bluuebunny/crossref_metadata_2025_split huggingface dataset:
VariantDirect: An extraction-free screening approach to detect circulating SARS-CoV-2 virus strains from pooled specimens
Authors: Saadalla Abdulrahman , Stroup Brooke , Parikh Bijal 
Published: October 2021

Abstract
Coronavirus disease (COVID-19) caused by the SARS-CoV-2 virus has exposed clinical laboratories to unprecedented challenges. With surging case numbers, clinical laboratories were forced to acquiesce and integrate multiple testing platforms with varying workflows and analytical sensitivities in order to meet testing volumes. Now a new challenge has emerged with the evolution of viral variants, both globally and locally, raising concerns for uncontrolled spread, increased disease severity, and weakened responses to vaccinations. Preliminary data suggests that these variants may be associated with higher viral titers and prolonged infections. While primarily leveraged for epidemiologic surveillance, the clinical utility of variant detection may quickly become paramount. Furthermore, laboratories must remain vigilant and nimble enough to pivot should variant identification play a role in the patient care. To prepare for the validation of clinical assays that identify important viral variants, we designed a novel method, termed VariantDirect, to screen SARS-CoV-2 positive samples for the presence of variants, focusing initially on the increasingly prevalent UK and South African (SA) variants. The detection strategy is based on primers designed to specifically target the viral receptor-binding domain mutation, N501Y, shared by the UK and SA strains. Screening for variants will be limited to nasopharyngeal swab samples of high viral titers (Ct values &lt;25 by RT-qPCR assay, Roche Diagnostics). Pools of 9 different samples, 50 µl each, are mixed and stored at -80°C along with aliquots of the 9 original samples. These pools will then be tested, and if positive for the N501Y variant, the pooled 9 samples will be thawed and tested separately to identify the affected specimen. Most of these specimens are also being independently sequenced via a comprehensive but more resource-intensive NGS approach. Advantages of our pooled workflow are primarily in time and cost, with the capacity of screening up to 837 specimens on a single run. In addition, our collection strategy establishes a “time capsule” to document the evolution of viral strains within our geographical region. Finally, these studies serve to optimize technical parameters for the development of clinical assays. A validated nucleic acid (NA) extraction-free RT-qPCR method will be utilized for this assay. Our internal validation data showed comparable analytical sensitivities to NA extraction-based methods. Pooled samples in transport medium are diluted in normal saline at a ratio of 1:1, and then heat-inactivated in the presence of proteinase-K and ultimately analyzed on the Applied Biosystems™ 7500 Fast Dx instrument. As new variants of interest emerge, primers and probes can be quickly redesigned and validated on clinical samples within our NGS-confirmed “time capsule”. This study will provide important information needed for current or future genomic and epidemiologic studies.
Combined utility of Glucose and HbA1C testing for screening diabetes mellitus
Authors: Samara Vishnu , Kelly Kathleen , Hilborne Lee 
Published: October 2021

Abstract
Screening for diabetes mellitus is accomplished by measuring fasting blood glucose or HbA1C. The American Diabetes Association (ADA) guidelines recommend HbA1C for screening patients for diabetes or pre-diabetes, the U.S. Preventative Services Task Force (USPSTF) includes HbA1C only for monitoring and either glucose or HbA1C can be used for screening. This project sought to provide clinical laboratory evidence to support HbA1C as a diabetes screening test. De-identified electronic health record (EHR) patient data from individuals visiting a large medical center and its affiliated clinics that were tested for blood glucose (either alone, basic metabolic profile or comprehensive metabolic profile) and HbA1C ordered together on the same date of service were collected. 333,360 combined glucose and HbA1C requests were received in 2020. For further analysis, we included patients only with ICD-10 routine visit code Z00.00, excluding known diabetics, patients with elevated blood glucose and HbA1C below 5.7 %because this combination may indicate a non-fasting or inadequate fasting state. From the patients with diagnosis code Z00.00 and glucose within the reference interval, 73 %had HbA1C levels greater than 5.7 %. Among them, 65 %are of pre-diabetes [HbA1C between 5.7 and 6.4%] and 35% with HbA1C over 6.5%. Medical record review of patient charts with HbA1C over 6.5 % suggested a diagnosis of diabetes and were prescribed hypoglycemic medications. Elevated glucose and HbA1C complement each other in the initial diagnosis for diabetes and pre-diabetes; where as HbA1C alone is a good indicator in screening diabetes and pre-diabetes individuals that were previously not diagnosed with diabetes. We are currently collecting 2019 data to examine the differences and adjust for the sample volume due to effect of COVID-19 pandemic on patient visits in the early 2020. We are also evaluating if other variables such as insulin levels, insulin resistance status, and their correlation with HbA1C as a screening measure.
An Examination of Non-Pathologist Physicians’ Experiences with and Perceptions of the Autopsy
Authors: Hagen E S , Mirza K M , Anderson E , Cox B 
Published: October 2021

