bluuebunny/crossref_metadata_2025 huggingface dataset:
A Comparison of Minimally Invasive and Open Transforaminal Lumbar Interbody Fusion for Grade 1 Degenerative Lumbar Spondylolisthesis: An Analysis of the Prospective Quality Outcomes Database
Authors: Chan Andrew K , Bisson Erica F , Bydon Mohamad , Foley Kevin T , Glassman Steven D , Shaffrey Christopher I , Wang Michael Y , Park Paul , Potts Eric A , Shaffrey Mark E , Coric Domagoj , Knightly John J , Fu Kai-Ming , Slotkin Jonathan R , Asher Anthony L , Virk Michael S , Kerezoudis Panagiotis , Alvi Mohammed A , Guan Jian , Haid Regis W , Mummaneni Praveen V
Published: March 2020

BACKGROUND

It remains unclear if minimally invasive transforaminal lumbar interbody fusion (MI-TLIF) is comparable to traditional, open TLIF because of the limitations of the prior small-sample-size, single-center studies reporting comparative effectiveness.

OBJECTIVE

To compare MI-TLIF to traditional, open TLIF for grade 1 degenerative lumbar spondylolisthesis in the largest study to date by sample size.

METHODS

We utilized the prospective Quality Outcomes Database registry and queried patients with grade 1 degenerative lumbar spondylolisthesis who underwent single-segment surgery with MI- or open TLIF methods. Outcomes were compared 24 mo postoperatively.

RESULTS

A total of 297 patients were included: 72 (24.2%) MI-TLIF and 225 (75.8%) open TLIF. MI-TLIF surgeries had lower mean body mass indexes (29.5 ± 5.1 vs 31.3 ± 7.0, P = .0497) and more worker's compensation cases (11.1% vs 1.3%, P < .001) but were otherwise similar. MI-TLIF had less blood loss (108.8 ± 85.6 vs 299.6 ± 242.2 mL, P < .001), longer operations (228.2 ± 111.5 vs 189.6 ± 66.5 min, P < .001), and a higher return-to-work (RTW) rate (100% vs 80%, P = .02). Both cohorts improved significantly from baseline for 24-mo Oswestry Disability Index (ODI), Numeric Rating Scale back pain (NRS-BP), NRS leg pain (NRS-LP), and Euro-Qol-5 dimension (EQ-5D) (P > .001). In multivariable adjusted analyses, MI-TLIF was associated with lower ODI (β = −4.7; 95% CI = −9.3 to −0.04; P = .048), higher EQ-5D (β = 0.06; 95% CI = 0.01-0.11; P = .02), and higher satisfaction (odds ratio for North American Spine Society [NASS] 1/2 = 3.9; 95% CI = 1.4-14.3; P = .02). Though trends favoring MI-TLIF were evident for NRS-BP (P = .06), NRS-LP (P = .07), and reoperation rate (P = .13), these results did not reach statistical significance.

CONCLUSION

For single-level grade 1 degenerative lumbar spondylolisthesis, MI-TLIF was associated with less disability, higher quality of life, and higher patient satisfaction compared with traditional, open TLIF. MI-TLIF was associated with higher rates of RTW, less blood loss, but longer operative times. Though we utilized multivariable adjusted analyses, these findings may be susceptible to selection bias.
Is Buprenorphine Effective for Chronic Pain? A Systematic Review and Meta-analysis
Authors: Lazaridou Asimina , Paschali Myrella , Edwards Robert R , Gilligan Christopher
Published: March 2020

Objective

The objective was to perform a systematic review and meta-analysis of the literature on the effects of buprenorphine on chronic pain outcomes (i.e., patient-reported pain intensity) in patients with and without opioid use disorder (OUD).

Design

Ovid/Medline, PubMed, Embase, and the Cochrane Library were searched for studies that explored the effectiveness (in reducing pain) of buprenorphine treatment for chronic pain patients with and without a history of OUD. Randomized controlled trials and observational studies were included in the review.

Methods

Two separate searches were conducted to identify buprenorphine trials that included chronic pain patients either with or without OUD. Five studies used validated pain report measures and included a chronic pain population with OUD. Nine studies used validated report measures and included chronic pain patients without OUD. Meta-analysis was performed using the R, version 3.2.2, Metafor package, version 1.9–7.

Results

The meta-analysis revealed that buprenorphine has a beneficial effect on pain intensity overall, with a small mean effect size in patients with comorbid chronic pain and OUD and a moderate- to large-sized effect in chronic pain patients without OUD.

Conclusions

Our results indicate that buprenorphine is modestly beneficial in reducing pain intensity in patients without OUD. Although informative, these findings should be carefully interpreted due to the small amount of data available and the variation in study designs.
The Conceptual–Contextual Gap between Non-recurrence and Transformative Police Reform in Post-Conflict States
Authors: McAuliffe Pádraig
Published: March 2020

The idea of a systemic and holistic approach to police reform that addresses larger structural issues, such as poverty or discrimination against marginalized groups, is an attractive one. It is understandable that reformers and critics aspire to develop police forces that are so well-trained, transparent, and open to external oversight that responsiveness to community needs broadly understood becomes second nature. However, it is not enough to identify the needs of the most marginalized—policy-makers must identify where and how aspirations for change fit the domestic political economy in the security sector. This article has outlined a conceptual–contextual gap in policebuilding, pin-pointing three other main barriers to transformation (i) the necessary preoccupation with and diversion of resources to technical reform, (ii) the need to deal with immediate post-conflict security needs, and (iii) a political economy that does not support the type of responsive, socially democratic culture where transformative policebuilding becomes feasible.
All the News That’s Fit to Ignore
Authors: Toff Benjamin , Kalogeropoulos Antonis
Published: March 2020

