Treatment of newly diagnosed severe aplastic anemia in children: Evidence-based recommendations.

Severe aplastic anemia (SAA) is a rare potentially fatal hematologic disorder. Although overall outcomes with treatment are excellent, there are variations in management approach, including differences in treatment between adult and pediatric patients. Certain aspects of treatment are under active investigation in clinical trials. Because of the rarity of the disease, some pediatric hematologists may have relatively limited experience with the complex management of SAA. The following recommendations reflect an up-to-date evidence-based approach to the treatment of children with newly diagnosed SAA.

Treatment of relapsed/refractory severe aplastic anemia in children: Evidence-based recommendations.

Severe aplastic anemia (SAA) is a rare potentially fatal hematologic disorder. Although overall outcomes with treatment are excellent, there are variations in management approach, including differences in treatment between adult and pediatric patients. Certain aspects of treatment are under active investigation in clinical trials. Because of the rarity of the disease, some pediatric hematologists may have relatively limited experience with the complex management of SAA. The following recommendations reflect an up-to-date evidence-based approach to the treatment of children with relapsed or refractory SAA.

Comparing narrative storytelling ability in individuals with autism and fetal alcohol spectrum disorders.

BACKGROUND: Narrative discourse, or storytelling, is used in daily conversation and requires higher-level language and social communication skills that are not always captured by standardised assessments of language. Many autistic individuals and individuals with fetal alcohol spectrum disorders (FASD) have difficulties with both social communication and language skills, and narrative discourse analysis offers an ecologically relevant approach to assessing those challenges. AIMS: This study investigated narrative discourse in individuals with autism and FASD, as well as an age- and sex-matched comparison group. METHODS AND PROCEDURES: Narratives from 45 adolescents and adults, 11 with autism, 11 with FASD and 23 age- and sex-matched comparison participants were elicited using a wordless storybook. They were then transcribed orthographically, formatted to the Systematic Analyses of Language Transcript (SALT) convention and scored based on the SALT Narrative Scoring Scheme (NSS), a standardised language analysis protocol. In addition to the NSS total score, which assesses the overall structure and cohesion of the narratives produced, local and global measures of language ability were also employed. The local language measures included the number of mental state and temporal relation terms produced, while the global language measures included mean length of utterance, total different words, total words, total utterances, rate of speech, the number of mazes (e.g., repetitions, 'um', 'uh' or self-corrections) per total word and the NSS total score. OUTCOMES AND RESULTS: Using the SALT Language Sample Analysis tool, our results revealed that on global language measures, group differences were found on rate of speech, number of mazes per total words and the description of conflict/resolution in the narratives produced. The autism group produced significantly more mazes per total word and scored higher on the NSS conflict/resolution category score compared to the FASD and comparison groups. Both the autism and FASD groups spoke at a lower rate than the comparison group. On local language measures of narrative production, all groups were comparable, on average. CONCLUSIONS AND IMPLICATIONS: While many aspects of narrative discourse in the autism and FASD groups were similar to each other and to the comparison group, we observed group differences on global measures of narrative production and significant individual variability within groups, suggesting that narrative abilities considered at an individual level may provide important clinical information for intervention planning. Future research should also consider additional variables that influence narrative discourse, such as motivation, distractibility or decision-making of individual participants. WHAT THIS PAPER ADDS: What is already known on the subject Narrative discourse, or storytelling, is used in daily conversational interactions and reveals higher-level language skills that may not be well captured by standardised assessments of language. Many autistic individuals and individuals with fetal alcohol spectrum disorders (FASD) show difficulty with pragmatic and expressive language skills. What this paper adds to existing knowledge We found that many aspects of the narratives produced by the adolescents/young adults in the autism and FASD groups were comparable to each other and to the neurotypical group. However, the groups differed on three global measures of narrative production: rate of speech, number of mazes per total words and the description of conflict/resolution in the narratives produced. Also, significant variability was observed within groups, suggesting that narrative abilities should be considered at an individual level as opposed to their clinical groups. What are the potential or actual clinical implications of this work? This study showed that narrative discourse is an appropriate task that can be added to routine clinical assessments of language abilities in autistic adolescents/young adults as well as those with FASD or typical development and has the potential to reveal higher-level, real-world language skills. An important clinical implication of this study is that narrative language abilities should be considered at an individual level and individual-tailored interventions based on ability level due to the variability observed across individuals.

