bluuebunny/crossref_metadata_2025 huggingface dataset:
Efficacy of eye movement desensitization and reprocessing on the phantom limb pain of patients with amputations within a 24-month follow-up
Authors: Rostaminejad Akbar , Behnammoghadam Mohammad , Rostaminejad Marzieh , Behnammoghadam Zargham , Bashti Somaye
Published: April 2017

The aim of this study was to evaluate the efficacy of eye movement desensitization and reprocessing (EMDR) on the phantom limb pain (PLP) of patients with amputations within a 24-month follow-up. This study was a randomized-controlled trial. A total of 60 patients with amputations were selected by a purposive sampling and patients were divided randomly into two experimental and control groups. Samples were assigned through randomized allocation. EMDR therapy was administered individually to the experimental group participants in 12 one-hour sessions over a 1-month period In each session, the patient completed the Subjective Units of Distress Scale and a pain-rating scale before and after the intervention. Follow-up measures were obtained 24 months later for the experimental group. The participants in the control group were measured on the two scales at an initial session and again after 1- and 24-month follow-up. The mean PLP decreased in the experimental group between the first and last sessions and remained so at a 24-month follow-up. No decrease occurred for the control group over the 1- and 24-month period. The differences were statistically significant (P<0.001) according to a repeated-measures analysis of variance. EMDR therapy proved to be a successful treatment for PLP. Because of its efficacy and the fact that the positive effects were maintained at the 24-month follow-up, this therapy is recommended for the treatment of PLP.
Evaluation of Text Messaging Effects on Health Goal Adherence in the Management of Participants With Chronic Diseases
Authors: Stagg Sharon J. , Speroni Karen Gabel , Daniel Marlon G. , Eigenbrode Melissa , Geisler Lori
Published: April 2017

Purpose of the Study:

The study purpose was to determine whether text messaging health-related messages, questions, and reminders to community case management participants with chronic diseases increased health goal adherence.

Primary Practice Setting:

This study was conducted by a rural community case management, hospital-affiliated program.

Methodology and Sample:

This pilot, quasiexperimental study measured health goal adherence, the degree to which an individual continues work toward self-identified health goals under limited supervision, before and after a text messaging intervention. All participants were receiving community case management services for chronic disease. Participants completed baseline and follow-up surveys regarding a text messaging intervention.

Results:

Most participants were African Americans, had diabetes, with equal numbers by gender, an average age of 57.8 years, and had been in the community case management program for 3–5 years. Participants were sent a total of 1,654 messages/questions and 571 reminders. At follow-up, respondents who reported “Did you work on your health goals?” increased significantly (p = .0430). However, no differences were found for “Did you go to your health care appointments?” and “Did you take your medicines as you should?” No differences were noted in reported visits/hospitalizations overall or specifically at the research site. Lastly, study member visit/hospitalization numbers did not change significantly at follow-up.

Implications for Community Case Management Practice:

Although text messaging is not meant to take the place of face-to-face interactions, it does provide community case managers with an additional modality of communication with patients to offer support and important care reminders, and to facilitate patient participation in his or her care.
A Statewide Survey Report of Roles and Responsibilities in Current Utah Care Management Processes
Authors: Luther Brenda , Martial Marc-Aurel , Barra Joyce
Published: April 2017

Purpose of the Study:

Measure current roles and responsibilities of care managers in the state of Utah.

Primary Practice Setting:

All settings of health care including inpatient, outpatient, community, payer, post-acute, and transitional care settings.

Methods and Sample:

A quantitative descriptive survey design was used to assess and describe current care management roles and responsibilities of 191 care managers within the state of Utah. Quantitative variables of roles and responsibilities were collected an electronic database (REDCap).

Results:

Major results conclude that care managers spend most of their time on direct patient interactions including discharge planning, population care, and utilization review. These care managers are highly experienced in their field, with most being in their professional practice for more than 10 years. Most of the care managers are bachelor's prepared nurses.

Implications for Care Management and Care Coordination Practice:

To create or expand care management processes to meet the goals of health care reform, systems first need to know what care managers/coordinators are doing and where their current focus on care presides. Educators, leaders, and, indeed, the care managers themselves are a part of preparing this dynamic workforce. The major responsibility of care management continues to be direct patient interactions, meaning that care managers are performing vital interpersonal patient interaction needed to achieve highly personalized patient care with assurances of quality and safety. No matter the name—care management, case management, or care coordination—these activities are an essential part of health care, with highly specialized skills that promote patient engagement and activation.
COLLABORATE©, Part IV: Ramping Up Competency-Based Performance Management
Authors: Treiger Teresa M. , Fink-Samnick Ellen
Published: April 2017

Purpose/Objectives:

The purpose of this fourth part of the COLLABORATE© article series provides an expansion and application of previously presented concepts pertaining to the COLLABORATE paradigm of professional case management practice. The model is built upon a value-driven foundation that:

improves the patient's experience of health care delivery,

provides consistency in approach applicable across health care populations, and

optimizes the potential for return on investment.

Primary Practice Setting(s):

Applicable to all health care sectors where case management is practiced.

