bluuebunny/crossref_metadata_2025 huggingface dataset:
Development and validation of the Dutch Stroke Score for predicting disability and functional outcome after ischemic stroke: A tool to support efficient discharge planning
Authors: de Ridder Inger R , Dijkland Simone A , Scheele Maaike , den Hertog Heleen M , Dirks Maaike , Westendorp Willeke F , Nederkoorn Paul J , van de Beek Diederik , Ribbers Gerard M , Steyerberg Ewout W , Lingsma Hester F , Dippel Diederik WJ
Published: January 2018

Introduction

We aimed to develop and validate a prognostic score for disability at discharge and functional outcome at three months in patients with acute ischemic stroke based on clinical information available on admission.

Patients and methods

The Dutch Stroke Score (DSS) was developed in 1227 patients with ischemic stroke included in the Paracetamol (Acetaminophen) In Stroke study. Predictors for Barthel Index (BI) at discharge (‘DSS-discharge’) and modified Rankin Scale (mRS) at three months (‘DSS-3 months’) were identified in multivariable ordinal regression. The models were internally validated with bootstrapping techniques. The DSS-3 months was externally validated in the PRomoting ACute Thrombolysis in Ischemic StrokE study (1589 patients) and the Preventive Antibiotics in Stroke Study (2107 patients). Model performance was assessed in terms of discrimination, expressed by the area under the receiver operating characteristic curve (AUC), and calibration.

Results

At model development, the strongest predictors of Barthel Index at discharge were age per decade over 60 (odds ratio = 1.55, 95% confidence interval (CI) 1.41–1.68), National Institutes of Health Stroke Scale (odds ratio = 1.24 per point, 95% CI 1.22–1.26) and diabetes (odds ratio = 1.62, 95% CI 1.32–1.91). The internally validated AUC was 0.76 (95% CI 0.75–0.79). The DSS-3 months, additionally consisting of previous stroke and atrial fibrillation, performed similarly at internal (AUC 0.75, 95% CI 0.74–0.77) and external validation (AUC 0.74 in PRomoting ACute Thrombolysis in Ischemic StrokE (95% CI 0.72–0.76) and 0.69 in Preventive Antibiotics in Stroke Study (95% CI 0.69–0.72)). Observed outcome was slightly better than predicted. Discussion: The DSS had satisfactory performance in predicting BI at discharge and mRS at three months in ischemic stroke patients.

Conclusion

If further validated, the DSS may contribute to efficient stroke unit discharge planning alongside patients' contextual factors and therapeutic needs.
Acitretin for the Treatment of Psoriasis: A Case Report of Long-Lasting Alopecia
Authors: Waldman Alexandra , Khattri Saakshi , Rose Sharon , Lebwohl Mark , Kellen Roselyn
Published: January 2018

Acitretin has been associated with alopecia and hair shaft abnormalities such as hair kinking, hair curling, poliosis, and re-pigmentation of hair color. In the majority of patients, these side effects are dose-dependent, mild, and only temporary, with hair growth reoccurring after cessation of treatment. A 65-year-old male developed severe hair loss over his entire body seven weeks into treatment. He presented to us more than six months after discontinuation of acitretin without evidence of substantial hair regrowth. Here we report one of the rare cases of long-lasting alopecia after therapy with acitretin that we believe to be a case of generalized telogen effluvium.
To Biopsy or not to Biopsy: A Review of Guidelines on the use of Methotrexate
Authors: Gantz Madeleine , Nia John
Published: January 2018

Hepatotoxicity is a major concern with methotrexate (MTX) therapy for psoriasis. Guidelines to help ensure safe use of MTX in this patient population are revisited periodically as new data become available. Much focus has been dedicated to establishing pre-treatment and monitoring protocols to detect MTX-induced hepatic injury. Here we review past and current guidelines, risk factors, population characteristics, and surveillance techniques with regard to MTX hepatotoxicity in psoriasis patients.
Assessment of the Use of Adrenocorticotropic Hormone in Psoriatic Arthritis
Authors: Madan Elena , Garber Caren , Saraiya Ami , Gottlieb Alice B.
Published: January 2018

Background

A 39-amino-acid peptide of the natural form of adrenocorticotropic hormone (ACTH) was designed to provide a prolonged release after administration by intramuscular or subcutaneous injection. It is FDA-approved as adjunctive therapy for psoriatic arthritis for short-term administration. Clinical data on the safety of ACTH in psoriatic arthritis is limited.

Objective

To assess the safety data for the use of ACTH in psoriatic arthritis and compare it with the safety data for corticosteroids.

Methods

We conducted a systematic review of the literature pertaining to the safety of ACTH versus corticosteroids in psoriatic arthritis. We queried the PubMed database for studies evaluating (i) ACTH and Acthar in psoriatic arthritis using the search terms “psoriatic arthritis” and “ACTH” or “acthar” or “adrenocorticotropic hormone” and (ii) ACTH and Acthar in RA or psoriatic arthritis using the terms “rheumatoid arthritis” or “psoriatic arthritis” and “ACTH” or “acthar” or “adrenocorticotropic hormone.” We placed no time limits on either search. From the search results, we selected studies that emphasize safety data. Due to limited psoriatic arthritis-related data, we included data related to rheumatoid arthritis (RA).

