bluuebunny/crossref_metadata_2025 huggingface dataset:
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.

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.
Impact of COVID-19 Pandemic on Timing of Childhood Cancer Diagnoses
Authors: Cox Jennifer A. , Karlson Cynthia W. , Dillard Benjamin C. , Collier Anderson B.
Published: May 2021

The COVID-19 pandemic impacted the health care system in unprecedented ways. We reviewed the registry of new cancer patients who presented to the Children’s of Mississippi Center for Cancer and Blood Disorders and showed the average number of new pediatric cancer diagnoses dropped during the initial COVID-19 months and rose significantly in June 2020. We must encourage families to seek health care when needed and keep scheduled appointments for routine vaccinations and health maintenance as we know the long-term sequela of delaying health maintenance far outweighs risks at present.
Which Factors Promote Shared Understanding Between Physicians and Nurses in Inpatient Oncology Care Settings?
Authors: Crist Kaycee , Lafferty Megan , Umberfield Elizabeth , Manojlovich Milisa
Published: May 2021

Background

Effective communication between physicians and nurses is crucial to the safety of patients, especially for those with cancer, which is a complex disease requiring multidisciplinary treatment. However, little is known about the factors that contribute to effective communication, which is defined as the development of shared understanding between two or more people.

Objective

This qualitative secondary analysis was conducted to identify factors that contribute to shared understanding between physicians and nurses from video-recorded conversations that occurred between them during inpatient rounds on oncology units.

Methods

We used inductive grounded theory to identify videos depicting moments of shared understanding. We then searched for preceding events to develop a preliminary conceptual model that described the factors contributing to shared understanding.

Results

Four factors emerged as contributors to shared understanding: engagement, clarification, confirmation, and resolution. These factors occurred in sequence with engagement occurring first and resolution occurring last, as the closure of a communication exchange.

Conclusions

Existing interventions to improve communication include some of the factors identified as contributing to shared understanding (eg, closed-loop communications require clarification and confirmation). However, nurses may need to pay attention to all four factors to develop shared understanding that will promote effective communication with physicians and thereby enhance cancer care.

Implications for Practice

Nurses achieve effective communication when they are assertive and avoid indirect communication. A greater awareness of body language and positioning in relation to a physician at the start of a communication exchange may increase the effectiveness of nurse-physician communication.
Applying Artificial Intelligence to Gynecologic Oncology: A Review
Authors: Mysona David Pierce , Kapp Daniel S. , Rohatgi Atharva , Lee Danny , Mann Amandeep K. , Tran Paul , Tran Lynn , She Jin-Xiong , Chan John K.
Published: May 2021

Importance

Artificial intelligence (AI) will play an increasing role in health care. In gynecologic oncology, it can advance tailored screening, precision surgery, and personalized targeted therapies.

Objective

The aim of this study was to review the role of AI in gynecologic oncology.

Evidence Acquisition

Artificial intelligence publications in gynecologic oncology were identified by searching “gynecologic oncology AND artificial intelligence” in the PubMed database. A review of the literature was performed on the history of AI, its fundamentals, and current applications as related to diagnosis and treatment of cervical, uterine, and ovarian cancers.

Results

A PubMed literature search since the year 2000 showed a significant increase in oncology publications related to AI and oncology. Early studies focused on using AI to interrogate electronic health records in order to improve clinical outcome and facilitate clinical research. In cervical cancer, AI algorithms can enhance image analysis of cytology and visual inspection with acetic acid or colposcopy. In uterine cancers, AI can improve the diagnostic accuracies of radiologic imaging and predictive/prognostic capabilities of clinicopathologic characteristics. Artificial intelligence has also been used to better detect early-stage ovarian cancer and predict surgical outcomes and treatment response.

Conclusions and Relevance

Artificial intelligence has been shown to enhance diagnosis, refine clinical decision making, and advance personalized therapies in gynecologic cancers. The rapid adoption of AI in gynecologic oncology will depend on overcoming the challenges related to data transparency, quality, and interpretation.

Artificial intelligence is rapidly transforming health care. However, many physicians are unaware that this technology is being used in their practices and could benefit from a better understanding of the statistics and computer science behind these algorithms. This review provides a summary of AI, its applicability, and its limitations in gynecologic oncology.

