bluuebunny/crossref_metadata_2025_split huggingface dataset:
Biosimilars and Novel Insulins
Authors: Ampudia-Blasco Francisco Javier 
Published: November 2019

Background:
Insulin therapy is the mainstay of treatment for type 1 diabetes and may be necessary in type 2 diabetes. Current insulin analogues present a more physiological profile, are effective, and with less risk of hypoglycemia, but they are expensive. Biosimilar insulins should offer the advantages of insulin analogues at reduced costs. In addition, current rapid-acting insulin analogues are not fast enough to control excessive postprandial glucose excursions in many patients.

Areas of Uncertainty:
Biosimilar insulins demonstrated that are safe and effective, but interchangeability and automatic substitution remain an issue. Ultrafast-acting insulins should reduce postprandial hyperglycemia and improve flexibility in insulin dosing.

Data sources:
This systematic review was conducted following widely recommended methods. We searched for each topic in Medline, Embase, the Cochrane Library, and SCISEARCH for relevant citations for the appropriate period.

Therapeutic Advances:
LY2963016 and MK-1293 are biosimilar insulins of insulin glargine, and SAR342434 is a biosimilar of insulin lispro. The abbreviated developed program demonstrated comparable efficacy and safety and supports their use for treatment of people with diabetes but no interchangeability. Faster-acting insulin aspart is a new formulation of insulin aspart with accelerated subcutaneous absorption. Faster aspart demonstrated noninferiority in reducing HbA1c as compared to insulin aspart with superiority in controlling postprandial hyperglycemia without increasing hypoglycemia, and flexible insulin dosing.

Conclusions:
Biosimilar insulins have comparable PK-PD profiles and equivalent efficacy and safety to original insulins at a lower price, making them available for more people with diabetes. Faster aspart is the first ultrafast-acting insulin. New upcoming clinical trials and more clinical experience with faster aspart will show the real potential of this new insulin.
Enhanced Recovery After Surgery
Authors: Wainwright Thomas W. , Immins Tikki , Antonis Johannes H. A. , Hartley Richard , Middleton Robert G. 
Published: November 2019

BACKGROUND:
Enhanced Recovery After Surgery (ERAS) focuses on optimizing each element on a treatment pathway and encouraging the patient to actively engage in his or her recovery and rehabilitation. It requires collaboration across a multidisciplinary team and has been successful in improving patient outcomes, length of stay (LOS), and costs for a wide range of surgical procedures, including musculoskeletal surgeries such as total hip and total knee replacement.

PURPOSE:
To examine the application of ERAS concepts to total shoulder replacement (TSR) surgery.

METHODS:
Hospital Episode Statistics (HES) in England on LOS for TSR surgery were examined, and a review of literature on the use of ERAS concepts in TSR was undertaken.

RESULTS:
Analysis of HES data suggested scope for improvement in reducing LOS. A review of the literature found some evidence of the use of ERAS concepts, particularly in multimodal pain management.

CONCLUSIONS:
Future research is now required for ERAS procedure-specific components for TSR surgery.
The Shifting Paradigm in Chronic Lymphocytic Leukemia
Authors: Jain Nitin , O'Brien Susan 
Published: November 2019

Abstract
Chemoimmunotherapy (CIT) was the standard treatment for patients with chronic lymphocytic leukemia for the last 2 decades. Recently, with the introduction of targeted therapies, the role of CIT has declined significantly. In the first-line setting, the role of CIT is limited to young fit patients with mutated immunoglobulin heavy chain variable region and without del(17p)/TP53 mutation. There is a limited role for CIT in relapsed chronic lymphocytic leukemia.
Contemporary Approaches to Postoperative Pain Management
Authors: Murphy Amanda M. , Haykal Siba , Lalonde Donald H. , Zhong Toni 
Published: November 2019

Learning Objectives:
After reading this article, the participant should be able to: 1. Describe the fundamental concepts of multimodal analgesia techniques and how they target pain pathophysiology. 2. Effectively educate patients on postoperative pain and safe opioid use. 3. Develop and implement a multimodal postoperative analgesia regimen.

Summary:
For many years, opioids were the cornerstone of postoperative pain control, contributing to what has become a significant public health concern. This article discusses contemporary approaches to multimodal, opioid-sparing postoperative pain management in the plastic surgical patient.
Histologic Analysis of Sensory and Motor Axons in Branches of the Human Brachial Plexus
Authors: Mioton Lauren M. , Dumanian Gregory A. , De la Garza Mauricio , Ko Jason H. 
Published: November 2019

Background:
The topographic distribution through histologic analysis of motor and sensory axons within peripheral nerves at the brachial plexus level is not clearly defined, as there has previously been little need to appreciate this microanatomy. A desire to better understand the topography of fascicle groups developed with the introduction of targeted muscle reinnervation.

