bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cost-effectiveness Analysis of Ado-trastuzumab Emtansine (T-DM1) for the Adjuvant Treatment of Patients With Residual Invasive HER2+ Early Breast Cancer in the United States
Authors: Sussell Jesse , Singh Jhuti Gurleen , Antao Vincent , Herrera-Restrepo Oscar , Wehler Elizabeth , Bilir S. Pinar 
Published: May 2021

Objective:
Ado-trastuzumab emtansine (T-DM1) was recently approved for patients with human epidermal growth factor receptor 2 positive (HER2+) early breast cancer (eBC) with residual invasive disease after neoadjuvant taxane and trastuzumab-based treatment. Cost-effectiveness analysis was conducted to compare T-DM1 versus trastuzumab in the United States.

Materials and Methods:
A Markov cohort-based model tracked clinical and economic outcomes over a lifetime horizon from a US payer perspective. The model included 6 health states: invasive disease-free, nonmetastatic (locoregional) recurrence, remission, first-line and second-line metastatic BC and death. Model state transitions were based on statistical extrapolation of the head-to-head KATHERINE study and published sources. Dosing and treatment duration reflected prescribing information and trials. Costs (2019 US dollars) associated with pharmaceutical treatment (wholesale acquisition costs), health state specific care, adverse events, and end-of-life care were included. Health state utilities were obtained from KATHERINE and published literature.

Results:
T-DM1 dominated trastuzumab, yielding lower lifetime costs (−$40,271), and higher life-years (2.980) and quality-adjusted life-years (2.336). Results were driven by patients receiving T-DM1 spending less time in more costly downstream health states, as these patients are less likely to experience a recurrence overall, despite having a higher likelihood of metastatic disease (distant recurrence) in the subset of patients who experience recurrence. Probabilistic sensitivity analysis indicated robust results, with 96.7% of 5000 stochastic simulations producing dominance for T-DM1. The most influential variables were related to treatment costs, off treatment utilities, and health state costs. Additional scenario analyses tested a range of model inputs and assumptions, and produced consistent results.

Conclusion:
Relative to trastuzumab, T-DM1 treatment for patients with HER2+ eBC who have residual invasive disease after neoadjuvant taxane and trastuzumab-based treatment is likely to reduce the overall financial burden of cancer, while simultaneously improving patient outcomes.
A Phase II Study of the Combination of Oxaliplatin, Capecitabine, and Trastuzumab and Chemoradiotherapy in the Adjuvant Setting in Operated Patients With HER2-positive Gastric or Gastroesophageal Junction Cancer (TOXAG Study)
Authors: Abali Huseyin , Yalcin Suayib , Onal Huseyin C. , Dane Faysal , Oksuzoglu Berna , Ozdemir Nuriye , Mertsoylu Huseyin , Artac Mehmet , Camci Celaletdin , Karabulut Bulent , Basal Fatma B. , Budakoglu Burcin , Sendur Mehmet A.N. , Goktas Burce , Ozdener Fatih , Baygul Arzu 
Published: May 2021

Background:
Trastuzumab prolonged the overall survival in patients with advanced gastric cancer with human epidermal growth factor receptor 2 (HER2) overexpression in combination with chemotherapy. In this phase II open-label prospective study, the tolerability and safety of trastuzumab with chemotherapy, and chemoradiotherapy for curatively resected patients with HER2-positive gastric carcinoma was investigated.

Methods:
The patients with HER2-positive gastric, or gastroesophageal junction adenocarcinoma, after gastrectomy plus D2 dissection, were included. They received 3 cycles of oxaliplatin (100 mg/m2 intravenously day 1) plus capecitabine (850 mg/m2 orally days 1 to 14), trastuzumab (8 mg/kg intravenously day 1 in cycle 1, 6 mg/kg thereafter) every 21 days, followed by chemoradiotherapy. Trastuzumab was given for 1 year.