Results

The current body of knowledge surrounding the safety of ACTH in psoriatic arthritis is limited. Twenty studies met our inclusion criteria, 14 of which directly compared ACTH to corticosteroids in either psoriatic arthritis or RA. Of these, five studies reported comparable safety between the two, four studies reported more adverse events with ACTH, two studies reported more adverse events with corticosteroids, and three studies were inconclusive.

Conclusion

There is no clear evidence that ACTH is safer than corticosteroids for psoriatic arthritis.
Apremilast and Cyclosporine Combination Therapy for a Patient with Both Psoriasis and Psoriatic Arthritis: A Case Report
Authors: Sasaki Jodie L. , Zhu Tian H. , Austin Annemieke , Nakamura Mio , Koo John
Published: January 2018

A 45-year-old male with both psoriasis and psoriatic arthritis was treated successfully with the combination of apremilast and cyclosporine. This was a very treatment-resistant case in which the patient was not able to tolerate phototherapy, had previously failed etanercept, adalimumab, and ustekinumab, and developed hepatic fibrosis on methotrexate. Apremilast initially allowed a “cyclosporine holiday” to be tolerable. Later, after cyclosporine was restarted, the patient achieved near complete clearance of his psoriasis on the combination of apremilast and cyclosporine for the first time, despite a lower dose of cyclosporine than was previously required over the past few years.
Treatment of New-Onset Psoriasis Post-Kidney Transplant
Authors: Kellen Roselyn , Nektalova Tatyana
Published: January 2018

Psoriasis is a chronic skin disorder with an autoimmune component primarily driven by overactive T cells culminating in an excessive inflammatory response. Patients have reported clearance of their psoriasis after organ transplant, due to their maintenance on immunosuppressive regimens. Flares of psoriasis post-organ transplant are more rare and often require carefully thought-out management plans. Here we report the treatment of a patient who was diagnosed with new-onset psoriasis eight months after a kidney transplant. In discussion with his nephrologist, the decision was made to increase the doses of tacrolimus and mycophenolate mofetil.
A Review of Current Evidence for TNF Inhibitor Switching in Psoriatic Arthritis
Authors: Abramson Sarah R. , Khattri Saakshi , Lebwohl Mark
Published: January 2018

TNF inhibitors have been proven to be effective in treating psoriatic arthritis, however not every patient responds to or tolerates treatment. Between 20% and 40% of patients are switched to a different TNF inhibitor, and 5% to 15% are eventually treated with three different TNF inhibitors. Loss of efficacy is the most common reason patients fail TNF inhibitor therapy, followed by adverse effects. Less than a quarter of patients who switched TNF inhibitors did so due to lack of primary response. The majority of data demonstrates that switching can be clinically beneficial after failure of one TNF inhibitor, but is associated with lower response rates compared to initial treatment. Drug survival rates also decrease with multiple courses of treatment. If a psoriatic arthritis patient fails two TNF inhibitors, it may be more efficacious to switch to one of the newer biologics with an alternate mechanism of action.
The Annual Economic Burden of Psoriasis
Authors: Kersh Dillon , Kellen Roselyn , Rose Sharon
Published: January 2018

Psoriasis is a chronic disease that affects approximately 2.2% of the U.S. population. The annual economic burden of this disease, both on an individual and national level, has not been clearly defined. Two recently published articles estimated the annual cost to be $35.2 billion (2013 $US) and $112-$135 billion (2013 $US), respectively. Notably, the two articles rely on different estimates of the 2013 U.S. psoriasis population. For patients with mild disease, the largest contributor to cost appears to be non-urgent care such as outpatient visits. For patients with moderate-to-severe disease, pharmacy costs dominate. Although we can partially explain the difference in estimates, this is not an exact science. Not all published articles include the direct, indirect, and intangible costs associated with psoriasis. The measurements themselves are subject to a degree of error. Furthermore, different estimates rely on different studies.
A Systematic Review of Concomitant Bullous Pemphigoid and Psoriasis
Authors: Donnelly Kevin M. , Ferris Laura K. , Kaffenberger Jessica A.
Published: January 2018

Background

Many reports in the medical literature describe patients with concurrent psoriasis and bullous pemphigoid (BP), but little is known about these patients.

Objective:

To characterize patients with concurrent BP and psoriasis and their disease course.

Methods

We performed a systematic review of the English literature for all documented cases of coexistent BP and psoriasis.

Results

Our search yielded 76 cases meeting inclusion criteria. The male-to-female ratio was 2.3:1. The average age of onset of BP was 65 years. Prior to BP eruption, 38% of the patients had acute worsening of their psoriasis. Ultraviolet radiation therapy was the most cited cause of BP outbreak (25%). The most used systemic treatments for BP outbreak were corticosteroids (45%) and methotrexate (18%).

Conclusion

Patients with BP and psoriasis are clinically distinct. Providers should be aware of the association between these diseases and be able to choose treatments that do not exacerbate either disease.
Secukinumab Provides Clearer Skin and Better Control on Patient-Reported Psoriasis Symptoms of Itching, Pain, and Scaling than Placebo and Etanercept
Authors: Strober Bruce , Sigurgeirsson Bárður , Popp Georg , Sinclair Rodney , Krell James , Stonkus Sigitas , Septe Marcis , Elewski Boni E. , Gottlieb Alice B. , Zhao Yang , Herrera Vivian , Mordin Margaret , Odom Dawn , Papavassilis Charis , Nyirady Judit , Lebwohl Mark
Published: January 2018

Background

Secukinumab, a fully human anti-interleukin 17A monoclonal antibody, has demonstrated rapid, strong, and sustained efficacy in moderate-to-severe plaque psoriasis.