Target Audience

Obstetricians and gynecologists, family physicians

Learning Objectives

After completing this CME activity, physicians should be better able to describe the basic functions of AI algorithms; explain the potential applications of machine learning in diagnosis, treatment, and prognostication of cervical, endometrial, and ovarian cancers; and identify the ethical concerns and limitations of the use of AI in the management of gynecologic cancer patients.
The Use of Host Cell DNA Methylation Analysis in the Detection and Management of Women With Advanced Cervical Intraepithelial Neoplasia: A Review
Authors: Kremer W. W. , Steenbergen R. D. M. , Heideman D. A. M. , Kenter G. G. , Meijer C. J. L. M.
Published: May 2021

(Abstracted from BJOG 2021;128:504–514)

Premalignant lesions such as cervical intraepithelial neoplasia (CIN) can develop into cervical cancer through a slow process taking up to 30 years from initial high-risk human papillomavirus (hrHPV) infection. Primary hrHPV DNA testing has superior sensitivity compared with cytology and has a high negative predictive value for high-grade CIN or worse (CIN2+).
Antenatal Dexamethasone for Early Preterm Birth in Low-Resource Countries
Authors:   The WHO ACTION Trial Collaborators
Published: May 2021

(Abstracted from N Engl J Med 2020;383:2514–2525)

The use of antenatal glucocorticoids to reduce infant morbidity and mortality associated with preterm birth has been supported by a number of studies conducted in high-resource countries. However, a 2015 population-based trial conducted in low-resource countries called their use into question.
Variations of P40 and P63 Immunostains in Different Grades of Esophageal Squamous Cell Carcinoma: A Potential Diagnostic Pitfall
Authors: Chi Zhikai , Balani Jyoti , Gopal Purva , Peng Lan , Hammer Suntrea
Published: May 2021

The distinction of esophageal squamous cell carcinoma (SCC) from adenocarcinoma (adenoCA) using targeted therapies has become critical for small biopsies. In the United States, esophageal SCC is relatively uncommon compared with AdenoCA, with only few detailed immunohistochemical (IHC) studies on esophageal SCC. We characterized p40 and p63 IHC across various grades of squamous differentiation in esophageal SCC and compared their sensitivities between esophageal SCC and adenoCA. Twenty-eight esophageal SCC and 26 esophageal adenoCA (control group) samples were stained for p40, p63, and CK5/6. All hematoxylin-and-eosin-stained SCC slides were reviewed. Tumors were graded according to the World Health Organization classification: well, moderately, or poorly differentiated (WD, MD, and PD, respectively). Considering morphological heterogeneity, individual differentiation components within the same tumor were scored separately (0% to 100%) according to the proportion of immunoreactive cells and marked as positive (≥5%) or negative (<5%). Among 28 esophageal SCC, 15 had mixed intratumoral differentiation. There were 16 WD, 19 MD, and 14 PD components. P40 immunoreactivity was significantly lower in WD than in MD or PD components (P<0.001), P63 immunoreactivity patterns were similar (P<0.001), while CK5/6 showed no differences (P>0.05). The sensitivities for SCC components were 98% (P40), 100% (P63), and 100% (CK5/6), while those for esophageal AdenoCA were significantly lower: 4% (P40), 4% (P63), and 8% (CK5/6). P40 and P63 were sensitive and specific for routine esophageal SCC diagnosis. However, their immunostaining was significantly lower in WD SCC than in higher grade tumors. IHC results for small biopsy specimens should be interpreted carefully, particularly in WD components.
Valosin-containing Protein in Psoriasis: A Clinical and Immunohistochemical Study
Authors: El Dein Mohamed Asmaa Shams. , Hagag Magda M. , Kassem Naira Mohamed Abd El-Aziz , Shehata Wafaa A.
Published: May 2021

Psoriasis is a chronic immune-mediated inflammatory skin disease, affects about 2% to 3% of the world population. Valosin-containing protein (VCP) is one of the newly discovered markers that is highly expressed in neoplasms and hyperproliferative lesions. This work aimed to study the role of VCP in psoriasis vulgaris by immunohistochemical study and correlate its expression with the available clinicopathologic data. This prospective case-control study was conducted on 25 patients with psoriasis vulgaris and 25 age-matched and sex-matched healthy individuals as a control group. Skin biopsies were taken under local anesthesia from cases and controls. VCP immunoreactivity showed that epidermal VCP expression had a significant stepwise increase (P=0.002) from control to lesional psoriatic sections. Epidermal VCP H-score was significantly associated with the progressive course (P=0.037). Similarly, VCP in the dermis showed a significant expression in lesional psoriatic skin (P≤0.001). Higher VCP in the dermis in cases with a history of joint affection (P<0.05) was detected. We concluded that VCP is a promising marker for follow-up and monitoring of psoriatic patients and may play a role as a therapeutic target.
Cutaneous Lymphadenoma Is a Distinct Trichoblastoma-like Lymphoepithelial Tumor With Diffuse Androgen Receptor Immunoreactivity, Notch1 Ligand in Reed-Sternberg–like Cells, and Common EGFR Somatic Mutations
Authors: Monteagudo Carlos , Fúnez Rafael , Sánchez-Sendra Beatriz , González-Muñoz José F. , Nieto Gema , Alfaro-Cervelló Clara , Murgui Amelia , Barr Ronald J.
Published: May 2021