Results:
Of the 212 patients screened, 35 were eligible, and 34 were treated. The median age was 56 years (minimum to maximum: 35 to 75 y), male patients constituted 73.5% (n=25), and 33 (97.1%) had gastric adenocarcinoma. R0 resection was performed in 30 (88.2%). The majority (26, 61.7%) were in stage III disease. Most of the adverse events were grade I/II, the most frequent grade III side effects were nausea (3, 8.8%), vomiting (3, 8.8%), diarrhea (2, 5.9%), and weight loss (n=2, 5.9%). Two patients died during the first 3 cycles of chemotherapy and chemoradiotherapy; 1 secondary to pulmonary thromboembolism, and the other due to cerebral ischemia. After excluding 2 with early progression and 1 consent withdrawal, of the remaining 31 patients, 28 (90.3%) were able to complete the chemotherapy and chemoradiotherapy part of the trial. After the 25 months follow-up period, 21 patients (61.8%) were alive. Overall survival at 12 and 24 months was 75.0% and 58.0%, while disease-free survival at 12 and 24 months was 65.7% and 55.0%, respectively.

Conclusions:
Trastuzumab in combination with capecitabine, oxaliplatin following chemoradiotherapy as the adjuvant therapy for gastric or gastroesophageal junction adenocarcinoma was considered as safe and tolerable. The frequency of HER2 overexpression in curatively resected patients is comparable to that in patients with metastatic disease (trial registration: clinicaltrials.gov the identifier: NCT01748773, December 13, 2012, https://clinicaltrials.gov/ct2/show/NCT01748773).
Endometrial Cancer, BRCA1, and BRCA2 in the UK Biobank Cohort
Authors: Lehrer Steven , Rheinstein Peter H. 
Published: May 2021

Objectives:
Endometrial cancer (EC) risk in BRCA1/2 mutation carriers has been uncertain. EC risk in women with germline BRCA1 or BRCA2 mutations was recently assessed in a multicenter cohort study. BRCA1/2 mutation carriers had a 2- to 3-fold increased risk for EC, with highest risk observed for the rare subgroups of serous-like and p53-abnormal EC in BRCA1 mutation carriers. To further evaluate risk, we looked at EC and BRCA1/2 in the UK Biobank cohort.

Methods:
EC diagnosis was ascertained using the 10th Revision of the International Classification of Diseases. We analyzed the single nucleotide polymorphisms (SNPs) rs799917 (BRCA1) and rs144848 (BRCA2). A case-control study found a possible association of rs799917 but not rs144848 with EC. Data processing was performed on Minerva, a Linux mainframe with Centos 7.6, at the Icahn School of Medicine at Mount Sinai.

Results:
Percentage ECs within genotypes for SNPs rs799917 and rs144848 was 0.6%. The variability within SNP genotypes was insignificant (P=0.288 for rs799917, 2-tailed Fisher exact test; P=0.931 for rs144848). In comparison, an estimated 70,200 women who had been diagnosed with uterine cancer between 1991 and 2010 were alive in the UK at the end of 2010. A total of 21,892,000 UK residents were ages 50 to 92; approximately half were women. Therefore, prevalence of EC in these UK women was 0.6%, identical to percentage EC within 6 genotypes for SNPs rs799917 and rs144848.

Conclusion:
Although we cannot rule out an increase in several rare types of EC, our analysis suggests that the overall incidence or risk of EC does not appear to be increased by the presence of BRCA1 or BRCA2 mutations.
Alternative therapies for dry eye disease
Authors: Mittal Rhiya , Patel Sneh , Galor Anat 
Published: May 2021

Purpose of review
Dry eye disease (DED) is a multifactorial disease affecting approximately 5–50% of individuals in various populations. Contributors to DED include, but are not limited to, lacrimal gland hypofunction, meibomian gland dysfunction (MGD), ocular surface inflammation, and corneal nerve dysfunction. Current DED treatments target some facets of the disease, such as ocular surface inflammation, but not all individuals experience adequate symptom relief. As such, this review focuses on alternative and adjunct approaches that are being explored to target underlying contributors to DED.

Recent findings
Neuromodulation, stem cell treatments, and oral royal jelly have all been studied in individuals with DED and lacrimal gland hypofunction, with promising results. In individuals with MGD, devices that provide eyelid warming or intense pulsed light therapy may reduce DED symptoms and signs, as may topical Manuka honey. For those with ocular surface inflammation, naturally derived anti-inflammatory agents may be helpful, with the compound trehalose being farthest along in the process of investigation. Nerve growth factor, blood-derived products, corneal neurotization, and to a lesser degree, fatty acids have been studied in individuals with DED and neurotrophic keratitis (i.e. corneal nerve hyposensitivity). Various adjuvant therapies have been investigated in individuals with DED with neuropathic pain (i.e. corneal nerve hypersensitivity) including nerve blocks, neurostimulation, botulinum toxin, and acupuncture, although study numbers and design are generally weaker than for the other DED sub-types.

