Clinical validity assessment of genes frequently tested on intellectual disability/autism sequencing panels.

PURPOSE: Neurodevelopmental disorders (NDDs), such as intellectual disability (ID) and autism spectrum disorder (ASD), exhibit genetic and phenotypic heterogeneity, making them difficult to differentiate without a molecular diagnosis. The Clinical Genome Resource Intellectual Disability/Autism Gene Curation Expert Panel (GCEP) uses systematic curation to distinguish ID/ASD genes that are appropriate for clinical testing (ie, with substantial evidence supporting their relationship to disease) from those that are not. METHODS: Using the Clinical Genome Resource gene-disease validity curation framework, the ID/Autism GCEP classified genes frequently included on clinical ID/ASD testing panels as Definitive, Strong, Moderate, Limited, Disputed, Refuted, or No Known Disease Relationship. RESULTS: As of September 2021, 156 gene-disease pairs have been evaluated. Although most (75%) were determined to have definitive roles in NDDs, 22 (14%) genes evaluated had either Limited or Disputed evidence. Such genes are currently not recommended for use in clinical testing owing to the limited ability to assess the effect of identified variants. CONCLUSION: Our understanding of gene-disease relationships evolves over time; new relationships are discovered and previously-held conclusions may be questioned. Without periodic re-examination, inaccurate gene-disease claims may be perpetuated. The ID/Autism GCEP will continue to evaluate these claims to improve diagnosis and clinical care for NDDs.

Feasibility of using the Multinational Association of Supportive Care in Cancer Antiemesis Tool for assessment of chemotherapy-induced nausea and vomiting at the Tom Baker Cancer Centre.

INTRODUCTION: Chemotherapy-induced nausea and vomiting (CINV) has been shown to adversely impact patient anxiety, quality of life, treatment adherence, and use of health care resources. CINV control still remains a challenge, and lack of effective communication between the patient and clinician has been highlighted in the literature as the main barrier to optimal control. The Multinational Association of Supportive Care in Cancer (MASCC) has developed a tool (MASCC Antiemesis Tool (MAT)) to improve assessment and subsequent management of CINV by enhancing communication between patients and their clinicians. This study assessed the feasibility of using the MAT in patients at the Tom Baker Cancer Centre. The secondary objective was to describe the incidence of CINV as identified by the tool. METHODS AND MATERIALS: This study involved a prospective survey using the MAT in patients receiving intravenous chemotherapy. Subjects completed the MAT twice post-chemotherapy regarding CINV symptoms and returned it at their next clinic appointment. Participants were also surveyed to evaluate feasibility with regard to using the MAT. RESULTS: Of the 50 patients recruited, 56% returned surveys. The majority of patients reported that the MAT facilitated communication with their clinician, particularly those who had experienced CINV. Fifty-four percent of patients who returned the MAT reported CINV; however, less than half of them had received American Society of Clinical Oncology-recommended antiemetic regimens. Only four patients with CINV had antiemetic changes made for subsequent cycles. CONCLUSION: The MAT is a feasible tool which can improve communication of CINV symptoms between patients and clinicians, a foundational step toward improving CINV management.

Prevalence of bilateral 'mirror-image' lesions in patients with oral potentially malignant epithelial lesions.

Early detection of oral potentially malignant epithelial lesions (PMELs) is aimed at improving survival rates as carcinogenesis is a multistep process and prevention is possible if these lesions are detected at an early and reversible stage of the disease. A prospective clinical study aimed at determining the prevalence of bilateral 'mirror-image' oral PMELs was carried out. Sample consisted of 32 (53.3%) Indians, 23 (38.3%) Chinese, 4 (6.7%) Malays and one (1.7%) Nepalese. All had histopathological confirmation of their primary existing PMEL as inclusion criteria. A total of 70 primary lesions were detected. The most common PMEL found was oral lichen planus. Of these, 28 (46.7%) patients exhibited bilateral 'mirror-image' lesions (n = 42) either synchronously (n = 32/42) or metachronously (n = 10/42). The remaining 32 (53.3%) patients had normal-looking contralateral mucosa. Present findings suggest that patients presenting with oral PMELs are at greater risk of developing a second lesion, most probably in the contralateral 'mirror-image' site.