Abstract

Introduction/Objective
The autopsy is an undervalued and underutilized resource in medicine. Many people believe autopsies are used solely in forensics while in fact much of what we know about human disease comes from examining the human body at autopsy. The decrease in requests for autopsy over the past several decades possibly results from medical professionals’ lack of exposure to and understanding of autopsy. We conducted a survey to explore non-pathologist physicians’ exposure to and understanding of the autopsy and discover challenges and barriers faced by non-pathologists when requesting an autopsy. Better understanding of non-pathologist physicians’ views and experiences can guide further inquiry or intervention to remove barriers to autopsy requests.

Methods/Case Report
We disseminated a Google Forms survey via Twitter, tweeting weekly between 10/26/20- 2/26/2021 to obtain a convenience sample. Mean differences in continuous variables were assessed using an independent samples T-test. Chi-squared analyses were employed to report proportional differences in categorical variables. Where appropriate, comparisons of Likert scores (percentages) were performed using ordinal regression methods and reported as odds ratios. Analyses were performed on SPSS statistical software (v.27). P-value was considered significant if &lt;0.05.

Results (if a Case Study enter NA)
162 physicians responded to the survey. 29 responses were excluded (work outside US, practice pathology, or in residency), resulting in 133 surveys for analysis. Preliminary analysis suggests that Likert scores were generally favorable (&gt;3) for questions that asked whether the autopsy was of benefit to the clinical team, public health, and family closure. Also, Likert scores revealed that physicians experience barriers surrounding the autopsy in terms of understanding and comfort with tasks related to the autopsy.

Conclusion
Our study reveals that physicians are often unsure about the cause of their patients’ death, highlighting the continued importance of the autopsy in patient care. Barriers to autopsy use may include limited understanding of the procedure, how it is financed, and how to request an autopsy. Physicians also express discomfort with discussing autopsy with families. Education and specific training on conversations about the autopsy may increase use.
Relationship between Usher Syndrome and Ciliary Dysfunction in a pregnant woman with Multidrug-resistant Pneumonia: A Case Report and Literature Review
Authors: Omo-Ogboi A C , Savariya B , Rivera Rivera X , Zhao B 
Published: October 2021

Abstract

Introduction/Objective
Usher syndrome is a rare genetic disorder that consists of auditory and visual disturbances, affecting approximately 4-17 per 100,000 people. In the airways, cilia function in concert with airway mucus for mucociliary clearance, cleansing the airways of inhaled particles and pathogens. Ciliary dysfunction could lead to recurrent pulmonary infections, including from organisms resistant to more than one antibiotic. Few cases have been reported in the literature suggesting a relationship between usher syndrome and ciliary dysfunction. Hence, we would like to report an autopsy case of multidrug-resistant bacterial pneumonia in a pregnant patient with usher syndrome, discussing the possible relationship between usher syndrome, ciliary dysfunction, and multidrug-resistant pneumonia in pregnancy.