Summary
Several alternatives and adjunct DED therapies are being investigated that target various aspects of disease. For many, more robust studies are required to assess their sustainability and applicability.
Effectiveness of antihistamines for itch and sleep disturbance in atopic dermatitis: a retrospective cohort study
Authors: Tay Charmaine J. , Zhao Xiahong , Allen John C. , Yew Yik Weng , Tey Hong Liang 
Published: May 2021

Introduction:
Atopic dermatitis (AD) is a common and debilitating condition, with pruritus being the hallmark symptom responsible for negative quality of life in AD patients. Oral antihistamines are commonly used to manage itch in AD, but evidence of its efficacy is lacking and debatable.

Methods:
A retrospective cohort study on patients with AD treated with antihistamines was conducted at the National Skin Centre from January 2015 to December 2018. Severity of disease was measured using the SCORing Atopic Dermatitis (SCORAD) index. Data was analyzed using a mixed-effects linear model to account for repeated measures on the same individual.

Results:
There were 161 unique patients with 380 treatment outcomes included in our analysis. Patients who were treated with antihistamines had higher baseline itch and sleep disturbance scores compared with those who were not. We found that the use of antihistamines resulted in significant improvement in itch and sleep disturbance scores with respective mean decreases of 0.67 [95% confidence interval (CI): 0.07, 1.27; P=0.03] and 0.87 (95% CI: 0.22, 1.52; P=0.01) compared with patients not treated with antihistamines. Specifically, second-generation antihistamines improved itch and sleep disturbance scores better than first-generation antihistamines, with a decrease of 0.65 (95% CI: −0.59, 1.88) and 0.61 (95% CI: −0.66, 1.88), respectively, although the difference in effect was not significant. Meanwhile, antihistamine use did not significantly improve total SCORAD and objective SCORAD scores.

Conclusion:
Treatment with second-generation antihistamines, may be an appropriate treatment modality for managing itch and sleep disturbance in patients with AD.
Compound Heterozygous Mutations Involving Splicing Mutations Cause Rothmund–Thomson Syndrome in Two Chinese Families
Authors: Pan Chao-Lan , Cao Qiao-Yu , Li Yue , Zhang Jia , Zhang Zhen , Wang Yu-Meng , Chen Fu-Ying , Cheng Ru-Hong , Wang Xiao-Xiao , Yao Zhi-Rong , Lu Zhi-Yong , Li Ming 
Published: May 2021

Abstract

Objective:
Biallelic mutations in the RecQ like helicase (RECQL) 4 gene, a guardian of the genome, cause Rothmund–Thomson syndrome type II (RTS-II). Two Chinese girls with mild-phenotype RTS-II mainly restricted to their skin are herein described.

Methods:
Blood specimens from two families with mild-phenotype RTS-II were collected. DNA isolation, RNA isolation and complementary DNA synthesis, and next-generation sequencing using a multi-gene panel were applied to verify the underlying pathogenic variants in the causative RECQL4 gene.

Results:
We analyzed two patients with mild phenotypes. One patient had an unreported paternal c.2885+1G>A alteration in intervening sequence 16 and the previously reported maternal exon 14 c.2272C>T (p.R758X), both resulting in premature termination codons. The other patient carried two novel alterations, c.2886-1G>A and c.2752G>T (p.E918X). Complementary DNA sequencing showed that different splice-site mutations within the same intron could lead to completely different splicing modes.

Conclusion:
We identified three novel pathogenic RECQL4 variants in two patients with RTS, thus expanding the mutational spectrum of RTS-II. We also explored their pathogenic effect by transcripts analysis to address genotype–phenotype correlations.
Simultaneous assessment of coronary stenosis relevance with automated computed tomography angiography and intravascular ultrasound analyses and fractional flow reserve
Authors: Blanco Pablo J. , Bulant Carlos A. , Bezerra Cristiano Guedes , Lemos Pedro A. , García-García Hector M. 
Published: May 2021

Objectives
To assess the diagnostic performance of computed tomography angiography (CTA) and intravascular ultrasound (IVUS) derived minimum lumen areas (MLA) from the same lesions that correspond to an FFR ≤0.80.

