bluuebunny/crossref_metadata_2025 huggingface dataset:
MIBiG 2.0: a repository for biosynthetic gene clusters of known function
Authors: Kautsar Satria A , Blin Kai , Shaw Simon , Navarro-Muñoz Jorge C , Terlouw Barbara R , van der Hooft Justin J J , van Santen Jeffrey A , Tracanna Vittorio , Suarez Duran Hernando G , Pascal Andreu Victòria , Selem-Mojica Nelly , Alanjary Mohammad , Robinson Serina L , Lund George , Epstein Samuel C , Sisto Ashley C , Charkoudian Louise K , Collemare Jérôme , Linington Roger G , Weber Tilmann , Medema Marnix H
Published: October 2019

Fueled by the explosion of (meta)genomic data, genome mining of specialized metabolites has become a major technology for drug discovery and studying microbiome ecology. In these efforts, computational tools like antiSMASH have played a central role through the analysis of Biosynthetic Gene Clusters (BGCs). Thousands of candidate BGCs from microbial genomes have been identified and stored in public databases. Interpreting the function and novelty of these predicted BGCs requires comparison with a well-documented set of BGCs of known function. The MIBiG (Minimum Information about a Biosynthetic Gene Cluster) Data Standard and Repository was established in 2015 to enable curation and storage of known BGCs. Here, we present MIBiG 2.0, which encompasses major updates to the schema, the data, and the online repository itself. Over the past five years, 851 new BGCs have been added. Additionally, we performed extensive manual data curation of all entries to improve the annotation quality of our repository. We also redesigned the data schema to ensure the compliance of future annotations. Finally, we improved the user experience by adding new features such as query searches and a statistics page, and enabled direct link-outs to chemical structure databases. The repository is accessible online at https://mibig.secondarymetabolites.org/.
Window-of-opportunity clinical trial of pembrolizumab in patients with recurrent glioblastoma reveals predominance of immune-suppressive macrophages
Authors: de Groot John , Penas-Prado Marta , Alfaro-Munoz Kristin , Hunter Kathy , Pei Be Lian , O’Brien Barbara , Weathers Shiao-Pei , Loghin Monica , Kamiya Matsouka Carlos , Yung W K Alfred , Mandel Jacob , Wu Jimin , Yuan Ying , Zhou Shouhao , Fuller Gregory N , Huse Jason , Rao Ganesh , Weinberg Jeffrey S , Prabhu Sujit S , McCutcheon Ian E , Lang Frederick F , Ferguson Sherise D , Sawaya Raymond , Colen Rivka , Yadav Shalini S , Blando Jorge , Vence Luis , Allison James , Sharma Padmanee , Heimberger Amy B
Published: October 2019

Background

We sought to ascertain the immune effector function of pembrolizumab within the glioblastoma (GBM) microenvironment during the therapeutic window.

Methods

In an open-label, single-center, single-arm phase II “window-of-opportunity” trial in 15 patients with recurrent (operable) GBM receiving up to 2 pembrolizumab doses before surgery and every 3 weeks afterward until disease progression or unacceptable toxicities occurred, immune responses were evaluated within the tumor.

Results

No treatment-related deaths occurred. Overall median follow-up time was 50 months. Of 14 patients monitored, 10 had progressive disease, 3 had a partial response, and 1 had stable disease. Median progression-free survival (PFS) was 4.5 months (95% CI: 2.27, 6.83), and the 6-month PFS rate was 40%. Median overall survival (OS) was 20 months, with an estimated 1-year OS rate of 63%. GBM patients’ recurrent tumors contained few T cells that demonstrated a paucity of immune activation markers, but the tumor microenvironment was markedly enriched for CD68+ macrophages.

Conclusions

Immune analyses indicated that pembrolizumab anti–programmed cell death 1 (PD-1) monotherapy alone can’t induce effector immunologic response in most GBM patients, probably owing to a scarcity of T cells within the tumor microenvironment and a CD68+ macrophage preponderance.
Molecular Diagnosis of Craniosynostosis Using Targeted Next-Generation Sequencing
Authors: Yoon Jihoon G , Hahn Hyung Min , Choi Sungkyoung , Kim Soo Jung , Aum Sowon , Yu Jung Woo , Park Eun Kyung , Shim Kyu Won , Lee Min Goo , Kim Yong Oock
Published: October 2019

BACKGROUND

Genetic factors play an important role in the pathogenesis of craniosynostosis (CRS). However, the molecular diagnosis of CRS in clinical practice is limited because of its heterogeneous etiology.

OBJECTIVE

To investigate the genomic landscape of CRS in a Korean cohort and also to establish a practical diagnostic workflow by applying targeted panel sequencing.

METHODS

We designed a customized panel covering 34 CRS-related genes using in-solution hybrid capture method. We enrolled 110 unrelated Korean patients with CRS, including 40 syndromic and 70 nonsyndromic cases. A diagnostic pipeline was established by combining in-depth clinical reviews and multiple bioinformatics tools for analyzing single-nucleotide variants (SNV)s and copy number variants (CNV)s.

RESULTS

The diagnostic yield of the targeted panel was 30.0% (33/110). Twenty-five patients (22.7%) had causal genetic variations resulting from SNVs or indels in 9 target genes (TWIST1, FGFR3, TCF12, ERF, FGFR2, ALPL, EFNB1, FBN1, and SKI, in order of frequency). CNV analysis identified 8 (7.3%) additional patients with chromosomal abnormalities involving 1p32.3p31.3, 7p21.1, 10q26, 15q21.3, 16p11.2, and 17p13.3 regions; these cases mostly presented with syndromic clinical features.