Methods/Case Report
We present a 31-year-old pregnant woman with a history of usher syndrome, hypothyroidism, and hydrocephalus presenting with shortness of breath, cough, and acute respiratory distress syndrome. She further developed refractory hypoxemia and hypercapnia complicated by multidrug-resistant bacteria infection, then intubated. Despite further management of the refractory respiratory failure, she showed no improvement. She was eventually placed on comfort care and died 49 days after she was admitted.

Results (if a Case Study enter NA)
At autopsy, the pleural surface has exudates and fibrotic adhesion. Both lungs are congested and have consolidations with variable severity on all lobes of both lungs. Microscopically, the most striking finding is the mucin accumulation in large and small airways, even in dilated alveolar spaces. There is evidence of chronic lung injury with significant interstitial fibrosis, diffuse peri-bronchial epithelial metaplasia, also with mucin accumulation. The respiratory epithelium has cilia present.

Conclusion
Although cilia were present microscopically, their function was not ascertained. The increase in progesterone during pregnancy inhibits cilia beat frequency. Therefore, the hormonal state of pregnancy and the proposed ciliary dysfunction in usher syndrome may worsen the severity of pulmonary infections seen in this patient and eventually caused her death.
Low-grade fibromyxoid sarcoma with heterotopic bone formation: case report and review of the literature
Authors: Serinelli S , Gitto L , de la Roza G , Zaccarini D J , Mookerjee G G , Damron T 
Published: October 2021

Abstract

Introduction/Objective
Low-grade fibromyxoid sarcoma (LGFMS) is an uncommon soft tissue malignancy with deceptively bland histologic appearance, and a tendency for late recurrence and metastasis. Cases with significant heterotopic ossification are rare. This presentation aims to characterize the features of LGFMSs showing heterotopic ossification reported in the literature, and further review the morphologic spectrum of this malignant neoplasm.

Methods/Case Report
We report the case of a 42-year-old male presenting with a 20-year history of a painless tumor in his left upper thigh. Computed tomography images showed coarse punctate peripheral calcifications, and the mass was resected. The tumor cells were immunohistochemically positive for MUC4, and positive for FUS (16p11.2) gene rearrangement by fluorescence in situ hybridization. Lamellar and woven bone with admixed adipose tissue was seen. Immunohistochemistry also showed focal weak to moderate staining for TLE-1. An English literature search using the terms “Evans tumor”, “low-grade fibromyxoid sarcoma”, “ossification”, “osseous metaplasia”, “bone metaplasia” and “bone formation” was performed. Nine cases were identified. The majority of subjects were males, with a mean age of 38 years (range of 12-61 years). The duration of symptoms before diagnosis ranged from a few months to 10 years. The tumor size ranged from 2.5 and to more than 12 cm. In a minority of subjects, calcifications were identified on imaging studies. Histologically, bone metaplasia was mainly seen at the periphery of the tumor. The majority of cases had a chromosomal translocation (FUS-CREB3L2 in 5 cases and EWSR1-CREB3L1 in one).

Results (if a Case Study enter NA)
NA

Conclusion
LGFMS is a tumor that can occur in a wide range of anatomical sites, and should be included in the differential diagnosis of any spindle cell neoplasm with hypocellular areas and bland cytology. Pathologists and clinicians should be aware of the rare possibility of heterotopic ossification in this tumor type, which can be radiologically detected as calcification and then confirmed histopathologically.
Is Oncotype DX Testing Necessary For Patients With Node Negative, Low-Grade Invasive Ductal Breast Carcinoma?
Authors: Ali M , Mandich D , Assaad M , Cartun R W 
Published: October 2021