The term “cutaneous lymphadenoma” was coined in this journal for an unusual lymphoepithelial cutaneous adnexal neoplasm, possibly with immature pilosebaceous differentiation. Some authors further proposed that cutaneous lymphadenoma was an adamantinoid trichoblastoma. However, although a hair follicle differentiation is widely accepted, the fact that this is a lymphoepithelial tumor is not appropriately explained by the trichoblastoma hypothesis. Our goal was to further clarify the phenotypic and genotypic features of cutaneous lymphadenoma in a series of 11 cases. Histologically, a lobular architecture surrounded by a dense fibrous stroma was present in all cases. The lobules were composed of epithelial cells admixtured with small lymphocytes and isolated or clustered large Reed-Sternberg–like (RS-L) cells. The epithelial cells were diffusely positive for the hair follicle stem cell markers CK15, PHLDA1, and for androgen receptor. No immunostaining for markers of sebaceous differentiation was found. Intraepithelial lymphocytes were predominantly CD3+, CD4+, FoxP3+ T cells. RS-L cells showed both strong Jagged-1 and Notch1 cytoplasmic immunostaining. Androgen-regulated NKX3.1 nuclear immunostaining was present in a subset of large intralobular cells in all cases. Double immunostaining showed coexpression of NKX3.1 and CD30 in a subset of RS-L cells. No immunostaining for lymphocytic or epithelial markers was present in RS-L cells. EGFR, PIK3CA, and FGFR3 somatic mutations were found by next-generation sequencing in 56% of the cases. We consider that cutaneous lymphadenoma is a distinct benign lymphoepithelial tumor with androgen receptor and hair follicle bulge stem cell marker expression, RS-L cell-derived Notch1 ligand, and common EGFR gene mutations.
ISUP Consensus Definition of Cribriform Pattern Prostate Cancer
Authors: van der Kwast Theodorus H. , van Leenders Geert J. , Berney Daniel M. , Delahunt Brett , Evans Andrew J. , Iczkowski Kenneth A. , McKenney Jesse K. , Ro Jae Y. , Samaratunga Hemamali , Srigley John R. , Tsuzuki Toyo , Varma Murali , Wheeler Thomas M. , Egevad Lars
Published: May 2021

The presence of a cribriform pattern is now recognized as a clinically important, independent adverse prognostic indicator for prostate cancer. For this reason the International Society of Urological Pathology (ISUP) recently recommended its inclusion in standard reporting. In order to improve interobserver agreement as to the diagnosis of cribriform patterns, the ISUP assembled an international panel of 12 expert urogenital pathologists for the purpose of drafting a consensus definition of cribriform pattern in prostate cancer, and provide their opinions on a set of 32 images and on potential diagnostic criteria. These images were selected by the 2 nonvoting convenors of the study and included the main categories where disagreement was anticipated. The Delphi method was applied to promote consensus among the 12 panelists in their review of the images during 2 initial rounds of the study. Following a virtual meeting, convened to discuss selected images and diagnostic criteria, the following definition for cribriform pattern in prostate cancer was approved: “A confluent sheet of contiguous malignant epithelial cells with multiple glandular lumina that are easily visible at low power (objective magnification ×10). There should be no intervening stroma or mucin separating individual or fused glandular structures” together with a set of explanatory notes. We believe this consensus definition to be practical and that it will facilitate reproducible recognition and reporting of this clinically important pattern commonly seen in prostate cancer. The images and the results of the final Delphi round are available at the ISUP website as an educational slide set (https://isupweb.org/isup/blog/slideshow/cribriform-slide-deck/).
A Novel NIPBL-NACC1 Gene Fusion Is Characteristic of the Cholangioblastic Variant of Intrahepatic Cholangiocarcinoma
Authors: Argani Pedram , Palsgrove Doreen N. , Anders Robert A. , Smith Steven C. , Saoud Carla , Kwon Regina , Voltaggio Lysandra , Assarzadegan Naziheh , Oshima Kiyoko , Rooper Lisa , Matoso Andres , Zhang Lei , Cantarel Brandi L. , Gagan Jeffrey , Antonescu Cristina R.
Published: May 2021

We report a novel NIPBL-NACC1 gene fusion in a rare primary hepatic neoplasm previously described as the “cholangioblastic variant of intrahepatic cholangiocarcinoma.” The 2 index cases were identified within our consultation files as morphologically distinctive primary hepatic neoplasms in a 24-year-old female and a 54-year-old male. The neoplasms each demonstrated varied architecture, including trabecular, organoid, microcystic/follicular, and infiltrative glandular patterns, and biphasic cytology with large, polygonal eosinophilic cells and smaller basophilic cells. The neoplasms had a distinctive immunoprofile characterized by diffuse labeling for inhibin, and patchy labeling for neuroendocrine markers (chromogranin and synaptophysin) and biliary marker cytokeratin 19. RNA sequencing of both cases demonstrated an identical fusion of NIBPL exon 8 to NACC1 exon 2, which was further confirmed by break-apart fluorescence in situ hybridization assay for each gene. Review of a tissue microarray including 123 cases originally diagnosed as well-differentiated neuroendocrine neoplasm at one of our hospitals resulted in identification of a third case with similar morphology and immunophenotype in a 52-year-old male, and break-apart fluorescence in situ hybridization probes confirmed rearrangement of both NIPBL and NACC1. Review of The Cancer Genome Atlas (TCGA) sequencing data and digital images from 36 intrahepatic cholangiocarcinomas (www.cbioportal.org) revealed one additional case with the same gene fusion and the same characteristic solid, trabecular, and follicular/microcystic architectures and biphasic cytology as seen in our genetically confirmed cases. The NIPBL-NACC1 fusion represents the third type of gene fusion identified in intrahepatic cholangiocarcinoma, and correlates with a distinctive morphology described herein.
Histopathology of Gastrointestinal Immune-related Adverse Events
Authors: Zhang M. Lisa , Deshpande Vikram
Published: May 2021