CONCLUSION

The present study shows the wide genomic landscape of CRS, revealing various genetic factors for CRS pathogenesis. In addition, the results demonstrate that an efficient diagnostic workup using target panel sequencing provides great clinical utility in the molecular diagnosis of CRS.
Interval between planning and frameless stereotactic radiosurgery for brain metastases: are our margins still accurate?
Authors: Bronnimann Charlotte , Huchet Aymeri , Benech-Faure Julie , Dutriaux Caroline , Saut Olivier , Blais Eivind , Mollier Olivier , Trouette Renaud , Vendrely Veronique
Published: October 2019

Background

Advances in intracranial stereotactic radiosurgery (SRS) have led to dramatically reduced planning target volume (PTV) margins. However, tumor growth between planning and treatment may lead to treatment failure. Our purpose was to assess the kinetics of tumor growth before SRS for brain metastases.

Methods

This retrospective, monocentric study included all consecutive patients (pts) treated for brain metastases secondary to melanoma (ML) and non-small cell lung cancer (NSCLC) between June 2015 and May 2016. All pts underwent diagnostic brain imaging and a radiosurgery planning MRI, during which gross tumor volume (GTV) was delineated. Linear and exponential models were used to extrapolate a theoretical GTV at first day of treatment, and theoretical time to outgrow the PTV margins.

Results

Twenty-three ML and 31 NSCLC brain metastases (42 pts, 84 brain imaging scans) were analyzed. Comparison of GTV at diagnosis and planning showed increased tumor volume for 20 ML pts (96%) and 22 NSCLC pts (71%). The shortest time to outgrow a 1 mm margin was 6 days and 3 days for ML and 14 and 8 days for NSCLC with linear and exponential models, respectively.

Conclusions

Physicians should bear in mind the interval between SRS planning and treatment. A mathematical model could screen rapidly progressing tumors.
Influenza vaccine uptake and attitudes of healthcare workers in Ireland
Authors: Hogan V , Lenehan M , Hogan M , Natin D P
Published: October 2019

Background

Influenza vaccination uptake by Irish healthcare workers remains sub-optimal despite local initiatives to increase it.

Aims

To investigate hospital workers' attitudes to influenza vaccination and how this influenced their decisions about vaccination.

Methods

A questionnaire survey of Irish hospital workers, measuring uptake of and attitudes to influenza vaccination.

Results

There were 747 responders, of whom 361 (48%) reported having received influenza vaccination. Attitudes predicting vaccination uptake included a belief that vaccination would protect family members (P < 0.0005, CI 1.191–1.739), a perception of susceptibility to ’flu (P < 0.0005, CI 1.182–1.685), a belief that all healthcare workers should be vaccinated (P < 0.005, CI 1.153–1.783), perceived ease of getting ’flu vaccination at work (P < 0.0005, CI 1.851–2.842) and encouragement by line managers (P < 0.05, CI 1.018–1.400). Attitudes negatively associated with vaccination uptake included fear of needles (P < 0.05, CI 0.663–0.985) and a belief that vaccination would cause illness (P < 0.0005, CI 0.436–0.647). Medical staff were significantly more likely to be vaccinated. Healthcare students were least likely to be vaccinated (P < 0.0005).

Conclusion

Addressing specific barriers to influenza vaccination in healthcare workers may improve uptake.
Sustained Response and Rationale of Programmed Cell Death-1-Targeting for Progressive Multifocal Leukoencephalopathy
Authors: Audemard-Verger Alexandra , Gasnault Jacques , Faisant Maxime , Besse Marie-Catherine , Martin-Silva Nicolas , Berra Mado , Fournier Luc , Boutemy Jonathan , Maigne Gwenola , De Boysson Hubert , Ruet Alexis , Vabret Astrid , Chapon Françoise , Martin-Blondel Guillaume , Aouba Achille
Published: October 2019

In this study, we report a complete (clinical, radiological, and virological) sustained (1 year) response after nivolumab salvage therapy in a progressive multifocal leukoencephalopathy patient. Analyses of the cells infiltrate in a pretreatment brain biopsy suggest that parenchymal programmed cell death-L1+ macrophages could be the T-cells partnership in immune exhaustion and virus escape.
Loss of perlecan heparan sulfate glycosaminoglycans lowers body weight and decreases islet amyloid deposition in human islet amyloid polypeptide transgenic mice
Authors: Templin Andrew T , Mellati Mahnaz , Soininen Raija , Hogan Meghan F , Esser Nathalie , Castillo J Josh , Zraika Sakeneh , Kahn Steven E , Hull Rebecca L
Published: October 2019