Methods:
Fourteen bilateral brachial plexus specimens from seven fresh human cadavers were harvested at the time of organ donation, and immunofluorescent staining of motor and sensory nerves with choline acetyltransferase and Neurofilament 200 was performed to determine whether a consistent somatotopic orientation exists at the brachial plexus level.

Results:
There was significant variability in the number of fascicles at the level of the brachial plexus. Qualitative analysis of choline acetyltransferase staining demonstrated that although motor axons tended to be grouped in clusters, there were high degrees of variability in somatotopic orientation across specimens. The radial nerve demonstrated the highest number of total myelinated axons, whereas the median nerve exhibited the greatest number of motor axons. The ulnar nerve contained only 13 percent motor axons, which was significantly lower than the median, radial, and musculocutaneous nerves.

Conclusions:
There was no consistent somatotopic organization of motor and sensory axons of the mixed major nerves of the arm just distal to the brachial plexus, but clustering of motor axons may facilitate the splitting of nerves into primarily “motor” and “sensory” fascicles.
Use of the dapivirine vaginal ring and effect on cervical cytology abnormalities
Authors: Reddy Krishnaveni , Kelly Cliff , Brown Elizabeth R. , Jeenarain Nitesha , Naidoo Logashvari , Siva Samantha , Bekker Linda-Gail , Nair Gonasagrie , Makanani Bonus , Chinula Lameck , Mgodi Nyaradzo , Chirenje Zvavahera , Kiweewa Flavia Matovu , Marrazzo Jeanne , Bunge Katherine , Soto-Torres Lydia , Piper Jeanna , Baeten Jared M. , Palanee-Phillips Thesla 
Published: November 2019

Objective:
We aimed to determine if the dapivirine vaginal ring and the ring device alone (flexible silicone matrix polymer) was associated with the development of cervical cytology abnormalities.

Design:
Secondary analysis comparing cervical cytology results between two randomized controlled microbicide trials (MTN-020/ASPIRE and MTN-003/VOICE).

Methods:
Data from ASPIRE, a phase III, placebo-controlled trial of the dapivirine vaginal ring, were used in this analysis. Cervical cytology smears were evaluated at baseline and at the final visit with product use. We compared cytology results between women randomized to dapivirine versus placebo vaginal ring. We further assessed for the effect of the vaginal ring device on cervical cytology by comparing results with data from the oral placebo arm of VOICE, a prior HIV-1 prevention trial conducted in a similar population.

Results:
Cervical cytology results for 2394 women from ASPIRE (1197 per study arm) were used in this analysis; median time between baseline and final visit with product use was 22.1 months. Cytology smear findings were comparable between dapivirine and placebo vaginal ring arms: at final visit, normal: 90.6 versus 91.5%, ASC-US//LSIL: 7.8 versus 7.4%, ASC-H/HSIL/AGC/AGC-favor neoplastic: 1.7 versus 1.1%, P = 0.44. Cytology data from VOICE had findings (normal: 87.8%, ASC-US/LSIL: 9.8%, ASC-H/HSIL/AGC/AGC-favor neoplastic: 2.4%) comparable with that of both dapivirine (P = 0.93) and placebo vaginal ring arms (P = 0.24).

Conclusion:
These findings indicate that neither use of the dapivirine vaginal ring nor the vaginal ring device alone, over a period of 2 years, is associated with development of cervical cytology abnormalities that could lead to precancerous or cancerous lesions.
Cost of Differentiated HIV Antiretroviral Therapy Delivery Strategies in Sub-Saharan Africa: A Systematic Review
Authors: Roberts D. Allen , Tan Nicholas , Limaye Nishaant , Irungu Elizabeth , Barnabas Ruanne V. 
Published: November 2019

Background:
Efficient and scalable models for HIV treatment are needed to maximize health outcomes with available resources. By adapting services to client needs, differentiated antiretroviral therapy (DART) has the potential to use resources more efficiently. We conducted a systematic review assessing the cost of DART in sub-Saharan Africa compared with the standard of care.

Methods:
We searched PubMed, Embase, Global Health, EconLit, and the grey literature for studies published between 2005 and 2019 that assessed the cost of DART. Models were classified as facility-vs. community-based and individual- vs group-based. We extracted the annual per-patient service delivery cost and incremental cost of DART compared with standard of care in 2018 USD.