Objective

To measure treatment effect on psoriasis-related itching, pain, and scaling during the first 12 weeks of treatment.

Methods

ERASURE and FIXTURE were double-blind, multicenter, phase 3 studies in adults randomly assigned to secukinumab (300 mg or 150 mg), placebo, or etanercept (FIXTURE only). Improvements in itching, pain, and scaling and their bothersomeness, proportions of responders and proportions reporting complete symptom relief were compared.

Results

Subjects treated with secukinumab reported significantly greater symptom improvement versus etanercept and placebo as well as bothersomeness reduction (all P < 0.01). The proportion of symptom responders and proportions reporting complete relief favored secukinumab.

Limitations

Approximately 39% of patients provided data on psoriasis-related itching, pain, and scaling.

Conclusions

Secukinumab significantly improves patient-reported itching, pain, and scaling compared with etanercept and placebo over 12-week psoriasis treatment.
Spreadability of Five Vehicles on Five Surfaces
Authors: Waldman Alexandra , Kellen Roselyn , Khattri Saakshi
Published: January 2018

There are many factors that determine the type of vehicle chosen for a topical medication. Physician considerations include the body region where the agent will be applied, the thickness of the skin, and the amount of surface area in question. Patient considerations include ease of application and removal and aesthetic appeal. We compared the spreadability of five delivery systems used for topical medications (cream, lotion, ointment, gel, and foam) on five types of surfaces (synthetic skin, cardboard, aluminum foil, hard plastic, and soft plastic). In our study (for a set quantity of medication), the foam had the highest spreadability on all tested surfaces, and the ointment the lowest, with the foam covering nine times the surface area of the ointment. This quality makes foam agents ideal for large surface areas. Spreadability can help improve patient tolerability and compliance.
Article Commentary: Explaining the Shift to Value-Based Reimbursement in the Setting of Dermatology and Psoriasis
Authors: Farahnik Benjamin , Nakamura Mio , Bhutani Tina , Koo John
Published: January 2018

The Department of Health and Human Services has announced a campaign for transitioning Medicare reimbursement from volume to value. A budget-neutral Value-Based Payment Modifier has been implemented that provides for differential payment to physicians based upon the quality of care delivered. The value modifier will be based partially on physician participation in the Physician Quality Reporting System (PQRS), which allows for reporting of information on quality of care to Medicare. The information reported includes both medical data and patient-reported experiences with health care providers. Starting in 2017, the value modifier payment adjustment will apply to all physicians who make Medicare part B fee-for-service charge claims. Physicians who do not participate in the PQRS and satisfy reporting requirements may be assessed negative adjustments to their payments. Dermatologists in particular will be impacted by these changes, as skin diseases, especially psoriasis, account for a significant economic burden in the U.S.
Successful Treatment of Recalcitrant Palmoplantar Pustulosis with Ixekizumab
Authors: Kamel Joseph , Routt Ethan
Published: January 2018

Palmoplantar pustulosis (PPP) is a chronic dermatosis that is often viewed as difficult to treat and manage. Many treatment modalities exist for PPP, starting with topical agents and moving to systemic medications in recalcitrant cases. We describe a patient with PPP who was initiated on ixekizumab following failure of several treatment modalities. After 3 months of using ixekizumab, the patient experienced significant improvement of symptoms with no reported side effects. This case demonstrates ixekizumab as an option in cases of recalcitrant PPP. To our knowledge, this is the first reported case of treatment success using ixekizumab monotherapy for PPP.
Off-Label uses of Biologic Agents Approved for Psoriasis and Psoriatic Arthritis for Dermatological Conditions: Part I
Authors: Elbendary Amira , Kellen Roselyn
Published: January 2018

Over the past decade or so, the treatment of patients with psoriasis has been revolutionized by the development of the biological agents, monoclonal antibodies that target specific aspects of the inflammatory cascades. The biologic agents approved by the Food and Drug Administration for psoriasis and psoriatic arthritis include adalimumab, etanercept, infliximab, ustekinumab, and secukinumab. The advantages of these agents are numerous: they are dosed less frequently than previously used systemic agents, they have a more favorable safety profile, and they have incredible efficacy even in patients resistant to standard treatment. There are abundant reports of off-label uses of these drugs for other dermatological conditions and inflammatory dermatoses. This review highlights the ability of the biologic agents to treat a wide spectrum of dermatologic diseases.
Inverse Psoriasis: A Review of Topical Therapies
Authors: Levy Zachary , Taliercio Mark , Nia John K. , Kimmel Grace , Hashim Peter W.
Published: January 2018

Inverse psoriasis, also known as intertriginous or flexural psoriasis, remains a challenging condition to treat. For decades, the mainstay therapy approach has been low-potency steroids for short durations due to the risk of cutaneous atrophy and striae. Other topical options include immunomodulators, vitamin D analogues, and tar-based products. In this paper, we review the literature on the treatment options available for inverse psoriasis.
Ustekinumab in the Treatment of Guttate Psoriasis and Crohn's Disease: A Case Report
Authors: Adalsteinsson Jonas A. , Amir Yasmin
Published: January 2018