Islet amyloid is a pathologic feature of type 2 diabetes (T2D) that is associated with β-cell loss and dysfunction. These amyloid deposits form via aggregation of the β-cell secretory product islet amyloid polypeptide (IAPP) and contain other molecules including the heparan sulfate proteoglycan perlecan. Perlecan has been shown to bind amyloidogenic human IAPP (hIAPP) via its heparan sulfate glycosaminoglycan (HS GAG) chains and to enhance hIAPP aggregation in vitro. We postulated that reducing the HS GAG content of perlecan would also decrease islet amyloid deposition in vivo. hIAPP transgenic mice were crossed with Hspg2Δ3/Δ3 mice harboring a perlecan mutation that prevents HS GAG attachment (hIAPP;Hspg2Δ3/Δ3), and male offspring from this cross were fed a high fat diet for 12 months to induce islet amyloid deposition. At the end of the study body weight, islet amyloid area, β-cell area, glucose tolerance and insulin secretion were analyzed. hIAPP;Hspg2Δ3/Δ3 mice exhibited significantly less islet amyloid deposition and greater β-cell area compared to hIAPP mice expressing wild type perlecan. hIAPP;Hspg2Δ3/Δ3 mice also gained significantly less weight than other genotypes. When adjusted for differences in body weight using multiple linear regression modeling, we found no differences in islet amyloid deposition or β-cell area between hIAPP transgenic and hIAPP;Hspg2Δ3/Δ3 mice. We conclude that loss of perlecan exon 3 reduces islet amyloid deposition in vivo through indirect effects on body weight and possibly also through direct effects on hIAPP aggregation. Both of these mechanisms may promote maintenance of glucose homeostasis in the setting of T2D.
Creating and Validating a Shortened Version of the Community Balance and Mobility Scale for Application in People Who Are 61 to 70 Years of Age
Authors: Gordt Katharina , Mikolaizak A Stefanie , Taraldsen Kristin , Bergquist Ronny , Van Ancum Jeanine M , Nerz Corinna , Pijnappels Mirjam , Maier Andrea B , Helbostad Jorunn L , Vereijken Beatrix , Becker Clemens , Schwenk Michael
Published: October 2019

Background

The Community Balance and Mobility Scale (CBM) has been shown to be reliable and valid for detecting subtle balance and mobility deficits in people who are 61 to 70 years of age. However, item redundancy and assessment time call for a shortened version.

Objective

The objective was to create and validate a shortened version of the CBM (s-CBM) without detectable loss of psychometric properties.

Design

This was a cross-sectional study.

Methods

Exploratory factor analysis with data from 189 young seniors (aged 61-70 years; mean [SD] age = 66.3 [2.5] years) was used to create the s-CBM. Sixty-one young seniors (aged 61–70 years; mean [SD] age = 66.5 [2.6] years) were recruited to assess construct validity (Pearson correlation coefficient) by comparing the CBM versions with Fullerton Advance Balance Scale, Timed Up-and-Go, habitual and fast gait speed, 8 Level Balance Scale, 3-m tandem walk, and 30-second chair stand test. Internal consistency (Cronbach α), ceiling effects, and discriminant validity (area under the curve [AUC]) between fallers and nonfallers, and self-reported high and low function (Late-Life Function and Disability Index) and balance confidence (Activities-Specific Balance Confidence Scale), respectively, were calculated.

Results

The s-CBM, consisting of 4 items, correlated excellently with the CBM (r = 0.97). Correlations between s-CBM and other assessments (r = 0.07-0.72), and CBM and other assessments (r = 0.06-0.80) were statistically comparable in 90% of the correlations. Cronbach α was .84 for the s-CBM, and .87 for the CBM. No CBM-version showed ceiling effects. Discriminative ability of the s-CBM was statistically comparable with the CBM (AUC = 0.66-0.75 vs AUC = 0.65-0.79).

Limitations

Longitudinal studies with larger samples should confirm the results and assess the responsiveness for detecting changes over time.

Conclusions

The psychometric properties of the s-CBM were similar to those of the CBM. The s-CBM can be recommended as a valid and quick balance and mobility assessment in young seniors.
A Technology-Enabled Concussion Care Pathway Reduces Costs and Enhances Care
Authors: Alberts Jay L , Modic Michael T , Udeh Belinda L , Zimmerman Nicole , Cherian Kay , Lu Xiaoyang , Gray Robert , Figler Richard , Russman Andrew , Linder Susan M
Published: October 2019

Background

The standardization of care along disease lines is recommended to improve outcomes and reduce health care costs. The multiple disciplines involved in concussion management often result in fragmented and disparate care. A fundamental gap exists in the effective utilization of rehabilitation services for individuals with concussion.

Purpose

The purpose of this project was to (1) characterize changes in health care utilization following implementation of a concussion carepath, and (2) present an economic evaluation of patient charges following carepath implementation.

Design

This was a retrospective cohort study.

Methods

A review of electronic medical and financial records was conducted of individuals (N = 3937), ages 18 to 45 years, with primary diagnosis of concussion who sought care in the outpatient or emergency department settings over a 7-year period (2010–2016). Outcomes including encounter length, resource utilization, and charges were compared for each year to determine changes from pre- to post-carepath implementation.

Results

Concussion volumes increased by 385% from 2010 to 2015. Utilization of physical therapy increased from 9% to 20% while time to referral decreased from 72 to 23 days post-injury. Utilization of emergency medicine and imaging were significantly reduced. Efficient resource utilization led to a 20.7% decrease in median charges (estimated ratio of means [CI] 7.72 [0.53, 0.96]) associated with concussion care.

Limitations

Encounter lengths served as a proxy for recovery time.

Conclusions

The implementation of the concussion carepath was successful in optimizing clinical practice with respect to facilitating continuity of care, appropriate resource utilization, and effective handoffs to physical therapy. The utilization of enabling technology to facilitate the collection of common outcomes across providers was vital to the success of standardizing clinical care without compromising patient outcomes.
Musculoskeletal consultations from childhood to adulthood: a longitudinal study
Authors: Prathivadi Bhayankaram N , Lacey R J , Barnett L A , Jordan K P , Dunn K M
Published: October 2019

Background

The Global Burden of Disease reports indicate that musculoskeletal conditions are important causes of disability worldwide. Such conditions may originate in childhood, but studies investigating changes longitudinally and from childhood to adulthood are infrequent.