Immune checkpoint inhibitors target checkpoint proteins with the goal of reinvigorating the host immune system and thus restoring antitumor response. With the dramatic increase in the use of checkpoint inhibitors for cancer treatment, surgical pathologists have assumed a major role in predicting the therapeutic efficacy (score based on programmed cell death ligand 1 immunohistochemistry and mismatch repair protein loss) as well as diagnosing the complications associated with these medications. Immune-related adverse events (irAEs) manifest as histologic changes seen in both the upper and lower gastrointestinal tract, and when viewed in isolation, may be morphologically indistinguishable from a wide range of diseases including infections, celiac disease, and inflammatory bowel disease, among others. Evaluation of biopsies from both the upper and lower gastrointestinal tract can aid in the distinction of gastrointestinal irAEs from their mimics. In the liver, the histologic changes of hepatic irAEs overlap with de novo diseases associated with hepatitic and cholangitic patterns of injury. The diagnosis of irAEs requires communication and collaboration from the pathologist, oncologist, and gastroenterologist. This review provides a background framework and illustrates the histologic features and differential diagnosis of gastrointestinal and hepatic irAEs.
Crohn Disease Infrequently Affects the Appendix and Rarely Causes Granulomatous Appendicitis
Authors: Mostyka Maria , Fulmer Clifton G. , Hissong Erika M. , Yantiss Rhonda K.
Published: May 2021

Data from previous studies suggest Crohn disease of the appendix accounts for ∼25% of granulomatous appendicitis cases. However, we have found that granulomatous inflammation in appendectomy specimens rarely heralds Crohn disease. We suspect that appendiceal involvement by Crohn disease is uncommon, even when patients have severe ileocolonic inflammation. We performed this study to determine the prevalence and nature of appendiceal inflammation among patients with Crohn disease. We reviewed 100 ileocolic specimens with strictures and fistulizing Crohn disease for the nature and distribution of inflammatory changes in the appendix and compared them with 100 appendices on colectomy specimens from age-matched and sex-matched patients with ulcerative colitis. We also evaluated 27 additional cases of granulomatous appendicitis in appendectomy specimens to determine the frequency with which this finding represented Crohn disease. The appendix was usually normal (26%) or showed fibrous obliteration (50%) in ileocolic resection specimens from patients with Crohn disease. Mucosal inflammation was much less common in appendices from patients with Crohn disease than ulcerative colitis (6% vs. 28%, P<0.0001); only 4 cases contained epithelioid granulomata, 3 showed mural fibrosis and lymphoid aggregates, and 10 displayed only periappendiceal inflammation. None of the patients with granulomatous appendicitis in appendectomy specimens had, or developed, evidence of Crohn disease. We conclude that Crohn disease infrequently affects the appendix. Interval appendectomy and infection are more important considerations when appendectomy specimens feature granulomatous inflammation and/or mural lymphoid aggregates, especially if there is no history of idiopathic inflammatory bowel disease.
Clinicopathologic and Genomic Characterization of Inflammatory Myofibroblastic Tumors of the Head and Neck
Authors: Kerr Darcy A. , Thompson Lester D.R. , Tafe Laura J. , Jo Vickie Y. , Neyaz Azfar , Divakar Prashanthi , Paydarfar Joseph A. , Pastel David A. , Shirai Keisuke , John Ivy , Seethala Raja R. , Salgado Claudia M. , Deshpande Vikram , Bridge Julia A. , Kashofer Karl , Brčić Iva , Linos Konstantinos
Published: May 2021