In a fragmented digital media environment where news is increasingly encountered passively in social media feeds and via automated mobile alerts, active avoidance of news, rather than deliberate consumption, takes on outsized importance in shaping what it means to be an informed citizen. This article systematically evaluates the factors that predict news avoidance behaviors, considering both individual- and country-level explanations. Using a large-scale quantitative, comparative approach, we examine more than 67,000 survey respondents across 35 countries worldwide and find consistent evidence for how factors including demographics, political attitudes, and news genre preferences shape avoidance consistently across information environments. But we also show how country-level contextual factors, what we call “cultures of news consumption,” influence behaviors beyond that which is explained by respondent-level differences. Specifically, levels of press freedom and political freedom and stability are shown to negatively predict rates of news avoidance. These findings suggest that many people’s news use practices depend not only on personal characteristics and preferences but quite sensibly on the news available to them, which they may have good reason to view as deficient or untrustworthy, as well as culturally specific norms around its value and utility.
The Cross-Section of Risk and Returns
Authors: Daniel Kent , Mota Lira , Rottke Simon , Santos Tano
Published: March 2020

A common practice in the finance literature is to create characteristic portfolios by sorting on characteristics associated with average returns. We show that the resultant portfolios are likely to capture not only the priced risk associated with the characteristic but also unpriced risk. We develop a procedure to remove this unpriced risk using covariance information estimated from past returns. We apply our methodology to the five Fama-French characteristic portfolios. The squared Sharpe ratio of the optimal combination of the resultant characteristic-efficient portfolios is 2.13, compared with 1.17 for the original characteristic portfolios.
Older age onset of systemic sclerosis – accelerated disease progression in all disease subsets
Authors: Moinzadeh Pia , Kuhr Kathrin , Siegert Elise , Mueller-Ladner Ulf , Riemekasten Gabriela , Günther Claudia , Kötter Ina , Henes Jörg , Blank Norbert , Zeidler Gabriele , Pfeiffer Christiane , Juche Aaron , Jandova Ilona , Ehrchen Jan , Schmalzing Marc , Susok Laura , Schmeiser Tim , Sunderkoetter Cord , Distler Jörg H W , Worm Margitta , Kreuter Alexander , Krieg Thomas , Hunzelmann Nicolas ,   and Registry of the German Network for Systemic Scleroderma
Published: March 2020

Objectives

Systemic sclerosis is a heterogeneous, multisystem disease. It can occur at any age, but most patients develop the disease between the age of 40 to 50 years. There is controversial evidence on whether/how the age at disease onset affects their clinical phenotype. We here investigate the relationship between age at disease onset and symptoms in a large cohort of SSc patients (lcSSc, dcSSc and SSc-overlap syndromes).

Methods

Clinical data of the registry of the German Network for Systemic Scleroderma including 3281 patients were evaluated and subdivided into three age groups at disease onset (<40 years, 40–60 years, >60 years).

Results

Among all SSc patients, 24.5% developed their first non-Raynaud phenomenon symptoms at the age <40 years, and 22.5% were older than 60 years of age. In particular, older patients at onset developed the lcSSc subset significantly more often. Furthermore, they had pulmonary hypertension more often, but digital ulcerations less often. Remarkably, the course of the disease was more rapidly progressing in the older cohort (>60 years), except for gastrointestinal and musculoskeletal involvement. No significant difference was found for the use of corticosteroids. However, significantly, fewer patients older than 60 years received immunosuppressive treatment.

Conclusion

In this large registry, ∼25% of patients developed SSc at an age above 60 years with an increased frequency of lcSSc. In this age group, an onset of internal organ involvement was significantly accelerated across all three subsets. These findings suggest that, in the elderly cohort, more frequent follow-up examinations are required for an earlier detection of organ complications.
A PERFORMANCE STUDY OF A NEW PERSONAL NEUTRON DOSIMETRY SYSTEM AT SNRC
Authors: Amit Gal , Even-Hen Ofir , Awad Oshrit , Levi Yaniv , Buchbinder Lotem , Datz Hann
Published: March 2020

This research reviews the performance of a commercial personal fast neutron dosimetry system that has recently been installed in the External Dosimetry Laboratory at Soreq Nuclear Research Center (SNRC). Different kinds of neutron sources like ${}{}^{\mathbf{241}}\boldsymbol{Am}$–Be, ${}{}^{\mathbf{252}}\boldsymbol{Cf}$ and some neutron generators are used in the industry as well as in some research institutes and reactors. The workers in these places need to be regularly monitored for neutron radiation. These workers’ individual neutron doses have been estimated at SNRC until recently by a 30-year-old in-house-made system based on the CR-39 ® solid state nuclear track (SSNT) detector technology. Last year, a new Landauer CR-39 ® neutron dosimetry system was adopted, the Neutrak system. This system employs a standard etching technique using NaOH solution, and measures the SSNT dosimeters automatically and in a repeatable manner. This paper reviews the performance of Landauer’s commercial personal neutron dosimetry system. The system performance shows excellent results in terms of linearity, repeatability, robustness, etch parameters sensitivity and detection threshold.
Neurocomputational mechanisms underlying immoral decisions benefiting self or others
Authors: Qu Chen , Hu Yang , Tang Zixuan , Derrington Edmund , Dreher Jean-Claude
Published: March 2020