Methods

Nine birth cohorts of children (starting at ages 7–15 years) were followed. Participants were identified from Consultations in Primary Care Archive, an electronic health record database of 11 English general practices. Musculoskeletal consultation prevalence figures were calculated, and reasons for consultation evaluated.

Results

Annual musculoskeletal consultation prevalence was similar across cohorts for each age. Prevalence increased from 6 to 16% between ages 7 and 22 and was higher in males until age 15, after which prevalence was higher in females. Pain was the most common reason for consultation. Back pain consultations increased from 1 consultation/1000 7 year olds to 84 consultations/1000 22 year olds. Lower limb pain consultations increased from 21 consultations/1000 7 year olds to 56 consultations/1000 22 year olds.

Conclusions

This study shows that from childhood, individuals are more likely to seek healthcare for musculoskeletal consultations as they age, but rates are not increasing over time. Changes in consultation rates by age, gender and pain region may inform studies on the development of chronic musculoskeletal pain over the life-course.
Association of SHI coverage and level of healthcare utilization and costs in the Philippines: a 10-year pooled analysis
Authors: Haw Nel Jason L , Uy Jhanna , Ho Beverly Lorraine
Published: October 2019

Background

The Philippine Health Insurance Corporation (PhilHealth), which manages the Philippine national health insurance program, is a critical actor in the country’s strategy for universal health coverage. Over the past decade, PhilHealth has passed significant coverage, benefits and payment reforms to contain costs and improve the affordability care for high-cost diseases, inpatient care and select outpatient services.

Methods

We studied the association of PhilHealth with health care utilization and health care costs using three rounds of the Philippine Demographic and Health Survey with data on individual outpatient and inpatient visits from 2008 to 2017.

Results

PhilHealth membership was associated with 42% greater odds of outpatient utilization and 47–100% greater odds inpatient utilization depending on survey year. Depending on facility type, use of PhilHealth to pay for care was associated with higher average health care costs of 244–865% for outpatient care and 135–206% for inpatient care.

Conclusions

PhilHealth has likely decreased barriers to health care utilization but may have inadvertently driven up health care costs in the country. Results align with past studies that suggest that reforms in the prior decade have done little to contain health care costs for Filipinos.
Chemical Weapons and public health: assessing impact and responses
Authors: Ekzayez Abdulkarim , Flecknoe M Daniel , Lillywhite Louis , Patel Preeti , Papamichail Andreas , Elbahtimy Hassan
Published: October 2019

Background

The recent use of Chemical Weapons (CWs) in armed conflicts and terror attacks highlights the importance of understanding their full impact in order to inform an effective response. This article argues that while the consequences of CWs on individual health have dominated our understanding of the impact of these weapons, far less attention has been directed to their impact on public health.

Methods

A review of the literature on the health impact of CWs was conducted, and two case studies of their use in urban settings were explored - Halabja in northern Iraq in 1988 and throughout Syria’s ongoing conflict.

Results

The importance of considering the long-term health consequences of CW use and their impact on healthcare and health systems was demonstrated.

Conclusions

This article highlights the importance of supporting future research on the topic and proposes a framework for assessing the public health impact of CW use.
Bank Regulation under Fire Sale Externalities
Authors: Kara Gazi I , Ozsoy S Mehmet
Published: October 2019

We examine the optimal design of and interaction between capital and liquidity regulations. Banks, not internalizing fire sale externalities, overinvest in risky assets and underinvest in liquid assets in the competitive equilibrium. Capital requirements can alleviate the inefficiency, but banks respond by decreasing their liquidity ratios. When capital requirements are the only available tool, the regulator tightens them to offset banks’ lower liquidity ratios, leading to fewer risky assets and less liquidity compared with the second best. Macroprudential liquidity requirements that complement capital regulations implement the second best, improve financial stability, and allow for more investment in risky assets.

Authors have furnished an Internet Appendix, which is available on the Oxford University Press Web site next to the link to the final published paper online.
Motherhood Wage Penalties in Latin America: The Significance of Labor Informality
Authors: Villanueva Aida , Lin Ken-Hou
Published: October 2019

revious research has established the presence of a motherhood wage penalty in many developed societies; however, whether mothers face similar disadvantages in developing countries remains underexplored. This article argues that different intervening factors emerge when considering mothers’ labor compensation in developing contexts. Labor informality, a key characteristic of labor markets in developing countries, could play a significant role in shaping the wage consequence of motherhood. Using microdata from 43 national household surveys conducted between 2000 and 2017, we analyze five Latin American countries: Argentina, Brazil, Chile, Mexico, and Peru. After accounting for selection into employment and human capital, we find that mothers receive lower wages than childless women in all five countries. The penalties are similar to those found in some developed countries, ranging from 12 percent in Brazil to 21 percent in Chile. Mothers’ higher likelihood to work in the informal sector accounts for part of the wage gap.
The Pathway to Improving Human and Economic Development: Girls’ Secondary Education, Governance, and Education Expenditures
Authors: Sommer Jamie M , Fallon Kathleen M
Published: October 2019