Findings/Conclusions:

As an industry, health care continues to evolve. Terrain shifts and new influences continually surface to challenge professional case management practice. The need for top-performing and nimble professionals who are knowledgeable and proficient in the workplace continues to challenge human resource departments. In addition to care setting knowledge, professional case managers must continually invest in their practice competence toolbox to grow skills and abilities that transcend policies and processes. These individuals demonstrate agility in framing (and reframing) their professional practice to facilitate the best possible outcomes for their clients. Therefore, the continued emphasis on practice competence conveyed through the performance management cycle is an essential ingredient to performance management focused on customer service excellence and organizational improvement.

Implications for Case Management Practice:

Professional case management transcends professional disciplines, educational levels, and practice settings. Business objectives continue to drive work process and priorities in many practice settings. However, competencies that align with regulatory and accreditation requirements should be the critical driver for consistent, high-quality case management practice. Although there is inherent value in what various disciplines bring to the table, this advanced model unifies behind case management's unique, strengths-based identity instead of continuing to align within traditional divisions (e.g., discipline, work setting, population served). This model fosters case management's expanding career advancement opportunities.
It May Be Simple, But It's Not Easy: Conscious Case Management
Authors: Treiger Teresa M. , Powell Suzanne K.
Published: April 2017

As in everything, case management has an evolutionary trajectory. Perhaps, the latest in case management is Conscious Case Management. In today's harried health care environment and with multiple “productivity” criteria to measure usefulness, case managers should not move to just finishing your daily responsibilities or trying to close the most cases; rather, a mindful approach, whether in listening or doing, will yield the best outcome. Instead of mindlessly completing tasks and checking off boxes, practice in-the-moment—and do so consciously.
Basal Cell Carcinoma With Matrical Differentiation
Authors: Kyrpychova Liubov , Carr Richard A. , Martinek Petr , Vanecek Tomas , Perret Raul , Chottová-Dvořáková Magdalena , Zamecnik Michal , Hadravsky Ladislav , Michal Michal , Kazakov Dmitry V.
Published: April 2017

Basal cell carcinoma (BCC) with matrical differentiation is a fairly rare neoplasm, with about 30 cases documented mainly as isolated case reports. We studied a series of this neoplasm, including cases with an atypical matrical component, a hitherto unreported feature. Lesions coded as BCC with matrical differentiation were reviewed; 22 cases were included. Immunohistochemical studies were performed using antibodies against BerEp4, β-catenin, and epithelial membrane antigen (EMA). Molecular genetic studies using Ion AmpliSeq Cancer Hotspot Panel v2 by massively parallel sequencing on Ion Torrent PGM were performed in 2 cases with an atypical matrical component (1 was previously subjected to microdissection to sample the matrical and BCC areas separately). There were 13 male and 9 female patients, ranging in age from 41 to 89 years. Microscopically, all lesions manifested at least 2 components, a BCC area (follicular germinative differentiation) and areas with matrical differentiation. A BCC component dominated in 14 cases, whereas a matrical component dominated in 4 cases. Matrical differentiation was recognized as matrical/supramatrical cells (n=21), shadow cells (n=21), bright red trichohyaline granules (n=18), and blue-gray corneocytes (n=18). In 2 cases, matrical areas manifested cytologic atypia, and a third case exhibited an infiltrative growth pattern, with the tumor metastasizing to a lymph node. BerEP4 labeled the follicular germinative cells, whereas it was markedly reduced or negative in matrical areas. The reverse pattern was seen with β-catenin. EMA was negative in BCC areas but stained a proportion of matrical/supramatrical cells. Genetic studies revealed mutations of the following genes: CTNNB1, KIT, CDKN2A, TP53, SMAD4, ERBB4, and PTCH1, with some differences between the matrical and BCC components. It is concluded that matrical differentiation in BCC in most cases occurs as multiple foci. Rare neoplasms manifest atypia in the matrical areas. Immunohistochemical analysis for BerEP4, EMA, and β-catenin can be helpful in limited biopsy specimens. From a molecular biological prospective, BCC and matrical components appear to share some of the gene mutations but have differences in others, but this observation must be validated in a large series.
SMARCB1/INI1 Loss in Epithelioid Schwannoma
Authors: Jo Vickie Y. , Fletcher Christopher D.M.
Published: April 2017