Inflammatory myofibroblastic tumor (IMT) is a distinctive fibroblastic and myofibroblastic spindle cell neoplasm with an accompanying inflammatory cell infiltrate and frequent receptor tyrosine kinase activation at the molecular level. The tumor may recur and rarely metastasizes. IMT is rare in the head and neck region, and limited information is available about its clinicopathologic and molecular characteristics in these subsites. Therefore, we analyzed a cohort of head and neck IMTs through a multi-institutional approach. Fourteen cases were included in the provisional cohort, but 1 was excluded after molecular analysis prompted reclassification. Patients in the final cohort included 7 males and 6 females, with a mean age of 26.5 years. Tumors were located in the larynx (n=7), oral cavity (n=3), pharynx (n=2), and mastoid (n=1). Histologically, all tumors showed neoplastic spindle cells in storiform to fascicular patterns with associated chronic inflammation, but the morphologic spectrum was wide, as is characteristic of IMT in other sites. An underlying fusion gene event was identified in 92% (n=11/12) of cases and an additional case was ALK-positive by IHC but could not be evaluated molecularly. ALK represented the driver in all but 1 case. Rearrangement of ALK, fused with the TIMP3 gene (n=6) was most commonly detected, followed by 1 case each of the following fusion gene partnerships: TPM3-ALK, KIF5B-ALK, CARS-ALK, THBS1-ALK, and a novel alteration, SLC12A2-ROS1. The excluded case was reclassified as spindle cell rhabdomyosarcoma after detection of a FUS-TFCP2 rearrangement and retrospective immunohistochemical confirmation of rhabdomyoblastic differentiation, illustrating an important diagnostic pitfall. Two IMT patients received targeted therapy with crizotinib, with a demonstrated radiographic response. One tumor recurred but none metastasized. These results add to the growing body of evidence that kinase fusions can be identified in the majority of IMTs and that molecular analysis can lead to increased diagnostic accuracy and broadened therapeutic options for patients.
Induction Therapy Strategies in the Transplant-Ineligible Population
Authors: Attar Narsis , O'Donnell Elizabeth K.
Published: May 2021

Multiple myeloma (MM), a plasma cell malignancy, accounts for ~10% of hematologic malignancies and predominantly affects the older population. It exhibits a heterogeneous biology and a complex genetic phenotype that affect patient prognosis. The treatment of MM has evolved significantly over the last decade with the use of autologous stem cell transplantation and several novel agents. Consequently, outcomes have improved in this time period, with the most impact in younger patients. Management of MM in elderly frail patients requires a thoughtful approach as majority of these patients carry multiple comorbidities and are precluded from high-dose chemotherapy and autologous stem cell transplantation—accounting for the more modest improvement in outcomes. Assessing transplant eligibility and performance status is a critical first step. Subsequently, the choice of frontline therapy in transplant-ineligible frail patients must balance efficacy with adverse effects to optimize quality of life. Here, we review the current state of induction regimens in this patient population.
Monoclonal Antibodies in Myeloma
Authors: Hartley-Brown Monique , Chitty David , Thakur Richa
Published: May 2021

In the past several years, there have been significant advances in the therapeutic arsenal of agents used to treat multiple myeloma (MM). Despite these advances, MM remains incurable. One of the most recent therapeutic advances is the development of targeted monoclonal antibodies (MoAbs). The MoAbs have significantly improved disease response rates, and extended survival in MM patients. In this review, we highlight the current US Food and Drug Administration approved MoAbs, namely, belantamab mafodotin, daratumumab, elotuzumab, and isatuximab. The mechanisms of action and pivotal clinical trials that led to US Food and Drug Administration approval of these agents and their current therapeutic use in the management of patients with MM are discussed in detail. Lastly, we describe several novel MoAbs under clinical investigation with potential for approval in the future.
From VAD to VRD
Authors: Parmar Harsh , Vesole David H. , Biran Noa
Published: May 2021

High-dose therapy followed by autologous stem cell transplantation (ASCT) is considered the standard of care for transplant-eligible patients with newly diagnosed multiple myeloma (MM). With new treatment combinations offering the advantage of improved clinical outcomes of MM patients, the utilization of ASCT is again being addressed in the evolving treatment landscape. In this article, we review the role of frontline ASCT in the management of patients with MM.
Strategies to Overcome High-Risk Multiple Myeloma
Authors: Sanchez Larysa
Published: May 2021

Multiple myeloma (MM) patients with high-risk cytogenetics continue to have inferior outcomes despite recent advances in the treatment of MM. As defined by the International Myeloma Working Group, the presence of t(4;14), t(14;16), del(17p), t(14;20) and amplification of 1q are considered to be high-risk chromosomal abnormalities associated with poor survival. Despite the use of immunomodulatory agents, proteasome inhibitors, autologous stem cell transplantation, and anti-CD38 monoclonal antibodies, clinical trials of current therapies have not shown strong statistical evidence of being able to overcome the poor prognosis of high-risk disease. Novel treatment approaches are urgently needed to improve survival in this subset of MM patients.
Managing uncertainty in antifungal dosing: antibiograms, therapeutic drug monitoring and drug-drug interactions
Authors: Lewis Russell E. , Andes David R.
Published: May 2021

Purpose of review

A number of pharmacokinetic and pharmacodynamic factors in critically ill or severely immunosuppressed patients influence the effectiveness of antifungal therapy making dosing less certain. Recent position papers from infectious diseases societies and working groups have proposed methods for dosage individualization of antibiotics in critically ill patients using a combination of population pharmacokinetic models, Monte-Carlo simulation and therapeutic drug monitoring (TDM) to guide dosing. In this review, we examine the current limitations and practical issues of adapting a pharmacometrics-guided dosing approaches to dosing of antifungals in critically ill or severely immunosuppressed populations.