An extensive field of research identifies girls’ secondary education as central to improving human and economic development. Despite improvements in girls’ secondary education enrollment, there are still over 34 million female adolescents out of school—the majority in developing nations. While gender equity in education has improved, girls still lag behind boys in secondary education enrollments. Building on existing research, we argue that the failures of education spending in creating equitable access to secondary education are due to a lack of governance. We contend that strong governance has the potential to increase the effectiveness of education expenditures at improving female secondary education relative to males. Using two-way fixed effects models for a sample of 105 low and middle-income nations from 1997 to 2012, we examine how the interaction between four measures of governance and education expenditures impact gender equity in secondary education. Our findings suggest that governance increases the effectiveness of education expenditures in improving girls’ secondary education enrollment compared to males.
The Silver Bullet? Assessing the Role of Education for Sustainability
Authors: Kelly Orla
Published: October 2019

The United Nations 2030 agenda for sustainable development calls on nation states to invest in national development trajectories that promote both human and environmental well-being. Given the complexity of this plan, and the increasing severity of the climate crisis, understanding the relationship between nations’ social and environmental outcomes is a critical task for social scientists. Raising national rates of educational attainment is a cornerstone national and international governance goal. This paper integrates Amartya Sen’s conceptualization of education as the expansion of human capabilities, with the ecological modernization position that more educated societies may be less ecologically intensive, and tests the resultant hypothesis that gains in education may support global sustainability. Specifically, this study uses two-way fixed effects longitudinal modeling techniques to assess the relationship between national educational attainment and the carbon intensity of well-being (CIWB) for 76 nations between 1960 and 2010. The CIWB ratio is a well-established metric for sustainability within sociology. The findings indicate that gains in educational attainment played an important historical role in reducing the carbon intensity with which nation states produce well-being for its citizens. Less encouraging, from a global sustainability perspective, is the uneven distribution of these desirable effects across regions, and the diminishment of the education effect over time in all regions outside of advanced economies.
Rural independent and corporate Supplemental Nutrition Assistance Program (SNAP)-authorized store owners’ and managers’ perceived feasibility to implement marketing-mix and choice-architecture strategies to encourage healthy consumer purchases
Authors: Houghtaling Bailey , Serrano Elena , Dobson Liza , Chen Susan , Kraak Vivica I , Harden Samantha M , Davis George C , Misyak Sarah
Published: October 2019

Supplemental Nutrition Assistance Program (SNAP) participants could benefit from exposure to marketing-mix and choice-architecture (MMCA) strategies that encourage healthy consumer purchases. However, the perceived feasibility of independent and corporate SNAP-authorized store owners and managers (e.g., retailers) to implement healthy MMCA strategies is understudied. The purpose of this study was to inform a healthy food retail program that meets both public health and business expectations by prioritizing retailer perspectives. A mixed methods approach was used. Retailers completed a card sorting exercise to determine perceived feasibility to implement MMCA strategies place, profile, portion, pricing, promotion, priming, prompting, and proximity. This process was audio-recorded. Chi-square was used to identify potential differences in perceived feasibility to implement healthy MMCA strategies between independent and corporate SNAP-authorized retailers. Qualitative data were coded among a panel to construct themes. Themes were organized by barriers and facilitators and coded for strategy acceptability, appropriateness, and feasibility. SNAP-authorized retailers’ (n = 29) considered prompting (e.g., labeling; 83%) and proximity (e.g., location; 90%) strategies to encourage healthy consumer purchases highly feasible. Few differences were detected between independent and corporate retailers’ perceived feasibility to implement healthy MMCA strategies. The largest barriers to implementing healthy MMCA strategies were related to strategy appropriateness. Priorities for healthy food retail initiatives included prompting and proximity changes that highlight products aligned with the DGA, without altering products available to consumers that are misaligned with the DGA. Future work is required to understand how other healthy MMCA strategies may be adapted to enhance their appropriateness for these settings.
The Health Economic Impact of Living Cell Tissue Products in the Treatment of Chronic Wounds: A Retrospective Analysis of Medicare Claims Data
Authors: Barbul Adrian , Gelly Helen , Masturzo Arti
Published: October 2019

OBJECTIVE

To investigate differences in wound-related costs; product waste; lower-extremity amputations; and number of applications, hospitalizations, and emergency room visits among patients treated with three cellular and/or tissue-based products.

METHODS

This retrospective intent-to-treat matched-cohort study analyzed the full Medicare claims dataset from 2011 to 2014. Patients who received either a bilayer cellular construct (BLCC), dermal skin substitute (DSS), or cryopreserved human skin allograft (CHSA) were concurrently matched for Charlson Comorbidity Index, age, sex, and region, resulting in 14,546 study patients. Key variables were reported at 60, 90, and 180 days after the first product application.

RESULTS

There were no statistically significant differences in the distribution of Charlson Comorbidity Index, age, sex, and region among cohorts. Wound-related costs and product wastage were lower for CHSA patients relative to both BLCC and DSS patients at all time intervals (P < .05). Patients treated with CHSA received fewer product applications than DSS at 90 and 180 days (P < .05). Amputations were significantly higher among patients treated with DSS than either CHSA or BLCC (P < .0001).