The epithelioid variant of schwannoma is rare, and loss of SMARCB1/INI1 expression has been observed in a subset of cases. Our aim was to further define the clinicopathologic features and to evaluate SMARCB1/INI1 deficiency in a large cohort of 65 epithelioid schwannomas diagnosed between 2002 and 2015, which consisted of 32 men and 33 women with median age at diagnosis of 45 years (range, 13 to 75 y). Most tumors arose in the extremities (upper, 20, lower, 15) and trunk (17); 9 were visceral (8 gastrointestinal). Most somatic tumors were in dermis/subcutis (53/54) and encapsulated (53/54) with an epithelial membrane antigen–positive perineurial capsule in 46 cases; visceral tumors were unencapsulated. No patients were reported to have any neurocristopathy. Three patients had multiple lesions (2 each). Tumor size range was 0.4 to 22.7 cm (median, 1.2 cm). Tumors showed multilobulated growth of uniform epithelioid cells in sheets and nests or singly dispersed within a frequently myxoid or hyalinized stroma. Tumor cells had round vesicular nuclei and abundant palely eosinophilic cytoplasm, usually lacking significant pleomorphism or hyperchromasia. Some tumors showed foci resembling conventional schwannoma (spindled morphology, 29; Antoni B foci or Verocay bodies, 8; hyalinized thick-walled vessels, 16). Mitoses ranged from 0 to 9 per 10 high-power fields (median count, 1). No tumor had necrosis. Twenty-three cases showed degenerative nuclear atypia. Focally striking cytologic atypia was present in 7 tumors, 3 of which showed transformation to epithelioid malignant peripheral nerve sheath tumor. All tumors showed diffuse positivity for S-100 protein and consistent positivity for SOX10 (50/50), while INI1 expression was lost in 24 of 57. Other positive immunohistochemical results were: glial fibrillary acidic protein (15/37) and focal keratin (2/40); epithelial membrane antigen (0/53) and melanocytic markers were negative (Mart-1 0/29; HMB-45 0/23). Most patients underwent local excision (13 complete; 47 marginal/positive margins). Follow-up data available for 31 patients (range, 1 to 108 mo; median, 37) indicated that no patient had developed metastatic disease, including 3 cases with cytologic atypia, one of which showed malignant transformation. One tumor without atypia developed local recurrence 48 months after marginal excision; all other patients were alive with no evidence of disease. Epithelioid schwannoma most commonly occurs as a superficial tumor on the extremities or trunk in adults. Loss of SMARCB1/INI1 expression is seen in 42% of tumors. Tumors follow a generally benign clinical course, although recurrence and malignant transformation are infrequent. Some tumors are characterized by notable cytologic atypia, the significance of which is uncertain but which may indicate a morphologic continuum with low-grade epithelioid malignant peripheral nerve sheath tumor.
Heterotopic Pancreas of the Gastrointestinal Tract and Associated Precursor and Cancerous Lesions
Authors: Jun Sun-Young , Son Dahye , Kim Mi-Ju , Kim Sung Joo , An Soyeon , Park Young Soo , Park Sook Ryun , Choi Kee Don , Jung Hwoon-Yong , Kim Song Cheol , Yook Jeong Hwan , Kim Byung-Sik , Hong Seung-Mo
Published: April 2017

Heterotopic pancreas (HP) can be detected by accompanying symptoms or incidentally during gastrointestinal (GI) tract tumor resection. We compared clinicopathologic features among 165 resected HPs (57 gastric [35%], 56 duodenal [34%], 30 omental [18%], and 22 jejunal [13%]). Symptomatic HPs (79/135 GI tract wall HPs, 59%) were larger (P=0.05), more common in younger patients and in a gastric location (both P<0.001), and more frequently associated with lymphoid cuffs (P=0.03) than incidentally found HPs. Gastric/jejunal HPs were more frequently symptomatic (P<0.001), deeply located (P=0.03), and associated with lymphoid cuffs (P=0.008) and pancreatic intraepithelial neoplasia/intraductal papillary mucinous neoplasms (PanIN/IPMN; P=0.001) than duodenal HPs. HP was frequently associated with acinar-ductal metaplasias (117/135 GI tract wall HPs, 87%) and PanINs/IPMNs (68/135, 50%); those with PanINs/IPMNs were larger (P<0.001), more frequently located in stomach (P=0.001), had deeper wall involvement (P=0.03), and more often showed infiltrative growth (P<0.001) and lymphoid cuffs (P=0.02). Four HPs containing PanINs abutted adenocarcinomas, all expressing wild-type KRAS and intact SMAD4/DPC4 expression. Thus, symptomatic HP is associated with younger age, larger size, gastric location, and lymphoid cuffs. HPs containing PanINs/IPMNs (usually low grade) are larger and more common in stomach, have deeper wall location, and show infiltrative growth and lymphoid cuffs. Adenocarcinomas are rarely observed adjacent to HPs with PanINs/IPMNs. KRAS mutational and SMAD4/DPC4 immunohistochemical studies can discriminate between adenocarcinoma derived from HP and concurrent adenocarcinoma with HP.
Nipple-Areola Complex Malposition in Nipple-Sparing Mastectomy: A Review of Risk Factors and Corrective Techniques from Greater than 1000 Reconstructions
Authors: Choi Mihye , Frey Jordan D. , Salibian Ara A. , Karp Nolan S.
Published: April 2017

Background:

Nipple-areola complex malposition after nipple-sparing mastectomy can be a challenging issue to correct. The current literature is largely limited to smaller series and implant-based reconstructions.

Methods:

A retrospective review of all nipple-sparing mastectomies from 2006 to 2016 at a single institution was performed. Incidence, risk factors, and corrective techniques of nipple-areola complex malposition were analyzed.

Results:

One thousand thirty-seven cases of nipple-sparing mastectomy were identified, of which 77 (7.4 percent) underwent nipple-areola complex repositioning. All were performed in a delayed fashion. The most common techniques included crescentic periareolar excision [n = 25 (32.5 percent)] and directional skin excision [n = 10 (13.0 percent)]. Cases requiring nipple-areola complex repositioning were significantly more likely to have preoperative radiation therapy (p = 0.0008), a vertical or Wise pattern incision (p = 0.0157), autologous reconstruction (p = 0.0219), and minor mastectomy flap necrosis (p = 0.0462). Previous radiation therapy (OR, 3.6827; p = 0.0028), vertical radial mastectomy incisions (OR, 1.8218; p = 0.0202), and autologous reconstruction (OR, 1.77; p = 0.0053) were positive independent predictors of nipple-areola complex repositioning, whereas implant-based reconstruction (OR, 0.5552; p < 0.0001) was a negative independent predictor of repositioning. Body mass index (p = 0.7104) and adjuvant radiation therapy (p = 0.9536), among other variables, were not predictors of nipple-areola complex repositioning.