Immoral behavior often consists of weighing transgression of a moral norm against maximizing personal profits. One important question is to understand why immoral behaviors vary based on who receives specific benefits and what are the neurocomputational mechanisms underlying such moral flexibility. Here, we used model-based functional magnetic resonance imaging to investigate how immoral behaviors change when benefiting oneself or someone else. Participants were presented with offers requiring a tradeoff between a moral cost (i.e. profiting a morally bad cause) and a benefit for either oneself or a charity. Participants were more willing to obtain ill-gotten profits for themselves than for a charity, driven by a devaluation of the moral cost when deciding for their own interests. The subjective value of an immoral offer, computed as a linear summation of the weighed monetary gain and moral cost, recruited the ventromedial prefrontal cortex (PFC) regardless of beneficiaries. Moreover, paralleling the behavioral findings, this region enhanced its functional coupling with mentalizing-related regions while deciding whether to gain morally tainted profits for oneself vs charity. Finally, individual differences in moral preference differentially modulated choice-specific signals in the dorsolateral PFC according to who benefited from the decisions. These findings provide insights for understanding the neurobiological basis of moral flexibility.
Contingent Negative Variation Blunting and Psychomotor Dysfunction in Schizophrenia: A Systematic Review
Authors: Osborne K Juston , Kraus Brian , Lam Phoebe H , Vargas Teresa , Mittal Vijay A
Published: March 2020

The contingent negative variation (CNV) is an event-related potential that provides a neural index of psychomotor processes (eg, attention and motor planning) well known to be dysfunctional in schizophrenia. Although evidence suggests that CNV amplitude is blunted in patients with schizophrenia (SZ) compared to healthy controls (HCs), there is currently no meta-analytic evidence for the size of the effect. Further, it is unknown how CNV blunting compares to closely related measures of psychomotor dysfunction, such as reaction time slowing. We used random-effects models to calculate the pooled effect size (ES) across 30 studies investigating CNV amplitude differences between patients and HCs (NSZ = 685, NHC = 714). Effect sizes for reaction time slowing across the studies were also quantified. Potential moderators, including sample characteristics and aspects of the CNV measurement, were examined. There was robust blunting of CNV activity in patients compared to HCs (ES = −0.79). The magnitude of this effect did not differ from reaction time slowing. Notably, CNV blunting in patients was significantly greater at central sites (ES = −0.87) compared to frontal sites (ES = −0.48). No other assessed methodological characteristics significantly moderated the magnitude of CNV differences. There is a large effect for CNV blunting in SZ that appears robust to potential confounds or methodological moderators. In addition, reduced CNV activity was statistically comparable to that of reaction time slowing. Blunting was the largest at central electrodes, which has been implicated in motor preparation. These findings speak to the complexity of psychomotor dysfunction in SZ and suggest significant promise for a biomarker.
Sex-specific association of poor sleep quality with gray matter volume
Authors: Neumann Nicola , Lotze Martin , Domin Martin
Published: March 2020

Study Objectives

Previous studies were inconsistent with regard to the association of sleep dysfunction on the brain’s gray matter volume (GMV). The current study set out to investigate if there is a moderating effect of sex on the relationship between sleep quality in healthy individuals and GMV.

Methods

We applied voxel-based morphometry in 1,074 young adults of the “Human Connectome Project.” An analysis of variance with the factors “sleep quality” (good/poor according to the Pittsburgh Sleep Quality Index, cutoff >5) and “sex” (male, female) on GMV was conducted. Additionally, linear relationships between sleep quality and GMV were tested.

Results

The analysis of variance yielded no main effect for sleep quality, but an interaction between sex and sleep quality for the right superior frontal gyrus. Post hoc t-tests showed that female good sleepers in comparison to female poor sleepers had larger GMV in the right parahippocampal gyrus extending to the right hippocampus (whole-brain family-wise error [FWE]-corrected), as well as smaller GMV in the right inferior parietal lobule (whole-brain FWE-corrected) and the right inferior temporal gyrus (whole brain FWE-corrected). There were no significant effects when comparing male good sleepers to male poor sleepers. Linear regression analyses corroborated smaller GMV in the right parahippocampal gyrus in women with poor sleep quality.

Conclusions

Poor sleep quality was associated with altered GMV in females, but not in males. Future studies are needed to investigate the neurobiological mechanisms that underlie the sex differences in the association of sleep quality and brain differences found in this study.
The Tipping Point: Examining the Effects of Heterosexist and Racist Stigma on Political Participation
Authors: Cravens Royal G.
Published: March 2020

Intersectionality suggests that stigmatization experienced across multiple identities has a demobilizing effect, making people less likely to challenge systemic inequalities through political engagement. Using data collected from a unique survey of lesbian, gay, bisexual, and transgender (LGBT) respondents, this study analyzes how experience with injustice across racial and sexual identities affects political participation. I find (1) heterosexist stigma is positively associated with political participation; (2) racist stigma is positively associated with participation in the form of political persuasion among both whites and racial minorities; and (3) there is a tipping point after which the compounded effects of stigma across multiple identities negatively affect political participation, but primarily among the most politically active LGBT people.
An honest mistake: two cases of mistaken dispositions
Authors: Watts Thomas , Gunson Hugh
Published: March 2020