CONCLUSIONS

The data demonstrate that wound-related costs, product waste, amputations, and frequency of applications are lower for CHSA than DSS. Wound-related costs and product waste are lower for CHSA compared with BLCC. Further claims analysis and prospective clinical trials could help develop appropriate quality measures and reimbursement models to ensure smarter spending for the growing population of patients with chronic wounds.
Disorders of CTLA-4 expression, how they lead to CVID and dysregulated immune responses
Authors: Sun Di , Heimall Jennifer
Published: October 2019

Purpose of review

The landscape of common variable immunodeficiency disorder (CVID) is rapidly evolving as the availability of next-generation sequencing leads to the discovery of new monogenic causes with the clinical phenotype of CVID. Herein, the biology of cytotoxic T lymphocyte-associated protein four (CTLA-4), differentially expressed in FDCP6 homolog (DEF6), and lipopolysaccharide responsive beige-like anchor protein (LRBA), and their impact on the development of a dysregulated, rather than an isolated, infectious phenotype of CVID are explored.

Recent findings

The broad clinical phenotype associated with these monogenic forms of CVID is described, and common approaches to treatment are reviewed.

Knowledge of the biology, clinical manifestations, and treatment options trialed thus far in patients with CTLA-4 insufficiency, DEF6 deficiency, and LRBA deficiency are essential in the consideration and effective management of patients with CVID stemming from these monogenic causes.
Pilot Study of an Integrated Smartphone and Breathalyzer Contingency Management Intervention for Alcohol Use
Authors: Oluwoye Oladunni , Reneau Hailey , Herron Jalene , Alcover Karl C. , McPherson Sterling , Roll John , McDonell Michael G.
Published: October 2019

Introduction:

Monitoring devices provide a platform for assessing alcohol use and implementing alcohol interventions. This pilot study focused on assessing the early-stage feasibility and usability of a smartphone-based application and breathalyzer used in a contingency management intervention for alcohol use.

Methods:

Six nontreatment-seeking participants completed a 9-week ABA within-subjects designed intervention targeting alcohol use. Participants submitted 2 to 8 alcohol breathalyzer samples per day and completed self-report drinking measures and usability assessments. During the A phases (weeks 1–3 and 8–9), participants received reinforces for submitting breathalyzer samples, regardless of their results. During the contingency management, B phase (weeks 4–7), and received reinforcers only when negative breathalyzer samples were submitted. Usability assessment of the application was also conducted during weeks 2 and 9.

Results:

Participants in the contingent B phase (49%) were more likely to submit alcohol-negative breathalyzer samples compared with the noncontingent A phases (27%; P < 0.001). Usability assessment of the application varied, and participants noted several technical concerns.

Conclusion:

The use of smartphones and breathalyzers may be a practical solution to extend the reach of contingency management during and after treatment.
Defining Low-threshold Buprenorphine Treatment
Authors: Jakubowski Andrea , Fox Aaron
Published: October 2019

Buprenorphine treatment for opioid use disorder is safe and effective, but only a fraction of Americans who need treatment receive it. One reason for this is that many buprenorphine treatment programs have rigid requirements for entry and continuation, limiting the number of people who receive treatment. “Low-threshold treatment” is a term used to describe an alternative approach that attempts to remove as many barriers to treatment as possible. However, few studies have described its essential features. In this article, we define low-threshold treatment and propose the approach be guided by the following principles: same-day treatment entry; harm-reduction approach; flexibility; and wide availability in places where people with opioid use disorder go. We discuss the evidence and rationale for these principles and directions for future research.
Self-reported Health Diagnoses and Demographic Correlates With Kratom Use: Results From an Online Survey
Authors: Bath Rhiannon , Bucholz Tanner , Buros Amy F. , Singh Darshan , Smith Kirsten E. , Veltri Charles A. , Grundmann Oliver
Published: October 2019

Objectives:

To determine whether diagnosed pre-existing health conditions correlate with Kratom demographics and use patterns.

Methods:

A cross-sectional, anonymous US national online survey was conducted among 8049 Kratom users in October, 2016 to obtain demographic, health, and Kratom use pattern information.

Results:

People who use Kratom to mitigate illicit drug dependence self-reported less pain and better overall health than individuals who used Kratom for acute/chronic pain. Self-reported improvements in pre-existing mental health symptoms (attention deficit and hyperactivity disorder/attention deficit disorder, anxiety, bipolar disorder, post-traumatic stress disorder, and depression) attributed to Kratom use were greater than those related to somatic symptoms (back pain, rheumatoid arthritis, acute pain, chronic pain, fibromyalgia). Demographic variables, including female sex, older age, employment status, and insurance coverage correlated with increased likelihood of Kratom use.

Conclusions:

Kratom use may serve as a self-treatment strategy for a diverse population of patients with pre-existing health diagnoses. Healthcare providers need to be engaging with patients to address safety concerns and potential limitations of its use in clinical practice for specific health conditions.
Lumbar Axial Rotation Kinematics in an Upright Sitting and With Forward Bending Positions in Men With Nonspecific Chronic Low Back Pain
Authors: Masharawi Youssef , Haj Alaa , Weisman Asaf
Published: October 2019

Study Design.

A controlled cross-sectional study.

Objective.

The aim of this study was to compare the kinematics of lumbar axial rotation while sitting in an upright and forward bending position in men suffering with and without nonspecific chronic low back pain (NSCLBP).

Summary of Background Data.

Lumbar rotation while sitting is an important factor in the mechanism of low back pain. Nevertheless, its kinematics has scarcely been investigated.

Methods.