Conclusions:

Nipple-areola complex malposition after nipple-sparing mastectomy can be successfully corrected with various techniques. Previous radiation therapy, vertical mastectomy incisions, and autologous reconstruction are independently predictive of nipple-areola complex malposition.

CLINICAL QUESTION/LEVEL OF EVIDENCE:

Therapeutic, III.
Autologous Fat Transfer for Thumb Carpometacarpal Joint Osteoarthritis: A Prospective Study
Authors: Herold Christian , Rennekampff Hans-Oliver , Groddeck Robert , Allert Sixtus
Published: April 2017

Background:

Most operations for carpometacarpal joint osteoarthritis of the thumb irreversibly alter or destroy the anatomy. There is a high demand for minimally invasive alternatives. The authors report the results of autologous fat transfer for treatment of thumb carpometacarpal joint osteoarthritis.

Methods:

In a prospective study, 50 patients with thumb carpometacarpal joint osteoarthritis were observed for 1 year after autologous fat transfer. Manual liposuction and centrifugation were performed. Pain rating according to visual analogue pain scale; objective force of pinch grip and fist closure; and Disabilities of the Arm, Shoulder, and Hand questionnaire scores before and after treatment were analyzed.

Results:

The average pain in stage 2 patients preoperatively was 7.7 ± 1.3; it was 1.8 ± 1.9 after 6 months and 2.4 ± 3.1 after 12 months. Patients with stage 2 osteoarthritis demonstrated a superior benefit from this treatment compared with patients with either stage 3 or stage 4 thumb carpometacarpal joint osteoarthritis. There were similar improvements for the parameters strength and Disabilities of the Arm, Shoulder, and Hand questionnaire score. No serious adverse events were observed.

Conclusions:

Autologous fat transplantation is an appealing alternative, especially in early-stage basal joint osteoarthritis of the thumb. The low invasiveness of the procedure and early recovery of patients compared with classical procedures such as trapeziectomy, and the superior long-term results compared with classical injection therapy, make this approach feasible as a first-line therapy in early-stage basal joint osteoarthritis of the thumb.

CLINICAL QUESTION/LEVEL OF EVIDENCE:

Therapeutic, IV.
Wound Healing from Dermal Grafts Containing CD34+ Cells Is Comparable to Wound Healing with Split-Thickness Skin Micrografts
Authors: Nuutila Kristo , Singh Mansher , Kruse Carla , Eriksson Elof
Published: April 2017

Background:

Epidermal stem cells present in the skin appendages of the dermis might be crucial in wound healing. In this study, the authors located these cells in the dermis and evaluated their contribution to full-thickness wound healing in a porcine model.

Methods:

Four sequentially deeper 0.35-mm-thick skin grafts were harvested from the same donor site going down to 1.4 mm in depth (layers 1 through 4). The layers were minced to 0.8 × 0.8 × 0.35-mm micrografts and transplanted (1:2) onto full-thickness porcine wounds. Healing was monitored up to 28 days and biopsy specimens were collected on days 6 and 10. Multiple wound healing parameters were used to assess the quality of healing.

Results:

The authors’ results showed that wounds transplanted with layer 2 (0.35 to 0.7 mm) and layer 3 (0.7 to 1.05 mm) micrografts demonstrated reepithelialization rates comparable to that of split-thickness skin graft (layer 1, 0.00 to 0.35 mm; split-thickness skin graft) at day 10. At day 28, dermal micrografts (layers 2 and 3) showed quality of healing comparable to that of split-thickness skin grafts (layer 1) in terms of wound contraction and scar elevation index. The amounts of epidermal stem cells [cluster of differentiation (CD) 34+] and basal keratinocytes (KRT14) at each layer were quantified by immunohistochemistry.

Conclusions:

The analysis showed that layers 2 and 3 contained the most CD34+ cells and layer 1 was the richest in KRT14+ cells. The immunohistochemistry also indicated that, by day 6, CD34+ cells had differentiated into KRT14 cells, which migrated from the grafts and contributed to the reepithelialization of the wound.
A Comparative Analysis of Recombinant Human Bone Morphogenetic Protein-2 with a Demineralized Bone Matrix versus Iliac Crest Bone Graft for Secondary Alveolar Bone Grafts in Patients with Cleft Lip and Palate: Review of 501 Cases
Authors: Hammoudeh Jeffrey A. , Fahradyan Artur , Gould Daniel J. , Liang Fan , Imahiyerobo Thomas , Urbinelli Leo , Nguyen JoAnna T. , Magee William , Yen Stephen , Urata Mark M.
Published: April 2017

Background:

Alveolar cleft reconstruction using iliac crest bone graft is considered standard of care for children with complete cleft lip and palate at the time of mixed dentition. Harvesting bone may result in donor-site morbidity and additional operating time and length of hospitalization. Recombinant human bone morphogenetic protein (rhBMP)-2 with a demineralized bone matrix is an alternative bone source for alveolar cleft reconstruction. The authors investigated the outcomes of rhBMP-2/demineralized bone matrix versus iliac crest bone graft for alveolar cleft reconstruction by reviewing postoperative surgical complications and cleft closure.