Neuroimaging Systematic Review in Persistent Postural-Perceptual Dizziness: The Elaborate Alterations in the Delicate Network to Remain Balanced.

OBJECTIVES: Persistent postural-perceptual dizziness (PPPD) is a chronic functional vestibular disorder that may have normal physical examination, clinical laboratory testing and vestibular evaluation. However, advances in neuroimaging have provided new insights in brain functional connectivity and structure in patients with PPPD. This systematic review was aimed at identifying significant structural or alterations in functional connectivity in patients with PPPD. DATABASES REVIEWED: Science Direct, Pubmed, Embase via Ovid databases, and Cochrane library. METHODS: This review following the guidelines of PRISMA, systematically and independently examined papers published up to March 2021 which fulfilled the predetermined criteria. PROSPERO Registration (CRD42020222334). RESULTS: A total of 15 studies were included (MRI = 4, SPECT = 1, resting state fMRI = 4, task-based fMRI = 5, task-based fMRI + MRI = 1). Significant changes in the gray matter volume, cortical folding, blood flow, and connectivity were seen at different brain regions involved in vestibular, visual, emotion, and motor processing. CONCLUSION: There is a multisensory dimension to the impairment resulting in chronic compensatory changes in PPPD that is evident by the significant alterations in multiple networks involved in maintaining balance. These changes observed offer some explanation for the symptoms that a PPPD patient may experience.Systematic Review Registration: This study is registered with PROSPERO (CRD42020222334).

A clinical laboratory-developed LSC17 stemness score assay for rapid risk assessment of patients with acute myeloid leukemia.

Leukemia stem cells (LSCs) are linked to relapse in acute myeloid leukemia (AML). The LSC17 gene expression score robustly captures LSC stemness properties in AML and can be used to predict survival outcomes and response to therapy, enabling risk-adapted, upfront treatment approaches. The LSC17 score was developed and validated in a research setting. To enable widespread use of the LSC17 score in clinical decision making, we established a laboratory-developed test (LDT) for the LSC17 score that can be deployed broadly in clinical molecular diagnostic laboratories. We extensively validated the LSC17 LDT in a College of American Pathologists/Clinical Laboratory Improvements Act (CAP/CLIA)-certified laboratory, determining specimen requirements, a synthetic control, and performance parameters for the assay. Importantly, we correlated values from the LSC17 LDT to clinical outcome in a reference cohort of patients with AML, establishing a median assay value that can be used for clinical risk stratification of individual patients with newly diagnosed AML. The assay was established in a second independent CAP/CLIA-certified laboratory, and its technical performance was validated using an independent cohort of patient samples, demonstrating that the LSC17 LDT can be readily implemented in other settings. This study enables the clinical use of the LSC17 score for upfront risk-adapted management of patients with AML.

Genomic Landscape of Malignant Peripheral Nerve Sheath Tumor‒Like Melanoma.

Malignant peripheral nerve sheath tumor (MPNST)-like melanoma is a rare malignancy with overlapping characteristics of both neural sarcoma and melanoma. Although the genomics of cutaneous melanoma has been extensively studied, those of MPNST-like melanoma have not. To characterize the genomic landscape of MPNST-like melanoma, we performed a single-center, retrospective cohort study at a tertiary academic cancer center. Consecutive patients with a confirmed histologic diagnosis of MPNST-like melanoma were screened, and those whose tissues were locally available were included in this analysis. Archival tissue from six patients (eight samples) was submitted for whole-exome and transcriptome sequencing analysis. We compared these data with available genomic studies of cutaneous melanoma and MPNST. NF1 was altered (mutated, deleted, or amplified) in 67% of patients. Genes related to cell cycle regulation were frequently altered, with frequent deletion of ZNF331, which, to the best of our knowledge, has not been previously described in cutaneous melanoma. The serine protease inhibitor SERPINB4 was deleted in 100% of the patients. We show that MPNST-like melanoma presents overlapping genomic features with cutaneous melanoma and MPNST, but it is unique by the frequency of loss of function of ZNF331 and SERPINB4.

Retrospective study on admission trends of Californian hummingbirds found in urban habitats (1991-2016).