Range of motion (ROM in), average velocity (AV), maximum velocity (MV), and maximal acceleration (MA) of lumbar rotation while sitting in an upright (UP-sitting) and full forward bending position (FFB-sitting) were examined using an industrial lumbar motion monitor in 50 men (25 with NSCLBP and 25 controls). Pain level and the Rolland Morris questionnaire (RMQ) were also included.

Results.

All examined kinematical parameters were significantly lower in men with NSCLBP compared with the controls (↓ROM = 16%–29%; ↓AV = 35%–53%; ↓MV = 3%–46%; ↓MA = 7%–44%) and significantly decreased when moving from UP-sitting to FFB-sitting. In the UP-sitting, the ROM and AV in both groups and the right rotation-MV in the NSCLBP group were always greater during the right rotation compared to the left (NSCLBP = ROM: Δ3.92°, AV: Δ2.74°/s, MV:Δ3.61°/s; controls = ROM: Δ3.46°, AV: Δ1.72°/s). The left rotation-MV was significantly greater compared to the right only in FFB-sitting in the controls (Δ3.03°/s). In all kinematical parameters in the NSCLBP group, no correlations were found in the visual analogue scale (VAS) levels (4.43 ± 1.47) or RMQ total score (12.32 ± 5.44).

Conclusion.

The kinematic parameters of lumbar rotation were reduced in men with NSCLBP compared with controls both in an UP-sitting and FFB-sitting. In both groups, NSCLBP and controls, asymmetry in lumbar rotation kinematics was indicated as well as a decrease when moving from UP-sitting to FFB-sitting.

Level of Evidence: 3
Immune-related Adverse Events and Survival in Solid Tumors Treated With Immune Checkpoint Inhibitors: A Systematic Review and Meta-Analysis
Authors: Petrelli Fausto , Grizzi Giulia , Ghidini Michele , Ghidini Antonio , Ratti Margherita , Panni Stefano , Cabiddu Mary , Ghilardi Mara , Borgonovo Karen , Parati Maria C. , Tomasello Gianluca , Barni Sandro , Berruti Alfredo , Brighenti Matteo
Published: October 2019

Immune-related adverse events (irAEs) are autoimmune-toxic effects associated with immune checkpoint inhibitors (ICIs) used for the treatment of advanced solid tumors. We performed a systematic review and meta-analysis of the published literature to assess the outcome for cancer patients treated with ICIs who develop irAEs. Two independent reviewers selected prospective or retrospective studies from PubMed, EMBASE, and the Cochrane Library database from their inception to November 2018. Data were pooled using hazard ratios (HRs) for overall survival or progression-free survival or odds ratio for overall response rate of irAEs versus no irAEs according to fixed or random-effect model. HRs for OS (the primary outcome measure) were pooled to provide an aggregate value. A total of 30 studies that included a total of 4324 patients treated with ICIs were selected. Patients who developed irAEs presented a reduced risk of death [HR=0.49, 95% confidence interval (CI): 0.38–0.62; P<0.001]. Similarly, the occurrence of irAEs was associated with a reduced risk of progression (HR=0.51, 95% CI: 0.42–0.64; P<0.001). The odds of response was 4.56 (95% CI: 3.72–5.59; P<0.001). In patients treated with ICIs, irAEs predict survival and response. Although this correlation cannot be fully explained, it may be related to the strongest T-cell activation.
CAIX-specific CAR-T Cells and Sunitinib Show Synergistic Effects Against Metastatic Renal Cancer Models
Authors: Li Huizhong , Ding Jiage , Lu Mengmeng , Liu Hongyan , Miao Yangna , Li Liantao , Wang Gang , Zheng Junnian , Pei Dongsheng , Zhang Qing
Published: October 2019

Treatment with chimeric antigen receptor-modified T cell (CAR-T) has demonstrated promising therapeutic efficacy in hematologic malignancies. However, the therapeutic efficacy is still very limited for solid tumors. An immunosuppressive microenvironment is one of the main reasons for the limited efficacy. Some chemotherapeutic agents exhibit immune microenvironment modulation. Therefore, combination with chemotherapeutic agents may be one of the promising strategies to enhance the therapeutic efficacy of CAR-T against solid tumors. Sunitinib modulates the antitumor immune response by improving T-cell infiltration and function while reducing immunosuppressive factors. The authors constructed a second-generation CAR targeting human renal cell carcinoma (RCC)-specific antigen carbonic anhydrase IX (CAIX) with the costimulatory domain of 4-1BB. The results of cytokine releasing and cell killing assays showed that the CAIX-CAR-T cells have specific effector functions against CAIX+ renal cancer cells in vitro. Combination therapy with CAIX-CAR-T and sunitinib showed synergistic efficacy against a mouse lung metastasis model of human RCC. CAIX-CAR-T cells in the mice of the combination therapy group showed stronger proliferation and tumor infiltration than that in the mice of the CAIX-CAR-T monotherapy group. The possible mechanisms of the synergistic efficacy are: (1) sunitinib caused upregulation of CAIX in tumor cells; (2) sunitinib decreased frequency of myeloid-derived suppressor cells in the tumor microenvironment. Our study supplied an innovative immunotherapeutic approach whereby combining CAIX-CAR-T with sunitinib induces a potent antitumor response in an experimental model of metastatic RCC. The combination strategy should be considered as a potential approach to augment adoptive CAR-T cell immunotherapy.
Associations Between Preconception Plasma Fatty Acids and Pregnancy Outcomes
Authors: Kim Keewan , Browne Richard W. , Nobles Carrie J. , Radin Rose G. , Holland Tiffany L. , Omosigho Ukpebo R. , Connell Matthew T. , Plowden Torie C. , Wilcox Brian D. , Silver Robert M. , Perkins Neil J. , Schisterman Enrique F. , Nichols Christina M. , Kuhr Daniel L. , Sjaarda Lindsey A. , Mumford Sunni L.
Published: October 2019

Background:

Although fatty acids are involved in critical reproductive processes, the relationship between specific fatty acids and fertility is uncertain. We investigated the relationship between preconception plasma fatty acids and pregnancy outcomes.