Two recent English cases, Hartogs v Sequent1and Payne v Tyler2, provide helpful examples of the application of the guidelines in the Supreme Court decision in Pitt v Holt3for claims seeking to set aside voluntary transactions on the grounds of mistake where significant unexpected tax liabilities are incurred. The facts and quantum of the cases are quite different and demonstrate the potentially wide application of the Pitt v Holt guidelines, as well as the willingness of the English Courts to hear such claims and grant the relief sought. The cases also offer guidance on a number of practical points for potential claimants for claims based on a mistake, in particular on the issues of proper forum, the role of HMRC and the position adopted by fiduciaries as non-contesting parties to the claims.
Confidential trust information and court proceedings: can privacy be maintained?
Authors: Sawyer Edward , Holmes Jamie
Published: March 2020

Trust litigation often involves highly confidential information, and it is common for all concerned to want any proceedings kept as confidential as possible. In this article, we explore four different ways in which such information might nonetheless be sought by, or become available to, a wider audience, namely through: (i) the publication of trusts judgments pursuant to the principle of open justice, (ii) applications to lift the confidentiality attaching to documents disclosed in Beddoe proceedings, (iii) the cross-examination of the trust’s own lawyers on a witness summons and (iv) the deployment of letters of request (formerly “rogatory”) against an overseas trustee.
Anti-neoplastic and immunomodulatory potency of co-treatment based on bovine lactoferrin and/or muramyl dipeptide in tumor-bearing mice
Authors: Ibrahim Hany M , Mohamed Azza H , Salem Mohamed L , Osman Gamalat Y , Morsi Dalia S
Published: March 2020

The current study investigates anti-neoplastic and immunomodulatory activities of co-treatment based on bovine lactoferrin (bLF) and/or muramyl dipeptide (MDP) with or without cisplatin (Cis) in tumor-bearing mice. In the present study, bLF (100 mg/kg; orally) and MDP (0.5 mg/kg; subcutaneously) was administered alone or together. MDP or bLF was co-treated with Cis (1 mg/kg; intraperitoneally) in mice-bearing Ehrlich solid carcinoma. Tumor size, tumor mass proliferation, apoptosis using immunohistochemistry, the alteration in spleen cell proliferation, phenotype using flow cytometry and white blood cells total and differential counts were detected. Treatment with Cis or (bLF and MDP) significantly reduced tumor size, upregulated the pro-apoptotic p53 expression and downregulated the anti-apoptotic Bcl-2 and proliferative marker PCNA expression compared to non-treated tumor-bearing animals. Moreover, co-treatment of MDP and Cis significantly potentiated the reduction of the tumor size, downregulated the Bcl-2 and PCNA expression and upregulated the p53 expression compared to Cis-treated animals. While bLF and Cis co-treatment positively controlled PCNA and p53 expression compared to tumor-bearing animals, it significantly potentiated the reduction of the tumor size and downregulated the Bcl-2 expression compared to Cis-treated animals. Co-treatment of (bLF and MDP), (bLF and Cis) or (MDP and Cis) increased the spleen cell proliferation and altered the immunological profile of the CD3+CD4+, CD3+CD8+, CD3+CD4+CD69+, CD3+CD8+CD69+ and CD11b+Ly6G+ cells to achieve better immune response against tumor. In conclusion, co-treatments based on bLF and/or MDP are promising therapies against cancer, through their potency to control proliferation, enhance apoptosis and improve the immune status against tumor cells.
Genetic Factors and Delayed TSB Monitoring and Treatment as Risk Factors Associated with Severe Hyperbilirubinemia in Term Neonates Admitted for Phototherapy
Authors: Boo Nem-Yun , Sin Shwe , Chee Seok-Chiong , Mohamed Maslina , Ahluwalia Anita Kaur , Ling Michelle Min-Min , Ong Han-Kiat
Published: March 2020

Objectives

This study aimed to determine whether maternal–fetal blood group isoimmunization, breastfeeding, birth trauma, age when first total serum bilirubin (TSB) was measured, age of admission, and genetic predispositions to hemolysis [due to genetic variants of glucose-6-phosphate dehydrogenase (G6PD) enzyme], and reduced hepatic uptake and/or conjugation of serum bilirubin [due to genetic variants of solute carrier organic anion transporter protein family member 1B1 (SLCO1B1) and uridine diphosphate glucuronosyltransferase family 1 member A1 (UGT1A1)] were significant risk factors associated with severe neonatal hyperbilirubinemia (SNH, TSB ≥ 342µmol/l) in jaundiced term neonates admitted for phototherapy.

Methods

The inclusion criteria were normal term neonates (gestation ≥ 37 weeks). Parents/care-givers were interviewed to obtain data on demography, clinical problems, feeding practice and age when first TSB was measured. Polymerase chain reaction-restriction fragment length polymorphism method was used to detect common G6PD, UGT1A1 and SLCO1B1 variants on each neonate’s dry blood specimens.

Results

Of 1121 jaundiced neonates recruited, 232 had SNH. Logistic regression analysis showed that age (in days) when first TSB was measured [adjusted odds ratio (aOR) = 1.395; 95% confidence interval (CI) 1.094–1.779], age (in days) of admission (aOR = 1.127; 95% CI 1.007–1.260) and genetic mutant UGT1A1 promoter A(TA)7TAA (aOR = 4.900; 95% CI 3.103–7.739), UGT1A1 c.686C>A (aOR = 6.095; 95% CI 1.549–23.985), SLCO1B1 c.388G>A (aOR = 1.807; 95% CI 1.242–2.629) and G6PD variants and/or abnormal G6PD screening test (aOR = 2.077; 95% CI 1.025–4.209) were significantly associated with SNH.