Psoriasis and Crohn's disease are autoimmune diseases believed to share a similar pathogenesis. Ustekinumab is FDA-approved for treatment of psoriasis in 45 mg and 90 mg dosages and is undergoing phase III trials for Crohn's disease in higher dosages. Data on ustekinumab in guttate psoriasis (GP) are limited. We report the case of a 21-year-old female with Crohn's disease on adalimumab who developed severe, generalized GP 2 months after a streptococcal infection. Her GP did not regress after discontinuation of adalimumab. She began ustekinumab 45 mg every 12 weeks, which led to complete regression of her psoriasis. Due to persistent bowel symptoms, ustekinumab was increased to 135 mg every 8 weeks, with improvement. In this case, GP may have been related to recent streptococcal infection, or a complication of TNF-inhibitor therapy. Here, we show ustekinumab has potential as a therapeutic option for both GP and Crohn's disease.
Secukinumab and Apremilast Combination Therapy for Recalcitrant Psoriasis
Authors: Hadi Ali , Lebwohl Mark
Published: January 2018

Psoriasis is a chronic inflammatory disorder of the skin and joints mediated by aberrant activity of Th1 and Th17 cells. It also has been shown to be associated with an increased risk of coronary artery disease and metabolic syndrome, highlighting the associated systemic inflammation. Despite the multitude of treatment options available, some cases are still refractory to the available agents, necessitating innovative combination therapies for management. Here we report the second case of plaque psoriasis and psoriatic arthritis treated successfully with a combination of apremilast and secukinumab.
Off-Label uses of Biologic Agents Approved for Psoriasis and Psoriatic Arthritis for Dermatological Conditions: Part II
Authors: Elbendary Amira , Kellen Roselyn
Published: January 2018

Over the past decade or so, the treatment of patients with psoriasis has been revolutionized by the development of the biological agents, monoclonal antibodies that target specific aspects of the inflammatory cascades. The biologic agents approved by the Food and Drug Administration for psoriasis and psoriatic arthritis include adalimumab, etanercept, infliximab, ustekinumab, and secukinumab. The advantages of these agents are numerous: they are dosed less frequently than previously used systemic agents, they have a more favorable safety profile, and they have incredible efficacy, even in patients resistant to standard treatment. There are abundant reports of off-label uses of these drugs for other dermatological conditions and inflammatory dermatoses. This review highlights the ability of the biologic agents to treat a wide spectrum of dermatologic diseases.
Patient-Reported Outcomes Measures in Psoriasis
Authors: Abdat Rana , Lim Yeun Jina , Joshipura Deep , Goldminz Ari , Gottlieb Alice
Published: January 2018

Psoriasis, a chronic systemic inflammatory disease, has a substantial impact on patients’ quality of life (QoL): physical limitations, psychologic impact, social embarrassment, and occupational burden, as well as treatment-related complications. This paper discusses some of the uses and limitations of commonly used patient-reported outcomes (PRO) in psoriasis. We reviewed 260 papers including original research and systemic review papers looking into the PRO used in psoriasis clinical trials. Although there is still no single best PRO measure in psoriasis nor in any other disease, it was interesting to examine the common instruments that are used in psoriasis clinical trials, especially those involving newly innovated biologics as Interleukin 17 inhibitors, and assessing the psychometric properties. The International Dermatology Outcome Measures works with patients, health care providers, payers, and regulators to develop validated patient-centered clinical outcome measures for clinical research as well as clinical practice.
Psoriasis and Depression: A Comprehensive Review for Clinicians
Authors: Jeon Caleb , Sekhon Sahil , Nakamura Mio , Wu Jashin J. , Koo John
Published: January 2018

Psoriasis has various systemic comorbidities including psychiatric disorders. Due to limited experience of dermatologists, psychiatric comorbidities are often not adequately addressed or treated. Recently, the association between depression, a risk factor for suicidality, and psoriasis has become a topic of interest due to suicides occurring in patients on new therapies such as apremilast and brodalumab for the treatment of psoriasis. A systematic literature search was conducted to provide an overview for clinicians on the epidemiological relationship between depression and psoriasis. Although there seems to be higher prevalence of depression in patients with psoriasis compared to non-psoriatic patients, the estimated prevalence of the comorbidity varies greatly and does not necessarily correlate with severity of psoriasis. Given the clear increased risk and association of depression with psoriasis, it is plausible that depression is not directly linked with the apremilast or brodalumab, but rather with psoriasis itself.
Frequency, Prevalence, and Burden of Flares on Patients with Moderate to Severe Psoriasis: A Retrospective Cross-Sectional Analysis
Authors: Hsu Ming-Ann , Lucas James , Wood Robert , Cappelleri Joseph C. , Piercy James
Published: January 2018

Background

Psoriasis impairs health-related quality of life (HRQoL).

Objective

To improve understanding of flare burden in patients with moderate to severe psoriasis.

Methods

A retrospective, cross-sectional study comparing data in U.S. patients with and without psoriasis flares. Physicians identified flaring patients as those not in remission, or in remission < 12 weeks, with worsening/unstable disease progression.

Results

Overall health status (EQ-5D-3L) was reduced in flaring versus matched non-flaring patients ( P = .001); this difference was clinically meaningful (> 0.074 difference in absolute value). Reduced HRQoL and activity impairment, measured by Dermatology Life Quality Index ( P = .0178) and Work Productivity and Activity Impairment Questionnaire ( P = .0002), respectively, were observed in flaring versus non-flaring patients. Anxiety was associated with flaring ( P = .0139). Flaring patients were less satisfied with treatment effectiveness than non-flaring patients ( P < .0001). The flaring group experienced a median of two flares over 12 months.