Methods:

We included 1,228 women attempting pregnancy with one to two previous pregnancy losses from the EAGeR trial (2007–2011). Plasma fatty acids were measured at baseline. We used log-binomial regression to assess associations between fatty acids and pregnancy, pregnancy loss, and live birth, adjusting for age, race, smoking, BMI, physical activity, income, parity, treatment arm, and cholesterol.

Results:

Although total saturated fatty acids (SFAs) were not associated with pregnancy outcomes, 14:0 (myristic acid; relative risk [RR] = 1.10, 95% confidence interval [CI] = 1.02, 1.19, per 0.1% increase) and 20:0 (arachidic acid; RR = 1.05, 95% CI = 1.01, 1.08, per 0.1% increase) were positively associated with live birth. Findings suggested a positive association between total monounsaturated fatty acids (MUFAs) and pregnancy and live birth and an inverse association with loss. Total polyunsaturated fatty acids (PUFAs) were associated with lower probability of pregnancy (RR = 0.97, 95% CI = 0.95, 1.00) and live birth (RR = 0.96, 95% CI = 0.94, 0.99), and increased risk of loss (RR = 1.10, 95% CI = 1.00, 1.20), per 1% increase. Trans fatty acids and n-3 fatty acids were not associated with pregnancy outcomes.

Conclusions:

Preconception total plasma MUFAs were positively associated with pregnancy and live birth. PUFAs were inversely associated with pregnancy outcomes. Specific SFAs were associated with a higher probability of live birth. Our results suggest that fatty acids may influence pregnancy outcomes.
Exposure to Persistent Organic Pollutants and Birth Characteristics
Authors: Bell Griffith A. , Perkins Neil , Buck Louis Germaine M. , Kannan Kurunthachalam , Bell Erin M. , Gao Chongjing , Yeung Edwina H.
Published: October 2019

Background:

Prenatal exposure to persistent organic pollutants (POPs) may be associated with obesogenic effects in offspring. Our study is the first to investigate associations between concentrations of POPs from newborn dried blood spots (DBS) and birth characteristics.

Methods:

Concentrations of 10 polychlorinated biphenyl congeners (PCBs), polybrominated diphenyl ether-47 (PBDE-47), and p,p′-dichlorodiphenyldichloroethylene (p,p′-DDE) were measured from DBSs collected at birth from 2,065 singleton infants. DBS samples were pooled in groups of five and assayed together to reach limits of detection. Differences in risk of large for gestational age (LGA, defined as >90th percentile of birth weight for sex and gestational age), small for gestational age (SGA, <10th), and preterm birth (gestational age <37 weeks) were estimated using logistic regression per unit (ng/ml) increase in concentration of each chemical, adjusting for individual-level covariates, including maternal age, race/ethnicity, prepregnancy BMI, education, parity, smoking, and infant sex while assuming a gamma distribution and using multiple imputation to account for pools.

Results:

There were 215 (11.3%) singletons born LGA, 158 (7.5%) born SGA, and 157 (7.6%) born preterm. Higher concentrations of POPs were positively associated with slightly higher risk of LGA and higher birth weight.

Conclusions:

Relationships between POPs measured in newborn DBS and birth size were mixed. Pooled analysis methods using DBS could address challenges in limits of detection and costs for population-based research.
Comparison of temperature-mortality associations estimated with different exposure metrics
Authors: Weinberger Kate R. , Spangler Keith R. , Zanobetti Antonella , Schwartz Joel D. , Wellenius Gregory A.
Published: October 2019

Background:

Studies of the short-term association between ambient temperature and mortality often use temperature observations from a single monitoring station, frequently located at the nearest airport, to represent the exposure of individuals living across large areas. Population-weighted temperature estimates constructed from gridded meteorological data may offer an opportunity to improve exposure assessment in locations where station observations do not fully capture the average exposure of the population of interest.

Methods:

We compared the association between daily mean temperature and mortality in each of 113 United States counties using (1) temperature observations from a single weather station and (2) population-weighted temperature estimates constructed from a gridded meteorological dataset. We used distributed lag nonlinear models to estimate the 21-day cumulative association between temperature and mortality in each county, 1987–2006, adjusting for seasonal and long-term trends, day of week, and holidays.

Results:

In the majority (73.4%) of counties, the relative risk of death on extremely hot days (99th percentile of weather station temperature) versus the minimum mortality temperature was larger when generated from the population-weighted estimates. In contrast, relative risks on extremely cold days (first percentile of weather station temperature) were often larger when generated from the weather station observations. In most counties, the difference in associations estimated from the two temperature metrics was small.

Conclusions:

In a large, multi-site analysis, temperature-mortality associations were largely similar when estimated from weather station observations versus population-weighted temperature estimates. However, spatially refined exposure data may be more appropriate for analyses seeking to elucidate local health effects.