Conclusion

Genetic predisposition, and delayed measuring first TSB and commencing phototherapy increased risk of SNH.
Management issues in rheumatoid arthritis-associated interstitial lung disease
Authors: England Bryant R. , Hershberger Daniel
Published: March 2020

Purpose of review

Summarize recent evidence on the identification and management of rheumatoid arthritis-associated interstitial lung disease (RA-ILD).

Recent findings

Clinical and subclinical interstitial lung disease (ILD) are frequent extra-articular manifestations of rheumatoid arthritis (RA). Better means of identifying and treating RA-ILD are needed to improve the prognosis, with a median survival of only 3–7 years after diagnosis. Several serum biomarkers are currently being evaluated for their ability to detect RA-ILD. Thorough evaluation and multidisciplinary discussion remains the gold standard for establishing the diagnosis of RA-ILD. Management is challenging with most RA disease-modifying antirheumatic drugs (DMARDs) linked to pneumonitis. Methotrexate is typically avoided in clinically significant ILD, although alternative therapies including leflunomide and biologic DMARDs also carry risks in RA-ILD. Antifibrotics appear to slow the progression of ILD, and a large phase II trial exclusively in RA-ILD is underway. In addition, smoking cessation, pulmonary rehabilitation, oxygen therapy, managing comorbidities, and lung transplantation evaluation are vital to improving patient outcomes in RA-ILD.

With little high-quality evidence to guide the management of RA-ILD, multidisciplinary teams with expertise in RA-ILD are highly valuable for diagnosing and treating RA-ILD. Clinical and translational research in RA-ILD is needed to fill the many evidence gaps.
Acquired lipodystrophy associated with immune checkpoint inhibitors
Authors: Gnanendran Subashini S. , Miller James A. , Archer Christine A. , Jain Swaranjali V. , Hwang Shelley J.E. , Peters Geoffrey , Miller Andrew
Published: March 2020

Immune checkpoint inhibitors have become the mainstay of treatment for metastatic melanoma. This article presents a new case of acquired generalised lipodystrophy (AGL) during anti-programmed cell death-1 (anti-PD-1) therapy and a systematic review of the literature with an aim to further understand the pathogenesis. A comprehensive search was conducted using PubMed, Embase, MEDLINE and Cochrane Central databases. We identified four cases of lipodystrophy associated with anti-PD-1 immunotherapy, including our own. Of these, three were associated with nivolumab, and one with pembrolizumab. Body composition changes occurred at a median of 7 months after anti-PD-1 initiation. All cases reported AGL, with subcutaneous fat loss affecting majority of the body. There were three reported cases of insulin resistance associated with AGL. AGL should be a recognised adverse event associated with anti-PD-1 therapy.
Recent developments with advancing gene therapy to treat chronic infection with hepatitis B virus
Authors: Maepa Mohube B. , Jacobs Ridhwaanah , van den Berg Fiona , Arbuthnot Patrick
Published: March 2020

Purpose of review

The available vaccine and therapies against hepatitis B virus (HBV) rarely eliminate chronic infection with the virus. High mortality resulting from complicating cirrhosis and hepatocellular carcinoma makes improving anti-HBV therapy an important priority. Recent advances with using gene therapy to counter HBV have potential and are the focus of this review.

Recent findings

The stable replication-competent HBV intermediate comprising covalently closed circular DNA (cccDNA) is the template for expression of all viral genes. Inactivating cccDNA has thus been a focus of research aimed at achieving cure for HBV infection. Many studies have reported profound inhibition of replication of the virus using silencing and editing techniques. Therapeutic gene silencing with synthetic short interfering RNA is now in clinical trials. Ability to mutate and permanently inactivate cccDNA with engineered gene editors, such as those derived from CRISPR/Cas or TALENs, is particularly appealing but has not yet reached clinical evaluation.

Gene silencing and gene editing potentially provide the means to cure HBV infection. However, achieving efficient delivery of therapeutic sequences, ensuring their specificity of action and progress with other antiviral strategies are likely to determine utility of gene therapy for chronic HBV infection.
Mohs Micrographic Surgery in Patients Younger Than 40 Years
Authors: Stewart Thomas Jonathan , Venning Victoria Louise , Moreno Bonilla Gilberto , Byth Karen , Lee Simon , Fernandez-Penas Pablo
Published: March 2020

BACKGROUND

As the availability of Mohs micrographic surgery (MMS) continues to expand in Australia and incidence of keratinocyte cancer increases in adolescents and young adults, there has been rising interest in the use of MMS in this population.

OBJECTIVE

This study aimed to evaluate the characteristics of MMS cases in patients younger than 40 years.

METHODS

A review was performed of all MMS cases in patients younger than 40 years at the time of their surgery from 2012 to 2017 at the Skin and Cancer Foundation Australia, with comparison to a control group, aged older than 40 years. Patient, tumor and management characteristics were analyzed.

RESULTS

Four hundred ninety-three cases were eligible. Study and control groups differed significantly regarding gender (p < .001), tumor pathology (p < .001), anatomic site of tumor (p < .001), Mohs surgery stages (p = .039), defect size (p < .001), and repair method (p < .001).