Recent findings

We review the current status of antifungal susceptibility testing and challenges in incorporating TDM into Bayesian dose prediction models. We also discuss issues facing pharmacometrics dosage adjustment of newer targeted chemotherapies that exhibit severe pharmacokinetic drug-drug interactions with triazole antifungals.

Although knowledge of antifungal pharmacokinetic/pharmacodynamic is maturing, the practical application of these concepts towards point-of-care dosage individualization is still limited. User-friendly pharmacometric models are needed to improve the utility of TDM and management of a growing number of severe pharmacokinetic antifungal drug-drug interactions with targeted chemotherapies.
Update on neuroimaging for categorization of Parkinson's disease and atypical parkinsonism
Authors: Chougar Lydia , Pyatigorskaya Nadya , Lehéricy Stéphane
Published: May 2021

Purpose of review

Differential diagnosis of Parkinsonism may be difficult. The objective of this review is to present the work of the last three years in the field of imaging for diagnostic categorization of parkinsonian syndromes focusing on progressive supranuclear palsy (PSP) and multiple system atrophy (MSA).

Recent findings

Two main complementary approaches are being pursued. The first seeks to develop and validate manual qualitative or semi-quantitative imaging markers that can be easily used in clinical practice. The second is based on quantitative measurements of magnetic resonance imaging abnormalities integrated in a multimodal approach and in automatic categorization machine learning tools.

These two complementary approaches obtained high diagnostic around 90% and above in the classical Richardson form of PSP and probable MSA. Future work will determine if these techniques can improve diagnosis in other PSP variants and early forms of the diseases when all clinical criteria are not fully met.
Ataxin-2 gene: a powerful modulator of neurological disorders
Authors: Laffita-Mesa Jose Miguel , Paucar Martin , Svenningsson Per
Published: May 2021

Purpose of review

To provide an update on the role of Ataxin-2 gene (ATXN2) in health and neurological diseases.

Recent findings

There is a growing complexity emerging on the role of ATXN2 and its variants in association with SCA2 and several other neurological diseases. Polymorphisms and intermediate alleles in ATXN2 establish this gene as a powerful modulator of neurological diseases including lethal neurodegenerative conditions such as motor neuron disease, spinocerebellar ataxia 3 (SCA3), and peripheral nerve disease such as familial amyloidosis polyneuropathy. This role is in fact far wider than the previously described for polymorphism in the prion protein (PRNP) gene. Positive data from antisense oligo therapy in a murine model of SCA2 suggest that similar approaches may be feasible in humans SCA2 patients.

ATXN2 is one of the few genes where a single gene causes several diseases and/or modifies several and disparate neurological disorders. Hence, understanding mutagenesis, genetic variants, and biological functions will help managing SCA2, and several human diseases connected with dysfunctional pathways in the brain, innate immunity, autophagy, cellular, lipid, and RNA metabolism.
Cerebellar ataxia, neuropathy, vestibular areflexia syndrome: genetic and clinical insights
Authors: Sullivan Roisin , Kaiyrzhanov Rauan , Houlden Henry
Published: May 2021

Purpose of review

This review aims to summarise the present cerebellar ataxia, neuropathy, vestibular ataxia syndrome (CANVAS) literature, providing both clinical and genetic insights that might facilitate the timely clinical and genetic diagnosis of this disease.

Recent findings

Recent advancements in the range of the clinical features of CANVAS have aided the development of a broader, more well-defined clinical diagnostic criteria. Additionally, the identification of a biallelic repeat expansion in RFC1 as the cause of CANVAS and a common cause of late-onset ataxia has opened the door to the potential discovery of a pathogenic mechanism, which in turn, may lead to therapeutic advancements and improved patient care.

The developments in the clinical and genetic understanding of CANVAS will aid the correct and timely diagnosis of CANVAS, which continues to prove challenging within the clinic. The insights detailed within this review will raise the awareness of the phenotypic spectrum and currently known genetics. We also speculate on the future directions of research into CANVAS.
Neuromuscular hyperexcitability syndromes
Authors: De Wel Bram , Claeys Kristl G.
Published: May 2021

Purpose of review

To provide an update on recent developments regarding acquired, antibody-mediated, neuromuscular hyperexcitability syndromes, including Isaac's and Morvan's syndromes, cramp-fasciculation syndrome and rippling muscle disease, and their genetic differential diagnoses.

Recent findings

Antibodies in auto-immune peripheral nerve hyperexcitability syndromes (PNHS) are directed against CASPR2 and LGI1, proteins of the voltage-gated potassium channel (VGKC) complex. We discuss the significance of ‘double-negative’ VGKC antibodies in PNHS and the rationale for ceasing VGKC antibody testing (but testing CASPR2 and LGI1 antibodies instead) in clinical practice. Recent case reports also expand the possible clinical phenotypes related to CASPR2/LGI1 antibodies, but the interpretation of these findings is complicated by the frequent association of antibody-mediated neuromuscular hyperexcitability syndromes with other auto-immune disorders (e.g. myasthenia gravis).