Methods:

A retrospective chart review was conducted for 258 rhBMP-2/demineralized bone matrix procedures (mean follow-up, 2.9 years) and 243 iliac crest bone graft procedures (mean follow-up, 4.1 years) on 414 patients over a 12-year period. The authors compared complications, canine eruption, and alveolar cleft closure between the two groups.

Results:

In the rhBMP-2/demineralized bone matrix group, one patient required prolonged intubation because of intraoperative airway swelling not thought to be caused by rhBMP-2, 36 reported facial swelling and one required outpatient steroids as treatment, and 12 had dehiscence; however, half of these complications resolved without intervention. Twenty-three of the 228 rhBMP-2/demineralized bone matrix patients and 28 of the 242 iliac crest bone graft patients required repeated surgery for alveolar cleft repair. Findings for canine tooth eruption into the cleft site through the graft were similar between the groups.

Conclusions:

The rhBMP-2/demineralized bone matrix appears to be an acceptable alternative for alveolar cleft repair. The authors found no increase in serious adverse events with the use of this material. Local complications, such as swelling and minor wound dehiscence, predominantly improved without intervention.

CLINICAL QUESTION/LEVEL OF EVIDENCE:

Therapeutic, III.
Effects of a Laboratory Health Information Exchange Intervention on Antiretroviral Therapy Use, Viral Suppression, and Racial/Ethnic Disparities
Authors: Cunningham William E. , Ford Chandra L. , Kinsler Janni J. , Seiden Danielle , Andrews Laral , Nakazono Terry , Bell Douglas S.
Published: April 2017

Background:

Although antiretroviral therapy (ART) is available to treat HIV+ persons and prevent transmission, ineffective delivery of care may delay ART use, impede viral suppression (VS), and contribute to racial/ethnic disparities along the continuum of care. This study tested the effects of a bi-directional laboratory health information exchange (LHIE) intervention on each of these outcomes.

Methods:

We used a quasi-experimental, interrupted time-series design to examine whether the LHIE intervention improved ART use and VS, and reduced racial/ethnic disparities in these outcomes among HIV+ patients (N = 1181) in a comprehensive HIV/AIDS clinic in Southern California. Main outcome measures were ART pharmacy fill and HIV viral load laboratory data extracted from the medical records over 3 years. Race/ethnicity and an indicator for the intervention (after vs. before) were the main predictors. The analysis involved 3-stage, multivariable logistic regression with generalized estimating equations.

Results:

Overall, the intervention predicted greater odds of ART use (odds ratio [OR] = 2.50; 95% confidence interval: 2.29 to 2.73; P < 0.001) and VS (OR = 1.12; 95% confidence interval: 1.04 to 1.21; P < 0.05) in the final models that included sociodemographic, behavioral, and clinical covariates. Before the intervention, there were significant black/white disparities in ART use OR = 0.75 (0.58–0.98; P = 0.04) and VS OR = 0.75 (0.61–0.92; P = 0.001). After the intervention, the black/white disparities decreased after adjusting for sociodemographics and the number of HIV care visits, and Latinos had greater odds than whites of ART use and VS, adjusting for covariates.

Conclusions:

The intervention improved overall ART treatment and VS, and reduced black/white disparities. LHIE interventions may hold promise if implemented among similar patients.
Critical Questions Regarding Gadolinium Deposition in the Brain and Body After Injections of the Gadolinium-Based Contrast Agents, Safety, and Clinical Recommendations in Consideration of the EMA's Pharmacovigilance and Risk Assessment Committee Recommendation for Suspension of the Marketing Authorizations for 4 Linear Agents
Authors: Runge Val M.
Published: April 2017

For magnetic resonance, the established class of intravenous contrast media is the gadolinium-based contrast agents. In the 3 decades since initial approval, these have proven in general to be very safe for human administration. However, in 2006, a devastating late adverse reaction to administration of the less stable gadolinium-based contrast agents was identified, nephrogenic systemic fibrosis. The result of actions taken by the European Medicines Agency and the US Food and Drug Administration, stratifying the agents by risk and contraindicating specific agents in severe renal dysfunction, has led to no new cases being identified in North America or Europe. Subsequently, in 2014, long-term deposition in the brain of gadolinium was first shown, after administration of 2 nonionic linear chelates, gadodiamide, and gadopentetate dimeglumine. This has led to an intense focus on the question of in vivo distribution, possible dechelation, and subsequent deposition of gadolinium, together with substantial clarification of the phenomenon as well as stratification of the agents on this basis. This review focuses on 8 critical questions regarding gadolinium deposition in the brain and body, with the answers and discussion therein important for future regulatory decisions and clinical practice. It is now clear that dechelation of gadolinium occurs in vivo with the linear agents and is responsible for this phenomenon, with key experts in the field recommending, except where there is no suitable alternative, a shift in clinical practice from the linear to macrocyclic agents. In addition, on March 10, 2017, the Pharmacovigilance and Risk Assessment Committee of the European Medicines Agency recommended suspension of the marketing authorization for 4 linear gadolinium contrast agents—specifically Omniscan, Optimark, Magnevist, and MultiHance (gadodiamide, gadoversetamide, gadopentetate dimeglumine, and gadobenate dimeglumine)—for intravenous injection. Cited in the report was convincing evidence of gadolinium deposition in the brain months after injection of these linear agents. Primovist/Eovist (gadoxetic acid disodium) will remain available, being used at a lower dose for liver imaging, because it meets an important diagnostic need. In addition, a formulation of Magnevist for intra-articular injection will remain available because of its very low gadolinium concentration.
Genetic Ancestry and Susceptibility to Late-Onset Alzheimer Disease (LOAD) in the Admixed Colombian Population
Authors: Moreno Diana J. , Pino Sebastián , Ríos Ángela , Lopera Francisco , Ostos Henry , Via Marc , Bedoya Gabriel
Published: April 2017