LIMITATIONS

Retrospective study at a single institution.

CONCLUSION

Mohs micrographic surgery cases in patients younger than 40 years exhibit unique patient and tumor characteristics influencing choice of repair method.
Toward Causally Interpretable Meta-analysis
Authors: Dahabreh Issa J. , Petito Lucia C. , Robertson Sarah E. , Hernán Miguel A. , Steingrimsson Jon A.
Published: March 2020

We take steps toward causally interpretable meta-analysis by describing methods for transporting causal inferences from a collection of randomized trials to a new target population, one trial at a time and pooling all trials. We discuss identifiability conditions for average treatment effects in the target population and provide identification results. We show that the assumptions that allow inferences to be transported from all trials in the collection to the same target population have implications for the law underlying the observed data. We propose average treatment effect estimators that rely on different working models and provide code for their implementation in statistical software. We discuss how to use the data to examine whether transported inferences are homogeneous across the collection of trials, sketch approaches for sensitivity analysis to violations of the identifiability conditions, and describe extensions to address nonadherence in the trials. Last, we illustrate the proposed methods using data from the Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis Trial.
Bacterial vaginosis diagnosis and treatment in postmenopausal women: a survey of clinician practices
Authors: Mark Katrina S. , Tenorio Beatriz , Stennett Christina A. , Ghanem Khalil G. , Brotman Rebecca M.
Published: March 2020

Objective:

Some diagnostic features of the genitourinary syndrome of menopause (GSM) and bacterial vaginosis (BV) overlap, such as low levels of vaginal Lactobacillus and pH > 5. We sought to determine clinicians’ diagnostic and treatment practices for postmenopausal women presenting with BV and GSM scenarios and how commercial molecular screening tests are utilized.

Methods:

Anonymous surveys were sent to practicing women's health clinicians to evaluate assessment and treatment strategies for postmenopausal women presenting with BV and GSM scenarios.

Results:

When given a scenario of a postmenopausal woman with symptoms overtly positive for BV, a majority of providers (73%) would conduct a wet mount, though only 35% would evaluate full Amsel's criteria. A majority (89%) recommended treatment with antibiotics, 28.2% recommended vaginal estrogen in addition to antibiotics, and 11.8% recommended vaginal estrogen alone. Of providers who would use a molecular swab, 30% would wait for results before treating the patient's symptoms. When given a scenario of a postmenopausal woman presenting with GSM, a majority (80%) recommended vaginal estrogen, and only 4.6% recommended antibiotics. Few (16%) responders would evaluate with a molecular swab, half of whom would wait for results before prescribing treatment. Clinicians in practice for less than 10 years were more likely to rely on molecular swabs than those who had been practicing longer (P < 0.0003).

Conclusions:

Methods used to evaluate postmenopausal women with vaginal symptoms vary. Future studies of postmenopausal women that differentiate diagnostic criteria between BV and GSM, and validate commercial molecular testing for BV in women over age 50 are needed.
The Women's Health Initiative Estrogen-alone Trial had differential disease and medical expenditure consequences across age groups
Authors: Donneyong Macarius M. , Chang Teng-Jen , Roth Joshua A. , Guilds McKenna , Ankrah Daniel , Najafzadeh Mehdi , Xu Wendy Y. , Chlebowski Rowan T. , Margolis Karen , Manson JoAnn E.
Published: March 2020

Objectives:

The Women's Health Initiative (WHI) randomized trial identified age differences in the benefit-risk profile of estrogen-alone (ET) use. The impact of WHI trial on disease-associated medical expenditures attributable to subsequent decreased ET utilization has, however, not been measured. Therefore, the objective of this analysis was to quantify the age-specific disease-associated medical expenditures attributable to reduced ET utilization after the WHI Hormone Therapy (HT) trials.

Methods:

Population-level disease counts and associated expenditures between 2003 and 2015 were compared between an observed ET-user population versus a hypothetical ET-user population assuming absence of the WHI HT trials, constructed by extrapolating ET utilization rates from 1996 to 2002 assuming pre-WHI HT rates would have continued without publication of the WHI HT trial data (2002-2004). Analyses were stratified by age (50-59, 60-69, and 70-79 years). Input data were extracted from Medical Expenditure Panel Survey and the literature. The primary outcomes were: ET utilization, chronic diseases (breast cancer, stroke, coronary heart disease, colorectal cancer, pulmonary embolism, and hip fracture) and disease-associated direct medical expenditures.

Results:

Over 13 years, the decline in ET utilization was associated with $4.1 billion expenditure for excess chronic diseases (37,549 excess events) among women in their 50s, compared to savings of $1.5 billion and $4.4 billion for diseases averted by lower ET utilization among women in their 60s (13,495 fewer events) and 70s (40,792 fewer events), respectively.

Conclusion:

The decline in ET utilization had differential disease and expenditure consequences by age groups in the United States. These results are limited by the lack of inclusion of vasomotor symptom benefit and costs of alternative medications for these symptoms in the analysis.
Nonadherence to antihypertensive medications is related to pill burden in apparent treatment-resistant hypertensive individuals
Authors: Lawson Alexander J. , Hameed Mohammed Awais , Brown Roger , Cappuccio Francesco P. , George Stephen , Hinton Thomas , Kapil Vikas , Lenart Jane , Lobo Melvin D. , Martin Una , Menon Madhavan , Nightingale Angus , Rylance Paul B. , Webb David J. , Dasgupta Indranil
Published: March 2020

Objective:

Nonadherence to medication is present in at least 50% of patients with apparent treatment-resistant hypertension. We examined the factors associated with nonadherence as detected by a liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based urine antihypertensive drug assay.