Finally, a hereditary origin of neuromuscular hyperexcitability should always be considered, even in non-VGKC-related genes, as evidenced by the recently discovered high frequency of HINT1 mutations in people of Slavic origin.

This review provides an update on recent clinical, immunological and genetic developments in neuromuscular hyperexcitability syndromes. We also provide a guide for the clinician for diagnosing and managing these disorders in clinical practice, with a special focus on the main differential diagnoses.
Larval habitats impose trait-dependent limits on the direction and rate of adult evolution in dragonflies
Authors: Moore Michael P.
Published: May 2021

Natural selection on juveniles is often invoked as a constraint on adult evolution, but it remains unclear when such restrictions will have their greatest impact. Selection on juveniles could, for example, mainly limit the evolution of adult traits that mostly develop prior to maturity. Alternatively, selection on juveniles might primarily constrain the evolution of adult traits that experience weak or context-dependent selection in the adult stage. Using a comparative study of dragonflies, I tested these hypotheses by examining how a species’ larval habitat was related to the evolution of two adult traits that differ in development and exposure to selection: adult size and male ornamentation. Whereas adult size is fixed at metamorphosis and experiences consistent positive selection in the adult stage, ornaments develop throughout adulthood and provide context-dependent fitness benefits. My results show that species that develop in less stable larval habitats have smaller adult sizes and slower rates of adult size evolution. However, these risky larval habitats do not limit ornament expression or rates of ornament evolution. Selection on juveniles may therefore primarily affect the evolution of adult traits that mostly develop prior to maturity.
Moving in fast waters: the exaggerated claw gape of the New River crayfish (
Cambarus chasmodactlyus
) aids in locomotor performance
Authors: Graham Zackary A.
Published: May 2021

Humans are inherently fascinated by exaggerated morphological structures such as elk antlers and peacock trains. Because these traits are costly to develop and wield, the environment in which they are used can select for specific sizes or shapes to minimize such costs. In aquatic environments, selection to reduce drag can constrain the form of exaggerated structures; this is presumably why exaggerated morphologies are less common in aquatic environments compared to terrestrial ones. Interestingly, some crayfish species possess claws with an exaggerated gape between their pinching fingers, but the function of this claw gape is unknown. Here, I describe and test the function of the exaggerated claw gape of the New River crayfish,
Cambarus chasmodactylus
. Specifically, I test the hypothesis that the claw gape aids in movement against flowing currents. I found that both claw size and gape size were sexually dimorphic in this species and that males have disproportionately larger gapes compared to females. By experimentally covering their claw gape and testing crayfish locomotor performance, I found that individuals with their gape blocked were 30% slower than crayfish with a natural gape. My results highlight a unique adaptation that compensates for wielding an exaggerated structure in aquatic environments.
Brain size predicts learning abilities in bees
Authors: Collado Miguel Á. , Montaner Cristina M. , Molina Francisco P. , Sol Daniel , Bartomeus Ignasi
Published: May 2021

When it comes to the brain, bigger is generally considered better in terms of cognitive performance. While this notion is supported by studies of birds and primates showing that larger brains improve learning capacity, similar evidence is surprisingly lacking for invertebrates. Although the brain of invertebrates is smaller and simpler than that of vertebrates, recent work in insects has revealed enormous variation in size across species. Here, we ask whether bee species that have larger brains also have higher learning abilities. We conducted an experiment in which field-collected individuals had to associate an unconditioned stimulus (sucrose) with a conditioned stimulus (coloured strip). We found that most species can learn to associate a colour with a reward, yet some do so better than others. These differences in learning were related to brain size: species with larger brains—both absolute and relative to body size—exhibited enhanced performance to learn the reward-colour association. Our finding highlights the functional significance of brain size in insects, filling a major gap in our understanding of brain evolution and opening new opportunities for future research.
Fractal characteristics of shale pore structure and its influence on seepage flow
Authors: Wang Shengwei , Li Xijian , Xue Haiteng , Shen Zhonghui , Chen Liuyu
Published: May 2021