THE PRESENT AND FUTURE OF THE MASS SPECTROMETRY-BASED INVESTIGATION OF THE EXOSOME LANDSCAPE.

Exosomes are critical intercellular messengers released upon the fusion of multivesicular bodies with the cellular plasma membrane that deliver their cargo in the form of extracellular vesicles. Containing numerous nonrandomly packed functional proteins, lipids, and RNAs, exosomes are vital intercellular messengers that contribute to the physiologic processes of the healthy organism. During the post-genome era, exosome-oriented proteomics have garnered great interest. Since its establishment, mass spectrometry (MS) has been indispensable for the field of proteomics research and has advanced rapidly to interrogate biological samples at a higher resolution and sensitivity. Driven by new methodologies and more advanced instrumentation, MS-based approaches have revolutionized our understanding of protein biology. As the access to online proteomics database platforms has blossomed, experimental data processing occurs with more speed and accuracy. Here, we review recent advances in the technological progress of MS-based proteomics and several new detection strategies for MS-based proteomics research. We also summarize the use of integrated online databases for proteomics research in the era of big data. © 2020 John Wiley & Sons Ltd. Mass Spec Rev.

Diagnostic work-up for severe aplastic anemia in children: Consensus of the North American Pediatric Aplastic Anemia Consortium.

The North American Pediatric Aplastic Anemia Consortium (NAPAAC) is a group of pediatric hematologist-oncologists, hematopathologists, and bone marrow transplant physicians from 46 institutions in North America with interest and expertise in aplastic anemia, inherited bone marrow failure syndromes, and myelodysplastic syndromes. The NAPAAC Bone Marrow Failure Diagnosis and Care Guidelines Working Group was established with the charge of harmonizing the approach to the diagnostic workup of aplastic anemia in an effort to standardize best practices in the field. This document outlines the rationale for initial evaluations in pediatric patients presenting with signs and symptoms concerning for severe aplastic anemia.

Pharmacological activation of estrogen receptor beta augments innate immunity to suppress cancer metastasis.

Metastases constitute the greatest causes of deaths from cancer. However, no effective therapeutic options currently exist for cancer patients with metastasis. Estrogen receptor ß (ERß), as a member of the nuclear receptor superfamily, shows potent tumor-suppressive activities in many cancers. To investigate whether modulation of ERß could serve as a therapeutic strategy for cancer metastasis, we examined whether the selective ERß agonist LY500307 could suppress lung metastasis of triple-negative breast cancer (TNBC) and melanoma. Mechanistically, while we observed that LY500307 potently induced cell death of cancer cells metastasized to lung in vivo, it does not mediate apoptosis of cancer cells in vitro, indicating that the cell death-inducing effects of LY500307 might be mediated by the tumor microenvironment. Pathological examination combined with flow cytometry assays indicated that LY500307 treatment induced significant infiltration of neutrophils in the metastatic niche. Functional experiments demonstrated that LY500307-treated cancer cells show chemotactic effects for neutrophils and that in vivo neutrophil depletion by Ly6G antibody administration could reverse the effects of LY500307-mediated metastasis suppression. RNA sequencing analysis showed that LY500307 could induce up-regulation of IL-1ß in TNBC and melanoma cells, which further triggered antitumor neutrophil chemotaxis. However, the therapeutic effects of LY500307 treatment for suppression of lung metastasis was attenuated in IL1B-/- murine models, due to failure to induce antitumor neutrophil infiltration in the metastatic niche. Collectively, our study demonstrated that pharmacological activation of ERß could augment innate immunity to suppress cancer metastatic colonization to lung, thus providing alternative therapeutic options for cancer patients with metastasis.