Methods:

All urine antihypertensive test results, carried out for uncontrolled hypertension (BP persistently >140/90 mmHg) between January 2015 and December 2016 at a single toxicology laboratory were analysed. Drugs detected were compared with the antihypertensive drugs prescribed. Patients were classified as adherent (all drugs detected), partially nonadherent (at least one prescribed drug detected) or completely nonadherent (no drugs detected). Demographic and clinical parameters were compared between the adherent and nonadherent groups. Binary logistic regression analysis was performed to determine association between nonadherence and demographic and clinical factors.

Results:

Data on 300 patients from nine hypertension centres across the United Kingdom were analysed. The median age was 59 years, 47% women, 71% Caucasian, median clinic BP was 176/95 mmHg and the median number of antihypertensive drugs prescribed was four. One hundred and sixty-six (55%) were nonadherent to prescribed medication with 20% of these being completely nonadherent. Nonadherence to antihypertensive medication was independently associated with younger age, female sex, number of antihypertensive drugs prescribed, total number of all medications prescribed (total pill burden) and prescription of a calcium channel blocker.

Conclusion:

This LC-MS/MS urine analysis-based study suggests the majority of patients with apparent treatment-resistant hypertension are nonadherent to prescribed treatment. Factors that are associated with nonadherence, particularly pill burden, should be taken into account while treating these patients.
The Protective Effect of an Eye Wash Solution on the Ocular Surface Damage Induced by Airborne Carbon Black Exposure
Authors: Li Xiangzhe , Kang Boram , Eom Youngsub , Lee Hyung Keun , Kim Hyo Myung , Song Jong Suk
Published: March 2020

Purpose:

To investigate the effects of an eye wash solution on the ocular surface damage induced by airborne carbon black (CB) exposure.

Methods:

Sprague–Dawley rats were exposed to ambient CB for 5 days. During the 5 days, a commercial eye wash solution (Eyebon-W) was used for irrigation twice daily on CB-exposed rat eyes; normal saline was used as the vehicle control. Lactic dehydrogenase (LDH) activity and matrix metallopeptidase (MMP)-9, histamine, and lactoferrin levels were measured in tears. The expression of inflammatory cytokines in the anterior segment of the eyeball was measured by Western blot analysis.

Results:

The ocular surface staining scores, tear LDH activity, tear MMP-9, histamine, and lactoferrin concentrations, and the expression of interleukin-4 and interferon-γ in the eye were significantly increased in the CB group versus the normal control group. When compared with CB group, the Eyebon-W eye wash treatment significantly reversed these elevations induced by CB, including ocular staining scores, tear LDH activity, histamine and MMP-9 concentrations in the tear fluid, and the expression of interleukin-4 in the eye. On the other hand, saline irrigation only reduced the concentrations of histamine and MMP-9 in tear fluid and the expression of interferon-γ in the eye.

Conclusions:

Both Eyebon-W eye wash treatment and saline irrigation reversed CB-induced ocular surface injury, but the efficacy of Eyebon-W was more significant than that of the saline solution when compared with CB group. The use of an eye wash solution seems to play a protective role for the ocular surface when exposed to airborne particulate matter.
Vascular elastic fiber heterogeneity in health and disease
Authors: Halabi Carmen M. , Kozel Beth A.
Published: March 2020

Purpose of review

Elastin has historically been described as an amorphous protein that functions to provide recoil to tissues that stretch. However, evidence is growing that elastin's role may not be limited to biomechanics. In this minireview, we will summarize current knowledge regarding vascular elastic fibers, focusing on structural differences along the arterial tree and how those differences may influence the behavior of affiliated cells.

Recent findings

Regional heterogeneity, including differences in elastic lamellar number, density and cell developmental origin, plays an important role in vessel health and function. These differences impact cell–cell communication, proliferation and movement. Perturbations of normal cell–matrix interactions are correlated with human diseases including aneurysm, atherosclerosis and hypertension.

Although classically described as a structural protein, recent data suggest that differences in elastin deposition along the arterial tree have important effects on heterotypic cell interactions and human disease.
Characteristics of Anorectal Malformations in Children at the United States‐Mexico Border
Authors: Rosas‐Blum Eduardo D. , Reddy Ajay , Shaban Mohamed A. , Aziz Sandra , Do Ailinh , Spurbeck William , Francis Denease
Published: March 2020

Background:

Anorectal malformations (ARMs) are a group of congenital malformations affecting the lower gastrointestinal, urogenital, and/or gynecological systems. They occur in approximately 1 in 5000 live births, with a slight male predominance. ARMs can appear in isolation or in association with other anomalies. The literature contains little information about the characteristics of ARMs in United States Hispanic populations.

Methods:

An institutional review board–approved chart review was conducted in all patients with ARMs seen at a single institution in El Paso, Texas, from January 2012 to December 2015. Data regarding demographics, types of ARMs, associated syndromes, and long‐term complications were recorded using the Krickenbeck classification system.

Results:

Of the 37 patients included in the study, 20 were boys and 17 were girls. The most common ARMs were rectoperineal fistula (46%), rectourethral fistula, and cloacal malformation. Constipation was the most common long‐term complication, especially in patients with recto‐perineal fistula.