Conclusion

Flares are associated with reduced health status and HRQoL and lower treatment satisfaction.
A Case of Unnecessary Panic: Dengue Infection during Anti-TNF Treatment for Psoriasis
Authors: Luna Paula Carolina , Arias Cintia Maricel , Manggiarotti German Gastón , Castro Pérez Gimena Antonia , Mazzuoccolo Luis Daniel
Published: January 2018

We report a patient who was infected by dengue virus during a rare epidemic in Argentina. As he was receiving anti-TNF therapy for psoriasis, we were afraid he might have a bad outcome. The patient had a good resolution, however, and a literature review showed that while TNF plays a very important role in the development of dengue fever symptoms, the use of anti-TNF drugs seems not to worsen the course of the disease, and might even protect patients from severe disease.
Nail Psoriasis: A Review of Treatment Options
Authors: Grinnell Madison , Bonomo Lauren , Rabach Morgan
Published: January 2018

Nail psoriasis is often found in patients with plaque psoriasis and can greatly impact quality of life. This is particularly true in more severe cases, as it affects the structure and function of the patient's nail. Treatment for nail psoriasis is often challenging, involving topical medications, injections, and systematic therapies. This article aims to give an overview of the varied clinical presentations of nail psoriasis and the current treatments available for patients with this condition. Risks and efficacies of these treatments will be evaluated to determine the best treatment protocols.
Patient Satisfaction Scores and Standard of Care Compliance in Patients on Biologic Therapy for Psoriasis
Authors: Abittan Brian J. , Bonomo Lauren , Conway Steven , Alesia Ahmad , Gantz Madeline , Lebwohl Mark G.
Published: January 2018

Background

Under the Affordable Care Act, patient satisfaction scores are used to determine reimbursements. There are limited data studying the correlation of patient satisfaction with physician adherence to standard of care practice.

Objective

To examine the correlation between patient satisfaction scores and provider adherence to tuberculosis (TB) monitoring in psoriasis patients on biologic therapy.

Methods

A multicenter retrospective chart review was conducted evaluating physicians’ compliance with TB testing. TB testing compliance was measured and Press Ganey scores of providers from the same time period were obtained.

Results

The correlation constant among providers was 0.41, suggesting no linear relationship between compliance and patient satisfaction scores.

Conclusions

This study did not show a correlation between increased patient satisfaction scores and adherence to appropriate medical standards of care. This contributes to the body of evidence suggesting that these scores are an unsuitable determinant of physician compensation. Further studies controlling multiple variables and with greater power are needed.
A Challenging Case of Poorly Differentiated Transitional Cell Carcinoma of the Kidney
Authors: Katsinis Brittany
Published: January 2018

When describing carcinomas, poorly differentiated defines how little the tumor tissue resembles the normal tissue it came from. The origin of these types of tumors cannot be determined by histological findings alone. Imaging findings and patient history play a strong role in determining the source of the patient’s cancer. Imaging features of urothelial cancer of the renal pelvicaliceal system can be challenging for any sonographer or radiologist. When tumors are hyperechoic relative to nearby renal parenchyma, they may be obscured by the surrounding hyperechoic renal sinus fat, causing these carcinomas to be difficult to detect regardless of whether they are well defined or poorly differentiated. This case study delves into the difficulty in sonographically imaging a poorly differentiated transitional cell carcinoma without sonographic evidence of a primary circumscribed mass.
Ring1A and Ring1B inhibit expression of Glis2 to maintain murine MOZ-TIF2 AML stem cells
Authors: Shima Haruko , Takamatsu-Ichihara Emi , Shino Mika , Yamagata Kazutsune , Katsumoto Takuo , Aikawa Yukiko , Fujita Shuhei , Koseki Haruhiko , Kitabayashi Issay
Published: January 2018

Key Points

MOZ-TIF2 AML cells harboring deletion of Ring1A/B lose self-renewal capacity. Gli-similar 2 promotes differentiation of MOZ-TIF2 AML cells and is derepressed in Ring1A/B-knockout cells.
Mutational dynamics of early and late relapsed childhood ALL: rapid clonal expansion and long-term dormancy
Authors: Spinella Jean-François , Richer Chantal , Cassart Pauline , Ouimet Manon , Healy Jasmine , Sinnett Daniel
Published: January 2018

Key Points

Two distinct evolutionary patterns govern early and late relapse. Evolutionary patterns suggest a mutation-driven resistance for early relapses and a re-expansion of dormant cells for late ones.
Physiology of the lung in idiopathic pulmonary fibrosis
Authors: Plantier Laurent , Cazes Aurélie , Dinh-Xuan Anh-Tuan , Bancal Catherine , Marchand-Adam Sylvain , Crestani Bruno
Published: January 2018

The clinical expression of idiopathic pulmonary fibrosis (IPF) is directly related to multiple alterations in lung function. These alterations derive from a complex disease process affecting all compartments of the lower respiratory system, from the conducting airways to the lung vasculature. In this article we review the profound alterations in lung mechanics (reduced lung compliance and lung volumes), pulmonary gas exchange (reduced diffusing capacity, increased dead space ventilation, chronic arterial hypoxaemia) and airway physiology (increased cough reflex and increased airway volume), as well as pulmonary haemodynamics related to IPF. The relative contribution of these alterations to exertional limitation and dyspnoea in IPF is discussed.
Pulmonary vascular development in congenital diaphragmatic hernia
Authors: Mous Daphne S. , Kool Heleen M. , Wijnen Rene , Tibboel Dick , Rottier Robbert J.
Published: January 2018