Diagnosis and treatment of pediatric myelodysplastic syndromes: A survey of the North American Pediatric Aplastic Anemia Consortium.

BACKGROUND: Myelodysplastic syndromes (MDS) represent a group of clonal hematopoietic stem cell disorders that commonly progress to acute myeloid leukemia (AML). The diagnostics, prognostics, and treatment of adult MDS are established but do not directly translate to children and adolescents. Pediatric MDS is a rare disease, characterized by unique cytogenetics and histology compared with adult MDS, and often arises secondary to germline predisposition or cytotoxic exposures. Our objective was to highlight aspects of diagnosis/management that would benefit from further systematic review toward the development of clinical practice guidelines for pediatric MDS. PROCEDURE: The North American Pediatric Aplastic Anemia Consortium (NAPAAC) is composed of collaborative institutions with a strong interest in pediatric bone marrow failure syndromes and hematologic malignancies. The NAPAAC MDS working group developed a national survey distributed to 35 NAPAAC institutions to assess data on (1) clinical presentation of pediatric MDS, (2) diagnostic evaluation, (3) criteria for diagnosis, (4) supportive care and treatment decisions, and (5) role of hematopoietic stem cell transplantation (HSCT). RESULTS: Twenty-eight of 35 institutions returned the survey. Most centers agreed on a common diagnostic workup, though there was considerable variation regarding the criteria for diagnosis. Although there was consensus on supportive care, treatment strategies, including the role of cytoreduction and HSCT, varied across centers surveyed. CONCLUSIONS: There is lack of national consensus on diagnosis and treatment of pediatric MDS. This survey identified key aspects of MDS management that will warrant systematic review toward the goal of developing national clinical practice guidelines for pediatric MDS.

Surgical stress and cancer progression: the twisted tango.

Surgical resection is an important avenue for cancer treatment, which, in most cases, can effectively alleviate the patient symptoms. However, accumulating evidence has documented that surgical resection potentially enhances metastatic seeding of tumor cells. In this review, we revisit the literature on surgical stress, and outline the mechanisms by which surgical stress, including ischemia/reperfusion injury, activation of sympathetic nervous system, inflammation, systemically hypercoagulable state, immune suppression and effects of anesthetic agents, promotes tumor metastasis. We also propose preventive strategies or resolution of tumor metastasis caused by surgical stress.

Superoptimal Perceptual Integration Suggests a Place-Based Representation of Pitch at High Frequencies.

Pitch, the perceptual correlate of sound repetition rate or frequency, plays an important role in speech perception, music perception, and listening in complex acoustic environments. Despite the perceptual importance of pitch, the neural mechanisms that underlie it remain poorly understood. Although cortical regions responsive to pitch have been identified, little is known about how pitch information is extracted from the inner ear itself. The two primary theories of peripheral pitch coding involve stimulus-driven spike timing, or phase locking, in the auditory nerve (time code), and the spatial distribution of responses along the length of the cochlear partition (place code). To rule out the use of timing information, we tested pitch discrimination of very high-frequency tones (>8 kHz), well beyond the putative limit of phase locking. We found that high-frequency pure-tone discrimination was poor, but when the tones were combined into a harmonic complex, a dramatic improvement in discrimination ability was observed that exceeded performance predicted by the optimal integration of peripheral information from each of the component frequencies. The results are consistent with the existence of pitch-sensitive neurons that rely only on place-based information from multiple harmonically related components. The results also provide evidence against the common assumption that poor high-frequency pure-tone pitch perception is the result of peripheral neural-coding constraints. The finding that place-based spectral coding is sufficient to elicit complex pitch at high frequencies has important implications for the design of future neural prostheses to restore hearing to deaf individuals.SIGNIFICANCE STATEMENT The question of how pitch is represented in the ear has been debated for over a century. Two competing theories involve timing information from neural spikes in the auditory nerve (time code) and the spatial distribution of neural activity along the length of the cochlear partition (place code). By using very high-frequency tones unlikely to be coded via time information, we discovered that information from the individual harmonics is combined so efficiently that performance exceeds theoretical predictions based on the optimal integration of information from each harmonic. The findings have important implications for the design of auditory prostheses because they suggest that enhanced spatial resolution alone may be sufficient to restore pitch via such implants.