Results:
We identified 12 articles that reported costs for 16 DART models in 7 countries. The majority of models were facility-based (n = 12) and located in Uganda (n = 7). The annual cost per patient within DART models (excluding drugs) ranged from $27 to $889 (2018 USD). Of the 11 models reporting incremental costs, 7 found DART to be cost saving. The median incremental saving per patient per year among cost-saving models was $67. Personnel was the most common driver of reduced costs, but savings were sometimes offset by higher overheads or utilization.

Conclusions:
DART models can save personnel costs by task shifting and reducing visit frequency. Additional economic evidence from community-based and group models is needed to better understand the scalability of DART. To decrease costs, programs will need to match DART models to client needs without incurring substantial overheads.
Getting to Zero San Francisco: A Collective Impact Approach
Authors: Buchbinder Susan P. , Havlir Diane V. 
Published: November 2019

Background:
Building on several decades of innovative HIV prevention and treatment programming in San Francisco, in 2014, a small group of academic, civic, and community leaders launched Getting to Zero San Francisco, a city-wide consortium focused on getting to zero HIV infections, zero HIV-related deaths, and zero HIV stigma and discrimination.

Setting:
San Francisco city and county.

Methods:
The consortium operates under the principles of collective impact composed of 5 components: a common agenda, shared measurement, mutually reinforcing activities, continuous communication, and organization backbone. Two flagship initiatives are described: citywide scale-up of pre-exposure prophylaxis and rapid antiretroviral therapy upon diagnosis.

Results:
The number of new HIV diagnoses declined by over 50% from 399 to 197 from 2013 to 2018; the time from diagnosis to viral suppression decreased from 134 to 62 days during that period. However, continued racial/ethnic disparities in new HIV diagnoses and viral suppression rates point to the need for the Getting to Zero San Francisco committees to focus on racial/ethnic equity as a primary focus. Cisgender and transgender women, people who inject drugs, and people who are homeless also have lower viral suppression rates; ongoing initiatives are attempting to address these disparities.

Conclusion:
A collective impact implementation strategy that operates by unifying municipal organizations toward a common goal was associated with citywide gains in reducing new HIV diagnosis and time to viral suppression in San Francisco. Formal evaluation of this strategy will help elucidate under which conditions this approach is most likely to succeed.
Implementation of HIV Interventions Into Faith-Based Organizations: Models and Methodological Considerations
Authors: Stewart Jennifer , Salas-Brooks Jessica , Kelly Brittany 
Published: November 2019

Background:
Implementation of evidence-based interventions aimed at reducing and treating HIV can have a wider spread if funneled through faith-based organizations. However, there is a paucity of frameworks or process models aimed at providing the best practices to implement HIV interventions into faith-based community organizations.

Setting:
Implementation framework and process model for African American faith settings.

Results:
Presented here is a systems multilevel implementation framework and implementation process model for integrating HIV interventions into faith-based organizations. We conclude with presentation of key methodological considerations and recommendations and discuss strategies for moving implementation science forward in faith-based organizations.

Conclusion:
Because of their key role in the African American community, faith-based settings must be engaged in implementing evidence-based HIV interventions. Through use of a multilevel systems framework and process model, the methods and approaches of implementation science can be leveraged to encourage the spread of HIV interventions in the African American community.
Security Hi-Tech Individual Extra-Light Device Mask 3.0: A Continuous Evolution
Authors: Vellone Valentino , Ramieri Valerio , Cascone Piero 
Published: November 2019

Abstract
In 2008, the authors presented their Security Hi-tech Individual Extra-Light Device Mask (SHIELD), a customizable protective shield based on the (soccer) player's face cast.
In 2017, the authors presented an update in the realization process, based on computer-aided design/computer-aided manufacturing technology, and called it SHIELD 2.0.
Now, the authors present a further update in the realization process.
Impact of Canthal Height on Horizontal Upper Eyelid Peak Position: A Guide for Blepharoptosis Surgery
Authors: Kitaguchi Yoshiyuki , Takahashi Yasuhiro , Kakizaki Hirohiko , Gomi Fumi , Nishida Kohji 
Published: November 2019