BACKGROUND: Hummingbirds are frequently presented to California wildlife rehabilitation centers for medical care, accounting for approximately 5% of overall admissions. Age, sex, and reason for admission could impact hummingbird survivability, therefore identification of these factors could help maximize rehabilitation efforts. METHODS: Mixed-effects logistic regression models were used to identify specific threats to the survival of 6908 hummingbirds (1645 nestlings and 5263 non-nestlings) consisting of five species (Calypte anna, Calypte costa, Selasphorus rufus, Selasphorus sasin, Archilochus alexandri), found in urban settings, and admitted to California wildlife rehabilitation centers over 26 years. RESULTS: In total, 36% of birds survived and were transferred to flight cage facilities for further rehabilitation and/or release. Nestlings were more likely to be transferred and/or released compared to adult hummingbirds. After accounting for age, birds rescued in spring and summer were twice as likely to be released compared to birds rescued in the fall. A high number of nestlings were presented to the rehabilitation centers during spring, which coincides with the nesting season for hummingbirds in California, with the lowest number of nestlings presented in fall. Reasons for presentation to rehabilitation centers included several anthropogenic factors such as window collisions (9.6%) and interactions with domesticated animals (12.9%). Survival odds were lower if a hummingbird was rescued in a "torpor-like state" and were higher if rescued for "nest-related" reasons. Evaluation of treatment regimens administered at wildlife rehabilitation centers identified supportive care, including providing commercial nutrient-rich nectar plus solution, to significantly increase hummingbird survivability. DISCUSSION: Our results provide evidence of threats to hummingbirds in urban habitats, based on reasons for rescue and presentation to rehabilitation centers. Reasons for hummingbird admissions to three California wildlife rehabilitation centers were anthropogenic in nature (i.e., being associated with domestic animals, window collisions, and found inside a man-made structure) and constituted 25% of total admissions. There was a clear indication that supportive care, such as feeding a commercial nectar solution, and medical treatment significantly increased the odds of survival for rescued hummingbirds.

Quantitative and qualitative assessments of intraosseous neurovascular canals in dentate and posteriorly edentulous individuals in lateral maxillary sinus wall.

OBJECTIVE: Knowledge and evaluation of the blood supply within the maxillary sinus before sinus augmentation are vital to avoid surgical complications. The lateral maxilla is supplied by branches of the posterior superior alveolar artery and infraorbital artery forming intraosseous anastomoses (IA) within the bony lateral antral wall. This study was undertaken to (i) measure mean diameter of IA and its distance from the alveolar ridge within dentate and posteriorly edentulous subjects and, (ii) qualitatively display the relationship of IA throughout its course within the lateral maxillary sinus in cone beam computed tomography (CBCT). METHOD: Maxillary CBCT images of two-hundred-and-fifty-seven consecutive patients (163 men, 94 women, mean age 42 years) were analyzed. Samples were later divided into dentate (n = 142) and posteriorly edentulous (n = 115) jaws. Using both alveolar ridge and tooth location as reference points, the distance and diameter of IA were assessed. RESULT: The IA was seen in 63.7% of all sinuses with 68.2% in dentate and 62.4% in edentulous. Mean distance and diameter of IA across the posterior tooth locations were 17.9 ± 3.0 mm and 1.4 ± 0.5 mm (dentate) and 15.1 ± 3.0 mm and 1.0 ± 0.5 mm (posteriorly edentulous), respectively. In each sample, there were no significant differences in distance-alveolar ridge and no significant correlations in diameter-tooth location. A statistically significant Pearson coefficient correlation between diameter and distance in dentate state was observed (r = -0.6). CONCLUSION: This study reveals that dentate maxillary jaws present larger diameters as compared to posteriorly edentulous jaws, although the IA course remains the same. As these canal structures contain neurovascular bundles with diameters that may be large enough to cause clinically substantial complications, a thorough pre-surgical planning is therefore highly advisable.

TaqMan quantitative real-time PCR for detecting Avipoxvirus DNA in various sample types from hummingbirds.