Abstract

Introduction/Objective
Oncotype DX (Genomic Health/Exact Sciences, Redwood City, CA) is a 21-gene expression test that is used to predict the risk of recurrence following hormonal therapy and adjuvant chemotherapy (CT) benefit for patients with early-stage, ER-positive and HER2-negative invasive breast carcinoma (IBC). Testing is performed on formalin-fixed, paraffin-embedded tumor tissue from patients that are either lymph node (LN) negative, have micro- metastases, or 1-3 positive LNs. For years pathologists have studied traditional prognostic features of IBC (tumor grade, size, and LN status), as well as biomarker testing results (ER, PR, HER2, and Ki-67), in an effort to identify surrogate equations that could help identify patients that would benefit from CT. The “TAILORx” clinical trial, performed to study CT benefit in patients with midrange recurrence scores (11-25), has shown that the majority of these patients do not derive benefit from CT. Post-TAILORx, we have observed that only a small subset of our node- negative patients who were tested showed a benefit for CT. Following the examination of Oncotype DX results from testing performed on our patients, we hypothesized that overall tumor grade (Nottingham) might predict which patients with invasive ductal breast carcinoma (IDBC) do not require Oncotype DX testing; therefore, eliminating the need for Oncotype DX testing.

Methods/Case Report
We reviewed the surgical pathology reports and Oncotype DX reports for 251 patients with node-negative disease who underwent surgery at our institution from September 2019 through June 2021. All excisional tumors sent for Oncotype DX testing were ER-positive (Allred score ≥6/8) and HER2-negative by IHC and/or FISH.

Results (if a Case Study enter NA)
Oncotype DX recurrence scores ranged from 0-65. A benefit for CT was seen in 10.4% (26/251) of the patients with node-negative IDBC. A benefit for CT was seen in 6.1% (7/114) of patients with an overall tumor grade of II and 44.2% (19/43) of patients with an overall grade of III. No patients (0/94) with IDBC and an overall tumor grade of I showed a benefit for CT.

Conclusion
In the post-TAILORx era, patients with ER-positive (Allred ≥6/8), HER2-negative IDBC, who are node- negative and show an overall tumor grade of I, apparently do not require Oncotype DX testing. Additional studies from other institutions are needed to confirm our observation.
HER2 testing in metastatic breast cancer – is reflex in situ hybridization necessary in cases that are equivocal by immunohistochemistry?
Authors: Liwski C R , Castonguay M , Barnes P , Bethune G , Rayson D 
Published: October 2021

Abstract

Introduction/Objective
Current guidelines recommend HER2 testing on all primary invasive breast cancers and at least one metastatic lesion. Typical HER2 testing involves immunohistochemistry (IHC), with reflex in situ hybridization (ISH) in the event of equivocal (2+) IHC. ISH testing is time consuming and resource intensive, and there may be situations where it is unnecessary. The incidence of discordance between HER2 negative primary tumors and HER2 IHC2+ metastases that are ISH positive is unknown. We hypothesize that the majority of such cases are non- amplified.

Methods/Case Report
A retrospective review of IHC2+ metastatic lesions further assessed with ISH at our center from 2013-2021 was undertaken. A total of 105 cases were identified after exclusion of cases missing HER2 results, with primaries of unconfirmed origin, and cases of synchronous primary and metastatic disease. IHC and ISH results were recorded, with a detailed slide review of discordant cases.

Results (if a Case Study enter NA)
91/105 metastases had HER2 negative primaries (87%). A metastasis was significantly more likely to be HER2 negative when the primary was HER2 negative (93%) versus positive (43%) (p &lt; 0.0001). 54/91 primaries were IHC2+/ISH negative, and 50/54 (93%) corresponding metastases had identical results. Of the 37 HER2 negative primaries that were IHC0/1+, 35 (95%) corresponding metastatic tumors were ISH negative. Six metastatic lesions in cases with HER2 negative primaries were discordant and slides were reviewed. Characteristics of metastatic tumors suggesting ISH testing was warranted to assess for discordance included IHC heterogeneity, morphological discordance, and increased staining of moderate intensity. These factors were present in all six discordant metastases.