The migration law of shale gas has a significant influence on the seepage characteristics of shale, and the flow of the gas is closely related to the pore structure. To explore the influence of shale pore parameters on permeability in different diffusion zones, the pore structure of the shale in the Niutitang Formation in Guizhou, China, was analysed based on liquid nitrogen adsorption experiments and nuclear magnetic resonance experiments. The relationship among fractal dimension, organic carbon content (TOC) and BET-specific surface area was analysed based on the fractal dimension of shale pores calculated using the Frenkel–Halsey–Hill model. Shale permeability was calculated using the Knudsen number (
Kn
) and permeability equation, and the influence of the fractal dimension and porosity in different diffusion zones on shale permeability was analysed. Previous studies have shown that: (i) the pores of shale in the Niutitang Formation, Guizhou are mainly distributed within 1–100 nm, with a small total pore volume per unit mass, average pore diameter, large BET specific surface area and porosity; (ii) fractal dimension has a negative correlation with average pore diameter and TOC content and a quadratic relationship with BET specific surface area; and (iii) permeability has a positive correlation with
Kn
, porosity and fractal dimension. In the transitional diffusion zone, fractal dimension and porosity have a significant impact on permeability. In the Knudsen diffusion zone, porosity has no obvious effect on permeability. The methodologies and results presented will enable more accurate characterization of the complexity of pore structures of porous media and allow further understanding of the seepage law of shale gas.
Fine-scale changes in speed and altitude suggest protean movements in homing pigeon flights
Authors: Garde Baptiste , Wilson Rory P. , Lempidakis Emmanouil , Börger Luca , Portugal Steven J. , Hedenström Anders , Dell'Omo Giacomo , Quetting Michael , Wikelski Martin , Shepard Emily L. C.
Published: May 2021

The power curve provides a basis for predicting adjustments that animals make in flight speed, for example in relation to wind, distance, habitat foraging quality and objective. However, relatively few studies have examined how animals respond to the landscape below them, which could affect speed and power allocation through modifications in climb rate and perceived predation risk. We equipped homing pigeons (
Columba livia
) with high-frequency loggers to examine how flight speed, and hence effort, varies in relation to topography and land cover. Pigeons showed mixed evidence for an energy-saving strategy, as they minimized climb rates by starting their ascent ahead of hills, but selected rapid speeds in their ascents. Birds did not modify their speed substantially in relation to land cover, but used higher speeds during descending flight, highlighting the importance of considering the rate of change in altitude before estimating power use from speed. Finally, we document an unexpected variability in speed and altitude over fine scales; a source of substantial energetic inefficiency. We suggest this may be a form of protean behaviour adopted to reduce predation risk when flocking is not an option, and that such a strategy could be widespread.
Process of overburden failure in steeply inclined multi-seam mining: insights from physical modelling
Authors: Wang Hai , Qin Yan , Wang Hanbin , Chen Yu , Liu Xuancheng
Published: May 2021

Ground surface damage caused by steeply inclined coal seam mining is widely distributed in China, but there is little research on the failure process and movement mechanism of strata induced by steeply inclined multi-seam mining. In this paper, a physical model test is carried out to study the failure process and movement mechanism of overburden in steeply inclined multi-seam stepwise mining. The results show that at the initial stage, the main failure of the rock mass is the small-scale collapse at the initial cut and the roof (stability stage of the rock mass). After the roof is exposed over a certain range, the rock mass in the downhill direction slips into the goaf and gradually destroys the interburdens of the goaf, similar to the displacement effect of dominoes (severe failure stage of the rock mass). When the structure of the goaf fails, the overburden subsides, causing extensive damage to the ground surface. The surface damage directly above the goaf is mainly caused by serious subsidence deformation, while the surface damage in the downhill direction is dominated by cracks.
Covid-19: predictive mathematical formulae for the number of deaths during lockdown and possible scenarios for the post-lockdown period
Authors: Fokas Athanassios S. , Dikaios Nikolaos , Kastis George A.
Published: May 2021

In a recent article, we introduced two novel mathematical expressions and a deep learning algorithm for characterizing the dynamics of the number of reported infected cases with SARS-CoV-2. Here, we show that such formulae can also be used for determining the time evolution of the associated number of deaths: for the epidemics in Spain, Germany, Italy and the UK, the parameters defining these formulae were computed using data up to 1 May 2020, a period of lockdown for these countries; then, the predictions of the formulae were compared with the data for the following 122 days, namely until 1 September. These comparisons, in addition to demonstrating the remarkable predictive capacity of our simple formulae, also show that for a rather long time the easing of the lockdown measures did not affect the number of deaths. The importance of these results regarding predictions of the number of Covid-19 deaths during the post-lockdown period is discussed.
Synchronization and coalescence in a dissipative two-qubit system
Authors: Cabot Albert , Luca Giorgi Gian , Zambrini Roberta
Published: May 2021

The possibility of detuned spins displaying synchronous oscillations in local observables is analysed in the presence of coupling, collective dissipation and incoherent pumping. We show that there exist two distinct scenarios in which synchronization can emerge, related respectively to the presence of a non-degenerate long-lived eigenmode and to the presence of a single-frequency regime. Both scenarios can arise by tuning parameters in this system, owing to the presence of coalascence. The former, known as transient synchronization, is here generalized in the presence of incoherent pumping, and is due to long-lasting coherences leading to a progressive frequency selection. On the other hand, in spite of the spins detuning, the dynamics can be governed by a single frequency. Still, we show that synchronization can be established only after a transient, when phase-locking arises. Spectral features of synchronization in these two scenarios are analysed for two-time correlations.