Epigenetics in ovarian cancer: premise, properties, and perspectives.

Malignant ovarian tumors bear the highest mortality rate among all gynecological cancers. Both late tumor diagnosis and tolerance to available chemical therapy increase patient mortality. Therefore, it is both urgent and important to identify biomarkers facilitating early identification and novel agents preventing recurrence. Accumulating evidence demonstrates that epigenetic aberrations (particularly histone modifications) are crucial in tumor initiation and development. Histone acetylation and methylation are respectively regulated by acetyltransferases-deacetylases and methyltransferases-demethylases, both of which are implicated in ovarian cancer pathogenesis. In this review, we summarize the most recent discoveries pertaining to ovarian cancer development arising from the imbalance of histone acetylation and methylation, and provide insight into novel therapeutic interventions for the treatment of ovarian carcinoma.

A mass spectrometric insight into the origins of benign gynecological disorders.

Applications of mass spectrometry (MS) are rapidly expanding and encompass molecular and cellular biology. MS aids in the analysis of in vivo global molecular alterations, identifying potential biomarkers which may improve diagnosis and treatment of various pathologies. MS has added new dimensionality to medical research. Pioneering gynecologists now study molecular mechanisms underlying female reproductive pathology with MS-based tools. Although benign gynecologic disorders including endometriosis, adenomyosis, leiomyoma, and polycystic ovarian syndrome (PCOS) carry low mortality rates, they cause significant physical, mental, and social detriments. Additionally, some benign disorders are unfortunately associated with malignancies. MS-based technology can detect malignant changes in formerly benign proteomes and metabolomes with distinct advantages of speed, sensitivity, and specificity. We present the use of MS in proteomics and metabolomics, and summarize the current understanding of the molecular pathways concerning female reproductive anatomy. Highlight discoveries of novel protein and metabolite biomarkers via MS-based technology, we underscore the clinical application of these techniques in the diagnosis and management of benign gynecological disorders. © 2015 Wiley Periodicals, Inc. Mass Spec Rev 36:450-470, 2017.

What are pharmacists recommending for infant teething treatment?

OBJECTIVES: In 2011, the Food and Drug Administration issued a warning to avoid the use of any benzocaine-containing products for infant teething treatment owing to a risk of methemoglobinemia. Several benzocaine-containing products targeted for infant teething are currently available over the counter. Pharmacists are commonly asked for medical advice in the community, and there is no current literature evaluating what pharmacists are recommending for infant teething. The objectives of this study were to evaluate what pharmacists are currently recommending for infant teething treatment and assess what percentage would inappropriately recommend a benzocaine-containing product. METHODS: From March to June 2016, a 16-item in-person paper-and-pen questionnaire was administered to 200 pharmacists in the San Francisco Bay area at 115 outpatient over-the-counter pharmacies. Questions included demographic information, work and educational background, infant teething recommendations, and preferred educational resources. RESULTS: The overall response rate was 94.3%. One-half (50.5%) of the pharmacists' approaches to infant teething treatment was to recommend a nondrug option first and then, if needed, an over-the-counter medication. A majority (63.0%) of the pharmacists surveyed would inappropriately select a benzocaine-containing product. CONCLUSION: Despite warnings, the majority of pharmacists would still inappropriately recommend a benzocaine-containing product for treatment of infant teething. Further education is warranted to ensure that all pharmacists, health care providers, and consumers are aware of the potential harm of benzocaine use in infants.

Infant pitch perception: Missing fundamental melody discrimination.