Introduction:

Differences in the prevalence of dementia among populations and in the effect of apolipoprotein E (APOE) on the emergence of Alzheimer disease (AD), which is the main type of dementia, have been reported.

Methods:

This study estimated the ancestry of a group of individuals with late-onset Alzheimer disease (LOAD) (N=280) and established whether there were any differences when compared with a control group (N=357) in a sample of the Colombian population.

Results:

When the analyses were adjusted for known risk factors such as age, sex, presence of APOEɛ4, socioeconomic status, educational attainment, and place of birth, African ancestry was associated with an increased LOAD risk (odds ratio: 1.55; 95% confidence interval, 1.09-2.03; P=0.029), whereas Native American ancestry was associated with lower risk (odds ratio: 0.75; 95% confidence interval, 0.61-0.98; P=0.046), for every 10% increase in ancestry. In addition, there were significant differences in the proportion of Native American ancestry between carriers and noncarriers of the APOEɛ4 allele (Mann-Whitney U test, P=0.047), with noncarriers having higher mean Native American ancestry when compared with carriers.

Conclusions:

Our results are consistent with the presence of variants of African origin in the genome of the Colombian population and different from APOEɛ4 that represents a risk factor for the development of LOAD, whereas variants of Native American origin may be conferring protection. However, unknown environmental factors or epigenetic differences among continental groups could also explain the observed associations.
Immunomodulation for glioblastoma
Authors: Reardon David A. , Wen Patrick Y. , Wucherpfennig Kai W. , Sampson John H.
Published: April 2017

Purpose of review

Immunotherapy has emerged as a cornerstone of modern oncology with regulatory approvals for a variety of immunotherapeutics being achieved for a spectrum of cancer indications. Nonetheless the role of these approaches for patients with glioblastoma (GBM), the most common and deadliest primary malignant brain neoplasm, remains unknown. In this review, we summarize the current status of clinical development for the major types of immunotherapeutics, including vaccines, cell-based therapies, and immune checkpoint modulators for GBM. We also highlight potential challenges confronting the development of these agents.

Recent findings

Growing preclinical and clinical data is emerging regarding the potential of immunotherapy strategies for GBM. In parallel, growing data demonstrating that historical dogma classifying the brain as immunoprivileged is inaccurate but that many tumors, including GBM evoke myriad mechanisms to suppress antitumor immune responses.

Ongoing initial trials will provide preliminary data on the role of immunotherapy for GBM patients. Subsequent clinical development steps will likely require rationally designed combinatorial regimens.
Rayleigh–Taylor instability in soft elastic layers
Authors: Riccobelli D. , Ciarletta P.
Published: April 2017

This work investigates the morphological stability of a soft body composed of two heavy elastic layers attached to a rigid surface and subjected only to the bulk gravity force. Using theoretical and computational tools, we characterize the selection of different patterns as well as their nonlinear evolution, unveiling the interplay between elastic and geometric effects for their formation. Unlike similar gravity-induced shape transitions in fluids, such as the Rayleigh–Taylor instability, we prove that the nonlinear elastic effects saturate the dynamic instability of the bifurcated solutions, displaying a rich morphological diagram where both digitations and stable wrinkling can emerge. The results of this work provide important guidelines for the design of novel soft systems with tunable shapes, with several applications in engineering sciences.

This article is part of the themed issue ‘Patterning through instabilities in complex media: theory and applications.’
Development of amplicon deep sequencing markers and data analysis pipeline for genotyping multi-clonal malaria infections
Authors: Lerch Anita , Koepfli Cristian , Hofmann Natalie , Messerli Camilla , Wilcox Stephen , Kattenberg Johanna H. , Betuela Inoni , O’Connor Liam , Mueller Ivo , Felger Ingrid
Published: April 2017

Amplicon deep sequencing permits sensitive detection of minority clones and improves discriminatory power for genotyping multi-clonePlasmodium falciparuminfections. Such high resolution is needed for molecular monitoring of drug efficacy trials. Targeted sequencing of molecular markercspand novel markercpmpwas conducted in duplicate on mixtures of parasite culture strains and 37 field samples. A protocol to multiplex up to 384 samples in a single sequencing run was applied. Software “HaplotypR” was developed for data analysis.Cpmpwas highly diverse (He=0.96) in contrast tocsp(He=0.57). Minority clones were robustly detected if their frequency was >1%. False haplotype calls owing to sequencing errors were observed below that threshold. To reliably detect haplotypes at very low frequencies, experiments are best performed in duplicate and should aim for coverage of >10’000 reads/amplicon. When compared to length polymorphic markermsp2, highly multiplexed amplicon sequencing displayed greater sensitivity in detecting minority clones.
A protein phosphatase network controls the temporal and spatial dynamics of differentiation commitment in human epidermis
Authors: Mishra Ajay , Pisco Angela Oliveira , Oules Benedicte , Ly Tony , Liakath-Ali Kifayathullah , Walko Gernot , Viswanathan Priyalakshmi , Nijjhar Jagdeesh , Dunn Sara-Jane , Lamond Angus I. , Watt Fiona M.
Published: April 2017