Abstract
This study was aimed at examining the relationship between the horizontal upper eyelid peak position (Δpeak-pupil) and the difference between the medial and lateral canthal heights (Δcanthi) in Japanese individuals. Images of the left eyelid of 71 participants without eyelid disease were acquired with a camera with a slit-lamp microscope. Multivariate linear regression analysis was performed to determine the influence of age, sex, distance from the pupil center to the upper eyelid margin (margin reflex distance-1), Δcanthi, and palpebral fissure width on Δpeak-pupil. In addition, Δpeak-pupil distribution in participants with Δcanthi <3 (Group A), 3 to 6 (Group B), and >6 mm (Group C) was calculated as the average±2x the standard deviation. The mean Δpeak-pupil was 1.12 ± 1.29 mm (range: −1.44 to 6.12) and the mean Δcanthi was 4.50 ± 1.71 mm (1.02–7.96). Δcanthi was a significant determinant factor of Δpeak-pupil (P < 0.0001), whereas age (P = 0.62), sex (P = 0.88), margin reflex distance-1 (P = 0.29), and the horizontal palpebral fissure width (P = 0.65) were not related to Δpeak-pupil. The normal Δpeak-pupil ranges were −1.47 to 1.52, −0.95 to 3.22, and −0.84 to 4.73 mm in Groups A, B, and C, respectively. There was a statistically significant difference between the Group A and B ranges and between the Group A and C ranges (Kruskal–Wallis test, P < 0.01). It was concluded that the normal eyelid peak position differs according to medial-to-lateral canthal positional difference. This finding may help intraoperative determination of the upper eyelid peak position in blepharoptosis surgery.
The Reproducibility of the Point of Care Microcirculation (POEM) Score When Used to Assess Critically Ill Patients: A Multicenter Prospective Observational Study
Authors: Watchorn James C. , Fargaly Hithem , Gilani Muhammad , Assadi Jordan , Deitchman Andrew R. , Naumann David N. , Wollborn Jakob , Goebel Ulrich , McCurdy Michael T. , Hutchings Sam D. 
Published: November 2019

ABSTRACT

Background:
The current standard of analyzing microcirculatory video microscopy is time-consuming and occurs away from the patient, limiting its clinical utility. Point-of-care assessment with incident dark field (IDF) microscopy, however, may offer greater clinical applicability. We aimed to determine the reproducibility of the Point of Care Microcirculation (POEM) tool when used at the bedside in critically ill patients.

Methods:
A multinational, multicenter, prospective observational study of adult intubated patients was undertaken during a 9-month period in Germany, the United Kingdom, and the United States. A user recorded a batch of four standardized video clips from each patient, calculated a POEM score and recorded the time for image acquisition. A second user blinded to the first repeated this process. Patients with video clips of poor quality were excluded. At a later date, the two users again blinded themselves to reassess both their own clips and those of the other user. Basic demographic information was recorded. Intrauser reliability (an individual user rescoring the same batch of videos after blinding), interuser reliability (a second user rescoring the other user's video batch after blinding), and test–retest reliability (two users individually capturing videos and recording POEM scores) were assessed using a linearly weighted kappa statistic for ordinal data.

Results:
Sixty-five patients were included in the final analysis. Observer agreement was substantial for all tests. Intrauser agreement was 0.73 (0.95 CI 0.64–0.81), interuser agreement 0.71 (0.95 CI 0.63–0.79), and test–retest agreement 0.75 (0.95 CI 0.65–0.86). Average time to record videos and assess POEM scores 7:34 ± 3:37 minutes.

Conclusions:
Point-of-care assessment of the microcirculation using IDF video microscopy and POEM scoring appears to be both a feasible and reproducible approach to microcirculatory assessment. Testing of the score in critically ill patients showed substantial agreement within and between investigators, but further studies should validate its utility as a tool to guide shock resuscitation.
Peptidylarginine Deiminase 2 Knockout Improves Survival in hemorrhagic shock
Authors: Zhou Jing , Biesterveld Ben E. , Li Yongqing , Wu Zhenyu , Tian Yuzi , Williams Aaron M. , Tian Shuo , Gao Wenbin , Bhatti Umar F. , Duan Xiuzhen , Wang Tianbing , Zhang Justin , Jiang Baoguo , Wang Zhong , Alam Hasan B. 
Published: November 2019

ABSTRACT

Background:
The peptidylarginine deiminase (PAD) family converts arginine into citrulline through protein citrullination. PAD2 and PAD4 inhibitors can improve survival in hemorrhagic shock (HS). However, the impact of isoform-specific PAD inhibition in improving survival has not been studied. In this study, we utilize selective Pad2−/− knockout mice to elucidate loss of function of PAD2 leads to pro-survival effect in HS.