Methods and results
A total of 24 patients (33 arteries) were collected retrospectively according to the following inclusion criteria: presence of a CTA diagnostic followed by an IVUS and FFR percutaneous coronary procedures. CTA and IVUS lumen contours were automatically performed using previously validated methods.
The correlation between CTA and IVUS for the MLA was r = 0.45. In terms of MLA, the mean difference between CTA and IVUS was 0.81 mm2. Of note, a much smaller CTA-derived MLA (2.10 mm2) was found to be related to significant FFR lesions compared to that of the MLA derived from IVUS (3.19 mm2). The area under the curve, accuracy, sensitivity and specificity for this CTA-derived MLA were 0.80, 0.76, 0.50 and 0.87, respectively, while these values for IVUS-derived MLA were 0.87, 0.85, 0.80 and 0.87.

Conclusions
Computed tomography angiography and intravascular ultrasound-derived minimum lumen areas have moderate diagnostic efficiency, albeit slightly better for IVUS, in identifying hemodynamically severe coronary stenoses. The utility of MLA, automatically derived from either CTA or IVUS as an alternative to FFR to guide the decision to revascularize, should be tested clinically.
The impact of cognitive impairment in patients with acute coronary syndrome undergoing percutaneous revascularization: a systematic review and meta-analysis
Authors: Prasitlumkum Narut , Doyle Kieran S. , Ding Kimberly R. , Natarajan Balaji , Mukherjee Ashish , Varadarajan Padmini , Pai Ramdas G. 
Published: May 2021

Background
Cognitive impairment has been known to be associated with negative health impacts. Several studies recently demonstrated inconsistent outcomes among cognitive impaired patients with acute coronary syndrome (ACS). Our study aimed to determine the impact of cognitive impairment for patients with ACS.

Methods
Databases were searched through October 2020. Studies reporting revascularization rates, short- and long-term mortality among ACS patients with cognitive impairment were included. Effect estimates from the individual studies were extracted and combined using random effect and generic inverse variance method of DerSimonian and Laird.

Results
In total, 11 observational studies were included in the analysis consisting of 810 122 ACS patients, with 3.5% cognitive impairment patients. Our analysis suggested that cognitive impairment was associated with a lower rate of percutaneous coronary intervention (PCI) [odds ratio (OR), 0.63; 95% confidence interval (CI), 0.42–0.96; I
2 = 98.5%; P = 0.033]. Among patients undergoing PCI, cognitive impairment was statistically associated with increased 30-day mortality (OR, 1.34; 95% CI, 1.14–1.57; I
2 = 83.1%; P < 0.001) and long-term mortality (OR, 1.80; 95% CI, 1.04–3.11; I
2 = 36.3%; P = 0.034).

Conclusion
Our study demonstrated that cognitive impairment was not only associated with lower rates of percutaneous revascularization but also with increased 30-day and long-term mortality.
Trends in ST-elevation myocardial infarction
Authors: Kheifets Mark , Vaknin-Assa Hana , Greenberg Gabriel , Orvin Katia , Assali Abid , Kornowski Ran , Perl Leor 
Published: May 2021

Aims
Despite recent progress in coronary artery disease treatment, ST-segment elevation myocardial infarction (STEMI) remains a very high-risk medical condition. Whether recent patients’ outcomes, following implementation of the 2012 European Society of Cardiology (ESC) STEMI guidelines have improved, is yet unclear.

Methods and results
The study was based on a prospective detailed registry of 2004 consecutive patients with STEMI treated with primary percutaneous coronary intervention (pPCI). We compared trends during two different time periods (2006–2012 vs. 2012–2018). Endpoints included mortality and major adverse cardiac events (MACE: death, repeat myocardial infarction, target vessel revascularization and coronary artery bypass surgery) at 1 month, 1 and 2 years. Rates of transradial interventions have risen significantly (67.3 vs. 42.0%; P < 0.01), as have rates of prasugrel administration (69.8 vs. 4.5%; P < 0.01) and use of drug eluting stents (75.5 vs. 56.5%; P < 0.01). Both at 1 and at 2 years, MACE was significantly lower in the later period (11.6 vs. 20.9%; P < 0.01 and 18.9 vs. 25.4%; P < 0.01 respectively), whereas mortality was only significantly lower after 1 year (5.8 vs. 8.6%; P = 0.02). Cox regression identified the later period (2012–2018) to independently and favorably impact MACE (hazard ratio, −0.69; 95% CI, 0.56–0.85; P < 0.01) but not mortality (hazard ratio, −0.76; 95% CI, 0.54–1.05; P = 0.09).