Congenital diaphragmatic hernia (CDH) is a rare congenital anomaly characterised by a diaphragmatic defect, persistent pulmonary hypertension (PH) and lung hypoplasia. The relative contribution of these three elements can vary considerably in individual patients. Most affected children suffer primarily from the associated PH, for which the therapeutic modalities are limited and frequently not evidence based. The vascular defects associated with PH, which is characterised by increased muscularisation of arterioles and capillaries, start to develop early in gestation. Pulmonary vascular development is integrated with the development of the airway epithelium. Although our knowledge is still incomplete, the processes involved in the growth and expansion of the vasculature are beginning to be unravelled. It is clear that early disturbances of this process lead to major pulmonary growth abnormalities, resulting in serious clinical challenges and in many cases death in the newborn. Here we provide an overview of the current molecular pathways involved in pulmonary vascular development. Moreover, we describe the abnormalities associated with CDH and the potential therapeutic approaches for this severe abnormality.
Impact of the financial crisis on COPD burden: Greece as a case study
Authors: Kotsiou Ourania S. , Zouridis Spyridon , Kosmopoulos Marinos , Gourgoulianis Konstantinos I.
Published: January 2018

Poverty and low socioeconomic status have been associated with chronic obstructive pulmonary disease (COPD). The current financial crisis has forced millions back into poverty. Greece is one of the countries hit the hardest, and is in the middle of a deep ongoing collapse. There have been early reports stating the apparent effects of the Greek downturn on respiratory health. This review summarises the overall impact of the financial crisis on COPD burden throughout the period of economic downturn by analysing the case study of Greece. In all levels of the healthcare system, current economic restrictions have reduced the capacity to prevent, diagnose and treat COPD in parallel with current higher detection rates of COPD. Remarkably, expenditure on healthcare has been reduced by >25%, resulting in major healthcare equipment shortages. Lower wages (by up to 20%) and higher co-payments of up to 25% of a drug's purchase price have led to patients struggling to afford inhaled medications. Treatment nonadherence has been reported, resulting in 11.5% more exacerbations and 14.1% more hospitalisations annually, while the mean cost per severe COPD exacerbation has been approximated as €2600. Greece is a noteworthy example illustrating how COPD burden, quality of care and patients' outcome can be affected by economic crisis.
ARDS: challenges in patient care and frontiers in research
Authors: Bos Lieuwe D. , Martin-Loeches Ignacio , Schultz Marcus J.
Published: January 2018

This review discusses the clinical challenges associated with ventilatory support and pharmacological interventions in patients with acute respiratory distress syndrome (ARDS). In addition, it discusses current scientific challenges facing researchers when planning and performing trials of ventilatory support or pharmacological interventions in these patients.

Noninvasive mechanical ventilation is used in some patients with ARDS. When intubated and mechanically ventilated, ARDS patients should be ventilated with low tidal volumes. A plateau pressure <30 cmH2O is recommended in all patients. It is suggested that a plateau pressure <15 cmH2O should be considered safe. Patient with moderate and severe ARDS should receive higher levels of positive end-expiratory pressure (PEEP). Rescue therapies include prone position and neuromuscular blocking agents. Extracorporeal support for decapneisation and oxygenation should only be considered when lung-protective ventilation is no longer possible, or in cases of refractory hypoxaemia, respectively. Tracheotomy is only recommended when prolonged mechanical ventilation is expected.

Of all tested pharmacological interventions for ARDS, only treatment with steroids is considered to have benefit.

Proper identification of phenotypes, known to respond differently to specific interventions, is increasingly considered important for clinical trials of interventions for ARDS. Such phenotypes could be defined based on clinical parameters, such as the arterial oxygen tension/inspiratory oxygen fraction ratio, but biological marker profiles could be more promising.
Quantitative analysis of phantom studies of 111In and 68Ga imaging of neuroendocrine tumours
Authors: Jönsson L. , Stenvall A. , Mattsson E. , Larsson E. , Sundlöv A. , Ohlsson T. , Hindorf C.
Published: January 2018

Background

Nuclear medicine imaging of neuroendocrine tumours is performed either by SPECT/CT imaging, using 111In-octreotide or by PET/CT imaging using 68Ga-radiolabelled somatostatin analogs. These imaging techniques will give different image quality and different detection thresholds for tumours, depending on size and activity uptake. The aim was to evaluate the image quality for 111In-SPECT and 68Ga-PET imaging, i.e. the smallest volume possible to visualize for different source-to-background activity ratios. The accuracy of quantification of lesion volume and activity was also investigated to develop an objective evaluation for radionuclide therapy eligibility.

The phantom study was performed using the NEMA IEC Body Phantom with six hot spheres having inner diameters of 10, 13, 17, 22, 28, and 37 mm, filled with either 68Ga or 111In with sphere-to-background ratios (SBRs) of no background activity, 5:1, 2.5:1, and 1.25:1. Activity ratios of 1.25:1 and 2.5:1 are clinically found for lesions close to the liver and spleen. Clinical acquisition and reconstruction protocols were applied. Line profiles were drawn to evaluate the smallest detectable volume within a given SBR. Recovery curves based on threshold-based VOIs, threshold-based VOIs adapted to the background and CT-based ROIs were obtained for all SBRs and sphere diameters, allowing for quantification.

