective review was performed on HIV-infected neonates who started ART within the first month of life between January 2013 and March 2015.

Results:

A total of 997 neonates had 1 HIV polymerase chain reaction test. Of the 997 neonates, 26 (2.6%) tested positive for HIV and 22 initiated therapy in the first month of life. The median age of first HIV polymerase chain reaction test was 7 days. Neonates were started on ART within a median of 7 days of their first HIV test, which equated to a median age of 13.5 [interquartile range (IQR) 7–20] days of life. Median gestational age was 35 weeks (IQR 33–38 weeks), and birth weight was 2170 g (IQR 1773–2480). Nineteen (86.4%) had low birth weight (<2.5 kg) and 16 (72.7%) were premature. Median baseline HIV viral loads were log 4.444 copies/mL (IQR 3.457–5.125), median CD4 counts were 1338 (IQR 803–1928) and CD4% percentages were 36.1% (22.2–45.4). All children initiated zidovudine and lamivudine, 10 with lopinavir/ritonavir and 12 with nevirapine. All children in care are now receiving lopinavir/ritonavir. Of the 22 neonates initiated on treatment, 11 are in care (mean age, 2.1 years), and 2 of these infants had a viral load of <50 copies/ mL when last measured.

Conclusions:

Early ART initiation in neonates is feasible. Challenges include safe, palatable regimens and continued close follow-up of mothers and infants.
Low Bone Mineral Density in Vertically HIV-infected Children and Adolescents
Authors: Jiménez Beatriz , Sainz Talía , Díaz Laura , Mellado María José , Navarro María Luisa , Rojo Pablo , González-Tomé María Isabel , Prieto Luis , Martínez Jorge , de José María Isabel , Ramos José Tomás , Muñoz-Fernandez María Ángeles
Published: December 2016

Background:

Our aim was to determine the prevalence and risk factors associated with low bone mineral density (BMD) in vertically HIV-infected patients and to investigate whether low BMD is related to immune activation and senescence induced by HIV infection.

Methods:

A cross-sectional study was performed in 98 vertically HIV-infected patients. BMD was measured by dual-energy radiograph absorptiometry at lumbar spine. Height adjustment of BMD Z score was performed using height-for-age Z score. T-cell immune activation and senescence were analyzed in a subgroup of 54 patients by flow cytometry.

Results:

Median age was 15.9 years, 71.4% were Caucasian, 99% received antiretroviral therapy and 80.6% had undetectable viral load. Low BMD (BMD Z score ≤ −2) was present in 15.3% of cases, but after height adjustment in 4.1% of cases. Height-adjusted BMD Z score was positively correlated with body mass index Z score, CD4/CD8 ratio and nadir CD4, and inversely with duration of severe immunosuppression and parathyroid hormone values. In the multivariate model including age, gender, ethnicity, encephalopathy, Tanner stage, nadir CD4, duration of viral suppression, CD4 count, CD4/CD8 ratio, body mass index, cumulative duration of antiretroviral therapy, tenofovir and protease inhibitors exposure, nadir CD4 was independently associated to height-adjusted BMD Z score. No association was found between height-adjusted BMD Z score and T-cell activation or senescence.

Conclusions:

The prevalence of low BMD in vertically HIV-infected patients was low after height adjustment. Nadir CD4, but not T-cell activation or senescence, was an independent predictor for low BMD. Larger and prospective studies are needed to achieve better knowledge of the pathogenesis of low BMD in vertical HIV infection.
Adherence to Antituberculosis Drugs in Children and Adolescents in A Low-Endemic Setting
Authors: Guix-Comellas Eva-Maria , Rozas Librada , Velasco-Arnaiz Eneritz , Morín-Fraile Victoria , Force-Sanmartín Enriqueta , Noguera-Julian Antoni
Published: December 2016