Although recent results show that 3-month-olds can discriminate complex tones by their missing fundamental, it is arguable whether they are discriminating on the basis of a perceived pitch. A defining characteristic of pitch is that it carries melodic information. This study investigated whether 3-month-olds, 7-month-olds, and adults can detect a change in a melody composed of missing fundamental complexes. Participants heard a seven-note melody and learned to respond to a change that violated the melodic contour. To ensure that participants were responding on the basis of pitch, the notes in the melody had missing fundamentals and varied in spectral content on each presentation. In experiment I, all melodies had the same absolute pitch, while in experiment II, the melodies were randomly transposed into one of three different keys on each presentation. Almost all participants learned to ignore the spectral changes and respond to the changed note of the melody in both experiments, strengthening the argument that complex tones elicit a sense of musical pitch in infants. These results provide evidence that complex pitch perception is functional by 3 months of age.

Pupillometry shows the effort of auditory attention switching.

Successful speech communication often requires selective attention to a target stream amidst competing sounds, as well as the ability to switch attention among multiple interlocutors. However, auditory attention switching negatively affects both target detection accuracy and reaction time, suggesting that attention switches carry a cognitive cost. Pupillometry is one method of assessing mental effort or cognitive load. Two experiments were conducted to determine whether the effort associated with attention switches is detectable in the pupillary response. In both experiments, pupil dilation, target detection sensitivity, and reaction time were measured; the task required listeners to either maintain or switch attention between two concurrent speech streams. Secondary manipulations explored whether switch-related effort would increase when auditory streaming was harder. In experiment 1, spatially distinct stimuli were degraded by simulating reverberation (compromising across-time streaming cues), and target-masker talker gender match was also varied. In experiment 2, diotic streams separable by talker voice quality and pitch were degraded by noise vocoding, and the time alloted for mid-trial attention switching was varied. All trial manipulations had some effect on target detection sensitivity and/or reaction time; however, only the attention-switching manipulation affected the pupillary response: greater dilation was observed in trials requiring switching attention between talkers.

Infectious disease, injection practices, and risky sexual behavior among anabolic steroid users.

Anabolic-androgenic steroids (AAS) and other performance-enhancing drugs (PEDs) are commonly misused to increase muscle size and strength, as well as improve physical appearance. Many AAS and certain PEDs are administered via injection and therefore pose a risk for transmission of infectious diseases such as human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV), and skin and soft tissue infections (SSTIs). Further, AAS users may be more likely to take part in high-risk sexual behaviors than non-AAS users. This review explores the prevalence of infectious diseases as well as risky injection practices and sexual behaviors of AAS users in the current literature. A comprehensive MEDLINE search (1984-17 April 2015) for English language reports was performed on AAS users. Ten studies analyzed the prevalence of HIV infection, 6 studies analyzed HBV infection, and 6 studies analyzed HCV infection; 20 studies analyzed injection practices and 7 studies analyzed high-risk sexual behaviors of AAS users. HIV, HBV, HCV, and SSTIs have been associated with AAS users. In particular, HIV infection seems much higher among homosexual male AAS users. AAS users also take part in high-risk injection practices but to a much lower extent than intravenous drug users. AAS users are also more likely to engage in high-risk sexual behaviors than the general population. Clinicians and health-policy leaders may utilize these findings to implement strategies to decrease the spread of infectious diseases.

Temporal alignment of pupillary response with stimulus events via deconvolution.

Analysis of pupil dilation has been used as an index of attentional effort in the auditory domain. Previous work has modeled the pupillary response to attentional effort as a linear time-invariant system with a characteristic impulse response, and used deconvolution to estimate the attentional effort that gives rise to changes in pupil size. Here it is argued that one parameter of the impulse response (the latency of response maximum, t(max)) has been mis-estimated in the literature; a different estimate is presented, and it is shown how deconvolution with this value of t(max) yields more intuitively plausible and informative results.