Epidermal homeostasis depends on a balance between stem cell renewal and terminal differentiation1,2. While progress has been made in characterising the stem and differentiated cell compartments3, the transition between the two cell states, termed commitment4, is poorly understood. Here we characterise commitment by integrating transcriptomic and proteomic data from disaggregated primary human keratinocytes held in suspension for up to 12h. We have previously shown that commitment begins at approximately 4h and differentiation is initiated by 8h5. We find that cell detachment induces a network of protein phosphatases. The pro-commitment phosphatases – including DUSP6, PPTC7, PTPN1, PTPN13 and PPP3CA – promote terminal differentiation by negatively regulating ERK MAPK and positively regulating key API transcription factors. Their activity is antagonised by concomitant upregulation of the anti-commitment phosphatase DUSP10. The phosphatases form a dynamic network of transient positive and negative interactions, with DUSP6 predominating at commitment. Boolean network modelling identifies a mandatory switch between two stable states (stem cell and differentiated cell) via an unstable (committed) state. In addition phosphatase expression is spatially regulated relative to the location of stem cells, both in vivo and in response to topographical cues in vitro. We conclude that an auto-regulatory phosphatase network maintains epidermal homeostasis by controlling the onset and duration of commitment.
Gamma and beta bursts during working memory read-out suggest roles in its volitional control
Authors: Lundqvist Mikael , Herman Pawel , Warden Melissa R. , Brincat Scott L. , Miller Earl K.
Published: April 2017

Working memory (WM) activity is not as stationary or sustained as previously thought. There are brief bursts of gamma (∼55–120 Hz) and beta (∼20–35 Hz) oscillations, the former linked to stimulus information in spiking. We examine these dynamics in relation to read-out from WM, which is still not well understood. Monkeys held a sequence of two objects and had to decide if they matched a subsequent sequence. Changes in the balance of beta/gamma suggested their role in WM control. In anticipation of having to use an object for the match decision, there was an increase in spiking information about that object along with an increase in gamma and a decrease in beta. When an object was no longer needed, beta increased and gamma as well as spiking information about that object decreased. Deviations from these dynamics predicted behavioral errors. Thus, turning up or down beta could regulate gamma and the information in working memory.
Quantitative agent-based modeling reveals mechanical stress response of growing tumor spheroids is predictable over various growth conditions and cell lines
Authors: Liedekerke Paul Van , Neitsch Johannes , Johann Tim , Alessandri Kevin , Nassoy Pierre , Drasdo Dirk
Published: April 2017

Model simulations indicate that the response of growing cell populations on mechanical stress follows the same functional relationship and is predictable over different cell lines and growth conditions despite the response curves look largely different. We develop a hybrid model strategy in which cells are represented by coarse-grained individual units calibrated with a high resolution cell model and parameterized measurable biophysical and cell-biological parameters. Cell cycle progression in our model is controlled by volumetric strain, the latter being derived from a bio-mechanical relation between applied pressure and cell compressibility. After parameter calibration from experiments with mouse colon carcinoma cells growing against the resistance of an elastic alginate capsule, the model adequately predicts the growth curve in i) soft and rigid capsules, ii) in different experimental conditions where the mechanical stress is generated by osmosis via a high molecular weight dextran solution, and iii) for other cell types with varying doubling times. Our model simulation results suggest that the growth response of cell population upon externally applied mechanical stress is the same, as it can be quantitatively predicted using the same growth progression function.

Author summary

The effect of mechanical resistance on the growth of tumor cells remains today largely unquantified. We studied data from two different experimental setups that monitor the growth of tumor cells under mechanical compression. The existing data in the first experiment examined growing CT26 cells in an elastic permeable capsule. In the second experiment, growth of tumor cells under osmotic stress of the same cell line as well as other cell lines were studied. We have developed and agent-based model with measurable biophysical and cell-biological parameters that can simulate both experiments. Cell cycle progression in our model is a Hill function of cell volumetric strain, derived from a bio-mechanical relation between applied pressure and cell compressibility. After calibration of the model parameters within the data of the first experiment, we are able predict the growth rates in the second experiment. We show that that the growth response of cell populations upon externally applied mechanical stress in the two different experiments and over different cell lines can be predicted using the same growth progression function once the growth kinetics of the cell lines in abscence of mechanical stress is known.
Multiplex genome editing by natural transformation (MuGENT) for synthetic biology inVibrio natriegens
Authors: Dalia Triana N. , Hayes Chelsea A. , Stolyar Sergey , Marx Christopher J. , McKinlay James B. , Dalia Ankur B.
Published: April 2017