Conclusion
Our results suggest that selective rather than reflex ISH testing on HER2 IHC2+ breast cancer metastases in the context of HER2 negative primary disease may be appropriate when there is careful review of the IHC. Validation of our findings await further studies with larger sample sizes.
Effect of 1 vs. 2 decimal place reporting of creatinine (mg/dL) for calculation of estimated glomerular filtration rate (eGFR)
Authors: Reganis M N , Stickle D 
Published: October 2021

Abstract

Introduction/Objective
Our multi-hospital system recently adopted uniform use of 2 decimal places for reporting of creatinine (mg/dL), in accordance with NIH guidelines. Surprisingly, this change in patient reports fostered complaints from clinicians. Use of 2 decimal places is both analytically appropriate and reduces imprecision in calculations of estimated glomerular filtration rate (eGFR). Primary literature is devoid, however, of a delineation of the scale of the effect of using 1 vs. 2 decimal places to calculate eGFR. We examined this effect for both the Modified Diet in Renal Disease (MDRD) and the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) eGFR equations.

Methods/Case Report
Creatinine is an input to a single multiplicative creatinine factor in eGFR calculations for MDRD and CKD-EPI equations. We calculated the creatinine factor for these equations for creatinine=0.6-10 mg/dL, and evaluated the % difference in this factor when using increments of 0.1 mg/dL (1 decimal place) compared to increments of 0.1±0.05 mg/dL (viz., the 2 decimal place boundaries of a rounded 1 decimal place report). The observed % differences reflect those that would be observed in associated eGFR results.

Results (if a Case Study enter NA)
Input of 1 vs. 2 decimal places for creatinine in eGFR calculations, using either MDRD or CKD-EPI, produces differences in eGFR of greater than ±5% only for creatinine &lt;1.2 mg/dL, and greater than ±10% only for creatinine &lt;0.6 mg/dL (MDRD only). These ranges for creatinine are within or near-to reference ranges for both males (0.7-1.4 mg/dL) and females (0.6-1.0 mg/dL), and encompass approximately 70% of all patient reports for our patient population. For comparison, eGFR has a 95% confidence interval of approximately ±30% across all eGFR’s.

Conclusion
The ±5% reduction in precision in eGFR for such a large fraction of results by use of only 1 decimal place for creatinine was deemed unwarranted. Clinician complaints were handled by one-to-one discussions.
Immunoglobulin D Multiple Myeloma with a “Hidden” Lambda Light Chain
Authors: Lee J K , Flowers A , Williams J , Li S , Yi X , Huang R 
Published: October 2021

Abstract

Introduction/Objective
In rare cases, the conventional immunofixation gel electrophoresis technique fails to detect the light chain of an M-protein. We report a case of immunoglobulin (Ig) D multiple myeloma with a hidden lambda (λ) light chain.

Methods/Case Report
Capillary electrophoresis (CE) (Sebia CAPILLARYS 2) was used to detect and quantify M- proteins in serum specimens. Immunosubtraction (IS) on the CAPILLARYS 2 systems was used to identify the classes of M-proteins. Conventional gel immunofixation electrophoresis (IFE) was performed, using monospecific antisera for IgD, IgE, kappa (κ) or λ in the Sebia HYDRASYS system, and IgG, IgA, IgM, κ or λ in the Helena SPIFE3000 system. Beta-mercaptoethanol (BME) with Fluidil were used as reduction agents.

Results (if a Case Study enter NA)
Results of serum CE showed two abnormal peaks in beta 2 and gamma regions, suspected to be positive for M-proteins. IS results showed subtraction for λ light chain only in both peaks, suggesting two monoclonal λ light chains. In contrary, no monoclonal λ light chain was detected in gamma region by IFE (Sebia). Epitope masking in the folded monoclonal protein was suspected to cause the “hidden λ light chain” and was further investigated by two laboratory approaches. IFE performed on the Helena SPIFE3000 system found two λ bands in beta 2 and gamma regions, which was consistent with the results from IS. The treatment of BME with Fluidil helped unmasking the hidden epitope and revealed the λ band in gamma region on IFE (Sebia).

Conclusion
The medical laboratories should be aware of the described scenario. The failure to detect light chains of certain intact M-proteins is most likely due to the structurally inaccessibility of light chains. It is recommended that treatment with reduction agents or use of an alternative methodology or IS might be helpful for investigating suspected heavy chain only cases, due to the limitation of conventional methodology.