Perception of the pitch of unresolved harmonics by 3- and 7-month-old human infants.

Three-month-olds discriminate resolved harmonic complexes on the basis of missing fundamental (MF) pitch. In view of reported difficulty in discriminating unresolved complexes at 7 months and striking changes in the organization of the auditory system during early infancy, infants' ability to discriminate unresolved complexes is of some interest. This study investigated the ability of 3-month-olds, 7-month-olds, and adults to discriminate the pitch of unresolved harmonic complexes using an observer-based method. Stimuli were MF complexes bandpass filtered with a -12 dB/octave slope, combined in random phase, presented at 70 dB sound pressure level (SPL) for 650 ms with a 50 ms rise/fall with a pink noise at 65 dB SPL. The conditions were (1) "LOW" unresolved harmonics (2500-4500 Hz) based on MFs of 160 and 200 Hz and (2) "HIGH" unresolved harmonics (4000-6000 Hz) based on MFs of 190 and 200 Hz. To demonstrate MF discrimination, participants had to ignore spectral changes in complexes with the same fundamental and respond only when the fundamental changed. Nearly all infants tested categorized complexes by MF pitch suggesting discrimination of pitch extracted from unresolved harmonics by 3 months. Adults also categorized the complexes by MF pitch, although musically trained adults were more successful than musically untrained adults.

A murine model to evaluate immunotherapy effectiveness for human Fanconi anemia-mutated acute myeloid leukemia.

Fanconi anemia (FA)-mutated acute myeloid leukemia (AML) is a secondary AML with very poor prognosis and limited therapeutic options due to increased sensitivity to DNA-damaging agents. PD-1 immune checkpoint inhibitors upregulate T-cell killing of cancer cells and is a class of promising treatment for FA-AML. Here, we developed a novel FA-AML murine model that allows the study of human AML with a humanized immune system in order to investigate immunotherapeutic treatments in vivo. FA-AML1 cells and non-FA-mutated Kasumi-1 cells were injected into 8-10 week old NSG mice. Once leukemic engraftment was confirmed by HLA-DR expression in the peripheral blood, human peripheral blood mononuclear cells (hPBMCs) were injected into the mice. One week post-hPBMCs injection, Nivolumab (PD-1 inhibitor) or PBS vehicle control was administered to the mice bi-weekly. In our Nivolumab treated mice, FA-AML1, but not Kasumi-1-engrafted mice, had significantly prolonged overall survival. Both FA-AML1 and Kasumi-1 engrafted mice had decreased spleen weights. Higher leukemic infiltration into vital organs was observed in FA-AML1 engrafted mice compared to Kasumi-1 engrafted mice. In conclusion, our novel humanized murine model of FA-mutated AML is an attractive tool for supporting further studies and clinical trials using PD-1 inhibitors to treat FA-mutated AML.

The prevalence and developmental course of auditory processing differences in autistic children.

Auditory processing differences, including hyper- or hyposensitivity to sound, aversions to sound, and difficulty listening under noisy, real-world conditions, are commonly reported in autistic individuals. However, the developmental course and functional impact of these auditory processing differences are unclear. In this study, we investigate the prevalence, developmental trajectory, and functional impact of auditory processing differences in autistic children throughout childhood using a longitudinal study design. Auditory processing differences were measured using the Short Sensory Profile, a caregiver questionnaire, in addition to adaptive behaviors and disruptive/concerning behaviors at 3, 6, and 9 years of age. Our results showed that auditory processing differences were reported in greater than 70% of the autistic children in our sample at all three timepoints, maintained a high prevalence through 9 years of age, and were associated with increased disruptive/concerning behaviors and difficulty with adaptive behaviors. Furthermore, in our sample of children, auditory processing differences at age 3 years predicted disruptive/concerning behaviors and difficulty with adaptive behaviors at age 9 years. These findings warrant further investigations of the potential benefit of incorporating measures of auditory processing during routine clinical evaluations as well as interventions targeting auditory processing differences in autistic children.