Conclusion
Among patients treated with pPCI for STEMI, adoption of the contemporary evidence-based treatments is associated with better MACE derived outcomes, following the inception of the 2012 ESC guidelines. Nonetheless, the long-term mortality was marginally (but not significantly) lower, which indicates an unmet need for further improvement.
Elevated asymmetric dimethylarginine level as biomarkers of adverse outcomes in individuals undergoing coronary angiography/percutaneous coronary interventions: a systematic review and meta-analysis
Authors: Wang Guofeng , Wanga Qi , Xu Weixue 
Published: May 2021

Background
No previous systematic review and meta-analysis have comprehensively evaluated the association of asymmetric dimethylarginine (ADMA) level with adverse prognosis in individuals undergoing percutaneous coronary interventions (PCI)/coronary angiography (CAG). The aim of this systematic review and meta-analysis was to assess the predictive value of the elevated ADMA level in individuals undergoing CAG/PCI.

Materials and methods
Two authors independently searched PubMed and Embase databases (up to 31 October 2020) for observational studies investigating the association between circulating ADMA level and adverse outcomes in individuals undergoing CAG/PCI. The predictive value of ADMA was expressed by pooling the multivariable-adjusted risk ratio with 95% confidence intervals (CI) for the highest versus lowest ADMA level.

Results
A total of nine prospective studies with 6374 participants were identified. Compared with those with the lowest ADMA level, patients with the highest ADMA level conferred an increased risk of all-cause mortality (risk ratio, 2.11; 95% CI, 1.38–3.21), cardiovascular mortality (risk ratio, 2.95; 95% CI, 1.14–7.68), major adverse cardiovascular events (risk ratio, 2.10; 95% CI, 1.35–3.27) and restenosis (risk ratio, 4.57; 95% CI, 2.52–8.30), respectively.

Conclusions
High level of ADMA level is possibly an independent predictor of mortality and cardiovascular events in individuals undergoing CAG/PCI. Detection of blood ADMA level before CAG/PCI may add valuable clinical prognosis information.
Future studies using histomorphometry in type 1 diabetes mellitus
Authors: Graeff-Armas Laura A. , Silverman Emily , Recker Robert R. 
Published: May 2021

Purpose of review
This article reviews the current state of research in type 1 diabetes and bone, focusing on human bone turnover markers and histomorphometry.

Recent findings
Bone turnover markers have been used for decades to document static bone turnover status in a variety of diseases but especially in diabetes. Two new studies focus on dynamic testing conditions to examine the acute effects of insulin and exercise on bone turnover. Publications of human bone histomorphometry in type 1 diabetes are few but there are several new studies currently underway.

Summary
Here, we review the most recent literature on human bone turnover markers and histomorphometry. Low bone turnover is thought to be a major underlying factor in bone fragility in T1DM. Further studies in human transilial bone biopsies will be helpful in determining the mechanisms.
Institutional Postacute Care Use May Help Reduce Readmissions for Ischemic Stroke Patients
Authors: Kim Yeunkyung , Thirukumaran Caroline , Temkin-Greener Helena , Hill Elaine , Holloway Robert , Li Yue 
Published: May 2021

Objectives:
Readmissions for Medicare patients initially admitted for stroke are common and costly. Rehabilitation in an institutional postacute care (PAC) setting is an evidence-based component of recovery for stroke. Under current Medicare payment reforms, care coordination across hospitals and PAC providers is key to improving quality and efficiency of care. We examined the causal impact of institutional PAC use on 30-day readmission rates for Medicare fee-for-service patients initially admitted for ischemic stroke.

Data Sources:
The 2010–2016 Medicare Provider Analysis and Review files.

Research Design:
We used the method of instrumental variable (IV) analysis to control for unobserved differences in the types of patients admitted to each PAC facility. We chose the distance from the patient’s residence to the closest institutional PAC provider and the number of PAC providers of each type within a county where the patient resides as IVs.

Principal Findings:
In the naive model, an increase in institutional PAC use was significantly associated with an increase in 30-day readmission by 0.03 percentage points. However, using IV analysis to control for endogeneity bias, an increase in institutional PAC use was associated with a decrease in 30-day readmission rate by 0.19 percentage points. Our findings indicate that reducing institutional PAC use among patients typically requiring rehabilitation in institutional settings for recovery may potentially lead to adverse postdischarge outcomes that require rehospitalization. Thus, payment incentives to reduce institutional PAC use should be balanced with postdischarge outcomes among ischemic stroke patients.