Results

The 10-mm sphere was not possible to detect in SPECT images. It was detectable in PET images for SBRs of 2.5:1 and higher. In a background corresponding to the activity uptake in the liver, spheres larger than 22–37 mm were detectable in the 111In-SPECT images and spheres larger than 13–22 mm were detectable in the 68Ga-PET images. The maximum activity concentration was accurately quantified for spheres larger than 22 mm in the PET images; however, the quantification was impaired by sphere size and background activity.

Conclusions

It was not possible to detect the 10-mm sphere in any of the SPECT images. In a background corresponding to the activity uptake in the liver, spheres larger than approximately 30 mm were visible in the 111In-SPECT images and spheres larger than approximately 17 mm were visible in the 68Ga-PET images. Sphere diameter and background activity strongly affect the possibility of a correct quantification.
Impact of Breast Cancer Early Detection Training on Rwandan Health Workers’ Knowledge and Skills
Authors: Pace Lydia E. , Dusengimana Jean-Marie Vianney , Keating Nancy L. , Hategekimana Vedaste , Rugema Vestine , Bigirimana Jean Bosco , Costas-Chavarri Ainhoa , Umwizera Aline , Park Paul H. , Shulman Lawrence N. , Mpunga Tharcisse
Published: January 2018

Purpose

In April 2015, we initiated a training program to facilitate earlier diagnosis of breast cancer among women with breast symptoms in rural Rwanda. The goal of this study was to assess the impact of the training intervention in breast cancer detection on knowledge and skills among health center nurses and community health workers (CHWs).

Methods

We assessed nurses’ and CHWs’ knowledge about breast cancer risk factors, signs and symptoms, and treatability through a written test administered immediately before, immediately after, and 3 months after trainings. We assessed nurses’ skills in clinical breast examination immediately before and after trainings and then during ongoing mentorship by a nurse midwife. We also examined the appropriateness of referrals made to the hospital by health center nurses.

Results

Nurses’ and CHWs’ written test scores improved substantially after the trainings (overall percentage correct increased from 73.9% to 91.3% among nurses and from 75.0% to 93.8% among CHWs ( P < .001 for both), and this improvement was sustained 3 months after the trainings. On checklists that assessed skills, nurses’ median percentage of actions performed correctly was 24% before the training. Nurses’ skills improved significantly after the training and were maintained during the mentorship period (the median score was 88% after training and during mentorship; P < .001). In total, 96.1% of patients seen for breast concerns at the project’s hospital-based clinic were deemed to have been appropriately referred.

Conclusion

Nurses and CHWs demonstrated substantially improved knowledge about breast cancer and skills in evaluating and managing breast concerns after brief trainings. With adequate training, mentorship, and established care delivery and referral systems, primary health care providers in sub-Saharan Africa can play a critical role in earlier detection of breast cancer.
Local Estrogen Synthesis Regulates Parallel Fiber–Purkinje Cell Neurotransmission Within the Cerebellar Cortex
Authors: Hedges Valerie L , Chen Gang , Yu Lei , Krentzel Amanda A , Starrett Joseph R , Zhu Jing-Ning , Suntharalingam Piratheepan , Remage-Healey Luke , Wang Jian-Jun , Ebner Timothy J , Mermelstein Paul G
Published: January 2018

Estrogens affect cerebellar activity and cerebellum-based behaviors. Within the adult rodent cerebellum, the best-characterized action of estradiol is to enhance glutamatergic signaling. However, the mechanisms by which estradiol promotes glutamatergic neurotransmission remain unknown. Within the mouse cerebellum, we found that estrogen receptor activation of metabotropic glutamate receptor type 1a strongly enhances neurotransmission at the parallel fiber–Purkinje cell synapse. The blockade of local estrogen synthesis within the cerebellum results in a diminution of glutamatergic neurotransmission. Correspondingly, decreased estrogen availability via gonadectomy or blockade of aromatase activity negatively affects locomotor performance. These data indicate that locally derived, and not just gonad-derived, estrogens affect cerebellar physiology and function. In addition, estrogens were found to facilitate parallel fiber–Purkinje cell synaptic transmission in both sexes. As such, the actions of estradiol to support cerebellar neurotransmission and cerebellum-based behaviors might be fundamental to understanding the normal processing of activity within the cerebellar cortex.
Plastid translation is essential for lateral root stem-cell patterning in Arabidopsis thaliana
Authors: Nakata Miyuki T. , Sato Mayuko , Wakazaki Mayumi , Sato Nozomi , Kojima Koji , Sekine Akihiko , Nakamura Shiori , Shikanai Toshiharu , Toyooka Kiminori , Tsukaya Hirokazu , Horiguchi Gorou
Published: January 2018