Methods:

HS: Pad2
−/− and wild-type (WT) mice (n = 5/group) were subjected to lethal HS (55% volume hemorrhage). Survival was monitored over 7 days. Myocardial infarction (MI): Pad2
−/− and WT mice (n = 9/group) were subjected to MI by permanent LAD ligation to examine the effect of ischemia on the heart. After 24 h cardiac function and infarct size were measured.

Results:

HS: Pad2
−/− mice demonstrated 100% survival compared with 0% for WT mice (P = 0.002). In a sub-lethal HS model, cardiac β-catenin levels were higher in Pad2
−/− compared with WT after 24 h. MI: WT mice demonstrated larger MI (75%) compared with Pad2
−/− (60%) (P < 0.05). Pad2
−/− had significantly higher ejection fraction and fractional shortening compared with WT (P < 0.05).

Conclusions:

Pad2
−/− improves survival in lethal HS. Possible mechanisms by which loss of PAD2 function improves survival include the activation of cell survival pathways, improved tolerance of cardiac ischemia, and improved cardiac function during ischemia. PAD2 is promising as a future therapeutic target for the treatment of HS and cardiac ischemia.
In Vivo Analysis of Human Immune Responses in Immunodeficient Rats
Authors: Ménoret Séverine , Ouisse Laure-Hélène , Tesson Laurent , Remy Séverine , Usal Claire , Guiffes Aude , Chenouard Vanessa , Royer Pierre-Joseph , Evanno Gwenaelle , Vanhove Bernard , Piaggio Eliane , Anegon Ignacio 
Published: November 2019

Background.
Humanized immune system immunodeficient mice have been extremely useful for the in vivo analyses of immune responses in a variety of models, including organ transplantation and graft versus host disease (GVHD) but they have limitations. Rat models are interesting complementary alternatives presenting advantages over mice, such as their size and their active complement compartment. Immunodeficient rats have been generated but human immune responses have not yet been described.

Methods.
We generated immunodeficient Rat Rag−/− Gamma chain−/− human signal regulatory protein alpha-positive (RRGS) rats combining Rag1 and Il2rg deficiency with the expression of human signal regulatory protein alpha, a negative regulator of macrophage phagocytosis allowing repression of rat macrophages by human CD47-positive cells. We then immune humanized RRGS animals with human peripheral blood mononuclear cells (hPBMCs) to set up a human acute GVHD model. Treatment of GVHD was done with a new porcine antihuman lymphocyte serum active through complement-dependent cytotoxicity. We also established a tumor xenograft rejection model in these hPBMCs immune system RRGS animals by subcutaneous implantation of a human tumor cell line.

Results.
RRGS animals receiving hPBMCs showed robust and reproducible reconstitution, mainly by T and B cells. A dose-dependent acute GVHD process was observed with progressive weight loss, tissue damage, and death censoring. Antihuman lymphocyte serum (L1S1) antibody completely prevented acute GVHD. In the human tumor xenograft model, detectable tumors were rejected upon hPBMCs injection.

Conclusions.
hPBMC can be implanted in RRGS animals and elicit acute GVHD or rejection of human tumor cells and these are useful models to test new immunotherapies.
Thiamethoxam exposure deregulates short ORF gene expression in the honey bee and compromises immune response to bacteria
Authors: Decio Pâmela , Ustaoglu Pinar , Derecka Kamila , Hardy Ian C. W. , Roat Thaisa C. , Malaspina Osmar , Mongan Nigel , Stöger Reinhard , Soller Matthias 
Published: November 2019

AbstractMaximizing crop yields relies on the use of agrochemicals to control insect pests. One of the most widely used classes of insecticides are neonicotinoids that interfere with signalling of the neurotransmitter acetylcholine, but these can also disrupt crop-pollination services provided by bees. Here, we analysed whether chronic low dose long-term exposure to the neonicotinoid thiamethoxam alters gene expression and alternative splicing in brains of Africanized honey bees,Apis mellifera, as adaptation to altered neuronal signalling. We find differentially regulated genes that show concentration-dependent responses to thiamethoxam, but no changes in alternative splicing. Most differentially expressed genes have no annotated function but encode short Open Reading Frames (sORFs), a characteristic feature of anti-microbial peptides. As this suggested that immune responses may be compromised by thiamethoxam exposure, we tested the impact of thiamethoxam on bee immunity by injecting bacteria. We show that intrinsically sub-lethal thiamethoxam exposure makes bees more vulnerable to normally non-pathogenic bacteria. Our findings imply a synergistic mechanism for the observed bee population declines that concern agriculturists, conservation ecologists and the public.