BACKGROUND: Avian pox is a viral disease documented in a wide range of bird species. Disease-related detrimental effects can cause dyspnea and dysphagia, and birds with high metabolic requirements, such as hummingbirds, are thus especially vulnerable to the pathogen. Hummingbirds have a strong presence in California, especially in urban environments. However, little is understood regarding the impact of pox virus on hummingbird populations. Currently, diagnosing a pox infection relies on obtaining a tissue biopsy, which poses significant risks to birds and challenges in the field. Understanding the ecology of hummingbird pox viral infections could be advanced by a minimally invasive ante-mortem diagnostic method. Our aim was to address whether pox infections can be diagnosed using integumentary system samples besides tissue biopsies. To meet this goal, we tested multiple integumentary sample types using a quantitative real-time PCR assay. A secondary study goal was to determine which sample types (ranging from minimally to highly invasive sampling) were optimal for identifying infected birds. METHODOLOGY AND PRINCIPAL FINDINGS: Pox-like lesion tissue, pectoral muscle, feathers, toenail clippings, blood, and swabs (both pox-like lesion tissue and non pox-like lesion tissue) were taken from live birds and carcasses of two species of hummingbirds found in California. To maximize successful diagnosis, especially for samples with low viral load, a real-time quantitative PCR assay was developed for detecting the hummingbird-specific Avipoxvirus 4b core protein gene. Avipoxvirus DNA was successfully amplified from all sample types obtained from 27 individuals. These results were compared to those of conventional PCR and comparisons were also made among sample types, utilizing lesion tissue samples as the gold standard. CONCLUSIONS AND SIGNIFICANCE: Hummingbird avian pox can be diagnosed without relying on tissue biopsies. We identify that feather samples, of which contour feathers yielded the best results, can be used for diagnosing infected birds, thus reducing sampling risk. In sum, the real-time PCR assay detected viral DNA in various integumentary system sample types and will be useful in future studies of hummingbird disease ecology.

Risk of the contralateral mucosa in patients with oral potentially malignant disorders.

BACKGROUND: It is known that abnormal changes may occur in any part of the oral mucous membrane exposed to a carcinogen. Therefore patients with oral potentially malignant disorders (PMDs) are at risk of developing similar lesions at multiple sites. OBJECTIVES: To determine the risk of the contralateral mucosa in patients presenting with oral PMDs. MATERIALS AND METHODS: Sixty individuals with PMDs were selected for this study. These comprised 32 (53.3%) Indians, 23 (38.3%) Chinese, four (6.7%) Malays and one (1.7%) Nepalese. All selected cases had histopathological confirmation of their primary existing lesion as inclusion criteria. Cases that subsequently presented with a lesion in the corresponding anatomical site also underwent scalpel incisional biopsy on this second lesion to verify its diagnosis. The remaining cases that presented with unilateral PMDs at the time of study were subjected to a cytobrush biopsy on the normal looking contralateral mucosa. RESULTS: A total of 70 primary PMDs were detected in 60 patients. The most common PMD found was oral lichen planus (n=40, 57.1%). Of the 60 patients studied, 28 (46.6%) exhibited bilateral lesions either synchronously (n=21, 35.0%) or metachronously (n=7, 11.6%). The remaining cases that had undergone cytobrush biopsy on the corresponding anatomical site yielded normal cytological results. CONCLUSIONS: Present findings demonstrated that patients presenting with PMDs in the upper aerodigestive tract are at a greater risk of developing a second lesion most probably in the contralateral anatomical site.

Activators of cylindrical proteases as antimicrobials: identification and development of small molecule activators of ClpP protease.

ClpP is a cylindrical serine protease whose ability to degrade proteins is regulated by the unfoldase ATP-dependent chaperones. ClpP on its own can only degrade small peptides. Here, we used ClpP as a target in a high-throughput screen for compounds, which activate the protease and allow it to degrade larger proteins, hence, abolishing the specificity arising from the ATP-dependent chaperones. Our screen resulted in five distinct compounds, which we designate as Activators of Self-Compartmentalizing Proteases 1 to 5 (ACP1 to 5). The compounds are found to stabilize the ClpP double-ring structure. The ACP1 chemical structure was considered to have drug-like characteristics and was further optimized to give analogs with bactericidal activity. Hence, the ACPs represent classes of compounds that can activate ClpP and that can be developed as potential novel antibiotics.