The plastid evolved from a symbiotic cyanobacterial ancestor and is an essential organelle for plant life, but its developmental roles in roots have been largely overlooked. Here, we show that plastid translation is connected to the stem-cell patterning in lateral root primordia. The RFC3 gene encodes a plastid-localized protein that is a conserved bacterial ribosomal protein S6 of β/γ proteobacterial origin. The rfc3 mutant developed lateral roots with disrupted stem-cell patterning and associated with decreased leaf photosynthetic activity, reduced accumulation of plastid rRNAs in roots, altered root plastid gene expression, and changes in expression of several root stem-cell regulators. These results suggest that deficiencies in plastid function affect lateral root stem cells. Treatment with the plastid translation inhibitor spectinomycin phenocopied the defective stem-cell patterning in lateral roots and altered plastid gene expression observed in the rfc3 mutant. Additionally, when prps17 defective in a plastid ribosomal protein was treated with low concentrations of spectinomycin, it also phenocopied the lateral root phenotypes of rfc3. The spectinomycin treatment and rfc3 mutation also negatively affected symplasmic connectivity between primary root and lateral root primordia. This study highlights previously unrecognized functions of plastid translation in the stem-cell patterning in lateral roots.
Vibration-guided mate searching in treehoppers: directional accuracy and sampling strategies in a complex sensory environment
Authors: Gibson Jeremy S. , Cocroft Reginald B.
Published: January 2018

Animal movement decisions involve an action-perception cycle in which sensory flow influences motor output. Key aspects of the action-perception cycle involved in movement decisions can be identified by integrating path information with measurement of environmental cues. We studied mate searching in insects for which the primary sensory cues are mechanical vibrations traveling through the tissues of living plants. We mapped search paths of male thornbug treehoppers locating stationary females through an exchange of vibrational signals. At each of the males’ sampling locations, we used two-dimensional laser vibrometry to measure stem motion produced by female vibrational signals. We related properties of the vibrational signals to the males’ movement direction, inter-sample distance, and accuracy. Males experienced gradients in signal amplitude and in the whirling motion of the plant stem, and these gradients were influenced to varying degrees by source distance and local stem properties. Males changed their sampling behavior during the search, making longer inter-sample movements farther from the source where uncertainty is higher. The primary directional cue used by searching males was the direction of wave propagation, and males made more accurate decisions when signal amplitude was higher, when time delays were longer between front and back legs, and when female responses were short in duration. The whirling motion of plant stems, including both the eccentricity and the major axes of motion, is a fundamental feature of vibrational environments on living plants, and we show for the first time that it has important influences on the decisions of vibrationally-homing insects.
Analysis of pluripotency marker expression in human glioblastoma multiforme cells treated with conditioned medium of umbilical cord-derived mesenchymal stem cells
Authors: Hardiany Novi Silvia , Huang Purnamawati , Dewi Syarifah , Paramita Reni , Wanandi Septelia Inawati
Published: January 2018

Background: Glioblastoma multiforme (GBM) is the most aggressive form of malignant glioma and is also known as grade IV astrocytoma. This might be due to the presence of cancer stem cells with high pluripotency and ability of self-renewal. Recently, it has been reported that tumor stroma cells, including mesencyhmal stem cells (MSCs), secrete factors that affect cancer cell growth. Until now, the role of MSC secretomes in cancer stem cell pluripotency remains unclear. The aim of this study was to analyze the effect of MSC secretomes in conditioned medium (CM) on the expression of pluripotency markers of GBM cells.

Methods: Umbilical cord-derived MSCs (UCSCs) were grown on serum-free alphaMEM for 24 hours to prepare the UCSC-CM. Human GBM T98G cells were treated with UCSC-CM for 24 hours. Following this treatment, expression of pluripotency markers SOX2, OCT4 and NANOG genes was analyzed using quantitative RT-PCR.

Results: SOX2 and OCT mRNA expression was 4.7-fold (p=0.02) and 1.3-fold (p=0.03) higher in CM-treated cells compared to the control. However, there was no change in NANOG mRNA expression. This might be due to there being others factors regulating NANOG mRNA expression.

Conclusions: UCSC-CM could affect the expression of SOX2 and OCT4 in human glioblastoma multiforme T98G cells. Further research is needed to elucidate the mechanism by which pluripotency markers are expressed when induced by the UCSC secretome.
Real world evidence (RWE) – a disruptive innovation or the quiet evolution of medical evidence generation?
Authors: Khosla Sajan , White Robert , Medina Jesús , Ouwens Mario , Emmas Cathy , Koder Tim , Male Gary , Leonard Sandra
Published: January 2018

Stakeholders in healthcare are increasingly turning to real world evidence (RWE) to inform their decisions, alongside evidence from randomized controlled trials. RWE is generated by analysing data gathered from routine clinical practice, and can be used across the product lifecycle, providing insights into areas including disease epidemiology, treatment effectiveness and safety, and health economic value and impact. Recently, the US Food and Drug Administration and the European Medicines Agency have stated their ambition for greater use of RWE to support applications for new indications, and are now consulting with their stakeholders to formalize standards and expected methods for generating RWE.

Pharmaceutical companies are responding to the increasing demands for RWE by developing standards and processes for each stage of the evidence generation pathway. Some conventions are already in place for assuring quality, whereas other processes are specific to the research question and data sources available. As evidence generation increasingly becomes a core role of medical affairs divisions in large pharmaceutical companies, standards of rigour will continue to evolve and improve. Senior pharmaceutical leaders can drive this change by making RWE a core element of their corporate strategy, providing top-level direction on how their respective companies should approach RWE for maximum quality.

Here, we describe the current and future areas of RWE application within the pharmaceutical industry, necessary access to data to generate RWE, and the challenges in communicating RWE. Supporting and building on viewpoints from industry and publicly funded research, our perspective is that at each stage of RWE generation, quality will be critical to the impact that RWE has on healthcare decision-makers; not only where RWE is an established and evolving tool, but also in new areas that have the potential to disrupt and to improve drug development pathways.