Adherence to antituberculosis drug regimens is critical for the prevention and treatment of tuberculosis in pediatrics. In a large retrospective series of children and adolescents in Barcelona, Spain, completion of treatment was worse among patients treated for latent infection, compared with those treated for active tuberculosis or receiving primary chemoprophylaxis. Toxicity and cultural and language barriers were identified as predictors of nonadherence.
Attitudes of Swiss Health Care Providers Toward Childhood Immunizations
Authors: Schuler Marianne , Schaedelin Sabine , Aebi Christoph , Berger Christoph , Crisinel Pierre-Alex , Diana Alessandro , Niederer-Loher Anita , Siegrist Claire-Anne , Vaudaux Bernard , Heininger Ulrich
Published: December 2016

Background:

INFOVAC is a network providing information about immunization issues to health professionals. The aim of this study was to assess the attitude of INFOVAC subscribers toward the current Swiss immunization schedule, potential modifications, and current and hypothetical immunization practices regarding their own children.

Methods:

In March 2015, a Web-based survey was sent to 4260 physicians and pharmacists subscribed to INFOVAC. Participation was anonymous and voluntary. The following information was obtained: (1) current immunization status of own children; (2) which immunizations would currently be accepted for a hypothetical own child and (3) attitudes toward potential modifications of the Swiss immunization schedule. Descriptive methods and multivariate models to correct for covariables were used for data analysis.

Results:

Nine hundred and fifty-five valid questionnaires were received: 886/3704 (23.9%) from physicians and 69/556 (12.4%) from pharmacists. Current (>95%) and hypothetical (>99%) immunization rates were high for diphtheria, tetanus, pertussis, poliomyelitis and measles-mumps-rubella. Most pediatricians (61%) would support more vaccines for their children than currently recommended by the Swiss immunization advisory committee, whereas about 50% of other physicians and pharmacists would decline at least one of the recommended immunizations, most frequently varicella, pneumococcal or meningococcal C conjugate vaccines. Strong general support was expressed for the expansion of human papillomavirus immunization to males, acceleration of the measles-mumps-rubella schedule and a 2 + 1 instead of 3 + 1 diphtheria-tetanus-pertussis, acellular-inactivated poliomyelitis vaccine (DTPa-IPV)/Haemophilus influenzae type b ± hepatitis B virus (HBV) schedule.

Conclusions:

Survey participants generally demonstrated a positive attitude toward immunization, with pediatricians being the most progressive subgroup with the largest percentage of participants (63.1%) neither declining nor postponing any recommended immunization.
Omega-3 Fatty Acid Supplementation and Warfarin: A Lethal Combination in Traumatic Brain Injury
Authors: Gross Brian W. , Gillio Maria , Rinehart Cole D. , Lynch Caitlin A. , Rogers Frederick B.
Published: December 2016

Polyunsaturated fatty acids such as omega-3 eicosapentaenoic acid and omega-6 docosahexaenoic acid, found in over-the-counter fish oil supplements, are often consumed for their beneficial, prophylactic, anti-inflammatory effects. Although the mechanisms of action are not fully known, a diet rich in polyunsaturated fats may reduce the risk of hyperlipidemia, atherosclerosis, high low-density lipoprotein cholesterol levels, hypertension, and inflammatory diseases. Masked by its many benefits, the risks of omega-3 fatty acid supplementation are often underappreciated, particularly its ability to inhibit platelet aggregation and promote bleeding in patients taking anticoagulant medications. The following details the clinical case of an elderly patient taking warfarin and fish oil supplementation whose warfarin-induced coagulopathy could not be reversed after suffering blunt head trauma.
Permissive Hypotension and Trauma: Can Fluid Restriction Reduce the Incidence of ARDS?
Authors: Kolarik Melissa , Roberts Eric
Published: December 2016

Emergency care, including the resuscitation of patients involved in traumatic events, has evolved over the years. A prior practice of utilizing large volumes of crystalloids has been found to contribute to complications such as coagulopathy, fluid overload, and adult respiratory distress syndrome (ARDS). In contrast, permissive hypotension is a method of fluid restriction that allows for low blood pressure and mean arterial pressure during the resuscitation period. When permissive hypotension occurs and fluids are restricted in trauma patients, the incidence of ARDS can be reduced significantly with improvement in patient outcomes. Using evidence, nurse practitioners in the emergency department have an important role in evaluating and updating protocols such as permissive hypotension.