Vibrio natriegenshas recently emerged as an alternative toEscherichia colifor molecular biology and biotechnology, but low-efficiency genetic tools hamper its development. Here, we uncover how to induce natural competence inV. natriegensand describe methods for multiplex genome editing by natural transformation (MuGENT). MuGENT promotes integration of multiple genome edits at high-efficiency on unprecedented timescales. Also, this method allows for generating highly complex mutant populations, which can be exploited for metabolic engineering efforts. As a proof-of-concept, we attempted to enhance production of the value added chemical poly-β-hydroxybutyrate (PHB) inV. natriegensby targeting the expression of nine genes involved in PHB biosynthesis via MuGENT. Within 1 week, we isolated edited strains that produced ~100 times more PHB than the parent isolate and ~3.3 times more than a rationally designed strain. Thus, the methods described here should extend the utility of this species for diverse academic and industrial applications.
Memory and Perception-based Facial Image Reconstruction
Authors: Chang Chi-Hsun , Nemrodov Dan , Lee Andy C. H. , Nestor Adrian
Published: April 2017

Visual memory for faces has been extensively researched, especially regarding the main factors that influence face memorability. However, what we remember exactly about a face, namely, the pictorial content of visual memory, remains largely unclear. The current work aims to elucidate this issue by reconstructing face images from both perceptual and memory-based behavioural data. Specifically, our work builds upon and further validates the hypothesis that visual memory and perception share a common representational basis underlying facial identity recognition. To this end, we derived facial features directly from perceptual data and then used such features for image reconstruction separately from perception and memory data. Successful levels of reconstruction were achieved in both cases for newly-learned faces as well as for familiar faces retrieved from long-term memory. Theoretically, this work provides insights into the content of memory-based representations while, practically, it opens the path to novel applications, such as computer-based ‘sketch artists’.
Gene-centric intra- and inter-clade recombination in a context ofEsche-richia colisubpopulations
Authors: Kang Yu , Shi Xing , Yuan Lina , Chu Yanan , Chen Fei , He Zilong , Gao Zhancheng , Jia Xinmiao , Lin Qiang , Ma Qin , Wang Jian , Fu Rongrong , Wu Jiayan , Xiao Jingfa , Hu Songnian , Yu Jun
Published: April 2017

Recombination is one of the most important mechanisms of prokaryotic species evolution but its exact roles are still in debate. Here we try to infer genome-wide recombination events within a species uti-lizing a dataset of 104 complete genomes ofEscherichia colifrom diverse origins, among which 45 from world-wide animal-hosts are in-house sequenced using SMRT (single-molecular real time) technology.Two major clades are identified based on evidences of ecological and physiological characteristics, as well as distinct genomic features implying scarce inter-clade genetic exchange. By comparing the synteny of identical fragments genome-widely searched for each genome pair, we achieve a fine-scale map of re-combination within the population. The recombination is rather extensive within clade, which is able to break linkages between genes but does not interrupt core genome framework and primary metabolic port-folios possibly due to natural selection for physiological compatibility and ecological fitness. Meanwhile,the recombination between clades declines drastically as the phylogenetic distance increases, generally 10-fold reduced than those of the intra-clade, which establishes genetic barrier between clades. These empirical data of recombination suggest its critical role in the early stage of speciation, where recombina-tion rate differs according to phylogentic distance. The extensive intra-clade recombination coheres sister strains into a quasi-sexual group and optimizes genes or alleles to streamline physiological activities,whereas shapely declined inter-clade recombination split the population into clades adaptive to divergent ecological niches.

Significance Statement

Roles of recombination in species evolution have been debated for decades due to difficulties in inferring recombination events during the early stage of speciation, especially when recombination is always complicated by frequent gene transfer events of bacterial genomes. Based on 104 high-quality completeE. coligenomes, we infer gene-centric dynamics of recombination in the formation of twoE. coliclades or subpopulations, and recombination is found to be rather intensive in a within-clade fashion, which forces them to be quasi-sexual. The recombination events can be mapped among individual genomes in the context of genes and their variations; decreased between-clade and increased intra-claderecombination engender a genetic barrier that further encourages clade-specific secondary metabolic portfolios for better environmental adaptation. Recombination is thus a major force that accelerates bacterial evolution to fit ecological diversity.
RNA-seq 2G: online analysis of differential gene expression with comprehensive options of statistical methods
Authors: Zhang Zhe , Zhang Yuanchao , Evans Perry , Chinwalla Asif , Taylor Deanne
Published: April 2017

RNA-seq has become the most prevalent technology for measuring genome-wide gene expression, but the best practices for processing and analysing RNA-seq data are still an open question. Many statistical methods have been developed to identify genes differentially expressed between sample groups from RNA-seq data. These methods differ by their data distribution assumptions, choice of statistical test, and computational resource requirements. Over 25 methods of differential expression detection were validated and made available through a user-friendly web portal, RNA-seq 2G. All methods are suitable for analysing differential gene expression between two groups of samples. They commonly use a read count matrix derived from RNA-seq data as input and statistically compare groups for each gene. The web portal uses a Shiny app front-end and is hosted by a cloud-based server provided by Amazon Web Service. The comparison of methods showed that the data distribution assumption is the major determinant of differences between methods. Most methods are more likely to find that longer genes are differentially expressed, which substantially impacts downstream gene set-level analysis. Combining results from multiple methods can potentially diminish this bias. RNA-seq 2G makes the analysis of RNA-seq data more accessible and efficient, and is freely available athttp://rnaseq2g.awsomics.org.