Conclusion:

Children in the Borderland community may have a higher percentage of recto‐perineal fistula than previously reported. Postoperative complications in Hispanic children with ARM were comparable to those reported in other populations.
Optimizing Antitumor Necrosis Factor Treatment in Pediatric Inflammatory Bowel Disease With Therapeutic Drug Monitoring
Authors: Pinto Pais Isabel , Espinheira Maria C. , Trindade Eunice , Amil Dias Jorge
Published: March 2020

Biological agents have revolutionized inflammatory bowel disease treatment but primary nonresponse and secondary loss of response are common with resulting adverse outcomes. Clinical trials demonstrated an association between serum drug concentrations, as well as the presence of antidrug antibodies, and loss‐of‐response. Therapeutic drug monitoring (TDM), defined as the evaluation of drug concentrations and antidrug antibodies, is appearing as a strategy to optimize treatment and take full advantage from these drugs. TDM appears to be a promising tool in clinical practice, especially in pediatric patients, who have pronounced fluctuations in the pharmacokinetics of the drugs.

The authors present a literature review about antitumor necrosis factor therapy optimization based on personalized treatment strategies according to TDM and possible strategies to recapture loss of response, including an algorithm for practical management.
KRAS Mutations in Papillary Fibroelastomas
Authors: Bois Melanie C. , Milosevic Dragana , Kipp Benjamin R. , Maleszewski Joseph J.
Published: March 2020

Papillary fibroelastoma (PFE) is an increasingly recognized cardiac tumor. Despite its prevalence, controversy exists as to whether it represents a reactive or neoplastic process due to histopathologic similarities with Lambl excrescences (LEs), an accepted reactive phenomenon. Recently, KRAS mutations were reported in a small collection of PFEs, but the incidence of mutations and conditions in which they arise in are unknown. Furthermore, the relationship between PFE and LE has yet to be investigated. Institutional archives were queried for cases of PFE (2001-2017). Paraffin-embedded tissue was microdissected for tumor isolation. Prospectively identified LEs (2018) were collected and wholly isolated. Extracted DNA underwent droplet digital polymerase chain reaction analysis of the most common KRAS mutations (codons 12/13 and 61). Relevant clinical information was abstracted from the medical record. Fifty-two PFEs were tested from 50 patients (32 women). The median patient age was 67 years. Seventeen (33%) PFEs harbored pathogenic variants in tested KRAS codons (12 in codons 12/13; 5 in codon 61). Mutations were mutually exclusive. No clinical or pathologic correlates differed significantly from cases without detectable pathogenic variants. No pathogenic mutation were detected in LEs (n=20; P=0.002). Herein, we report on the largest series of PFE tested for KRAS mutations and present the largest cohort of KRAS-mutant PFEs to date, providing evidence in support of the notion that at least a subset of PFEs represents neoplasia. Moreover, the lack of KRAS mutations in LEs provides evidence as to the separate etiology of this accepted reactive lesion.
The Effect of Imputation of Pao 2/Fi o 2 From Spo 2/Fi o 2 on the Performance of the Pediatric Index of Mortality 3*
Authors: Slater Anthony , Straney Lahn , Alexander Janet , Schell David , Millar Johnny
Published: March 2020

Objectives:

To investigate if the performance of Pediatric Index of Mortality 3 is improved by including imputed values for the Pao
2/Fio
2 ratio where measurements of Pao
2 or Fio
2 are missing.

Design:

A prospective observational study.

Setting:

A bi-national pediatric intensive care registry.

Patients:

The records of 37,983 admissions of children less than 16 years old admitted to 19 ICUs.

Interventions:

None.

Measurements and Main Results:

Seven published equations describing an association between Pao
2/Fio
2 and oxygen saturation measured by pulse oximetry (Spo
2)/Fio
2 were used to derive an alternative variable d100 × Fio
2/Pao
2 for the Pediatric Index of Mortality 3 variable 100 × Fio
2/Pao
2. Six equations exclude Spo
2/Fio
2 values if Spo
2 is greater than 96–98%. 100 × Fio
2/Pao
2 was missing in 72% of patient records primarily due to missing Pao
2, d100 × Fio
2/Pao
2 was missing in 71% of patient records if values of Spo
2greater than 97% were excluded or in 17% of patient records if all measurements of Spo
2 were included. Univariable analysis supported the inclusion of Spo
2 values greater than 97%. Compared to the standard Pediatric Index of Mortality 3 model, two alternative models imputing 100 × Fio
2/Pao
2 from d100 × Fio
2/Pao
2 only if 100 × Fio
2/Pao
2 was missing, or using d100 × Fio
2/Pao
2 values exclusively, resulted in a small but statistically significant improvements in discrimination of Pediatric Index of Mortality 3 (area under the receiver operator curve 0.9068 [0. 8965–0. 9171]; 0.9083 [0.8981–0.9184]; 0.9087 [0.8987–0.9188], respectively).

Conclusions:

Imputation of the Pao
2/Fio
2 ratio in cases where arterial sampling was not performed resulted in a large reduction in the rate of missing data if all values of Spo
2 were included. The imputation technique improved the discrimination of Pediatric Index of Mortality 3; however, the magnitude of the increment in overall model performance was small. A possible benefit of the approach is reducing the potential for bias resulting from variation in practice for invasive monitoring of oxygenation.