ABSTRACT
Understanding of the social environment has the potential to benefit dairy cow welfare and production. Our aim was to evaluate the associations of stocking density, calving density, days spent in a pre-partum group before calving (days spent in close-up, DCU) and the number of days from a pen filling event (addition of new cows to the pre-partum pen) on early-lactation health, production, pregnancy and culling outcomes in dairy cows. Data were gathered from 2780 cows in 2 herds. Herd management and reproductive records were analyzed for cows receiving treatment in the first 30 d of lactation (days in milk, DIM) for clinical mastitis, reproductive tract disease, ketosis, milk fever and displaced abomasum. Principal component analysis was used to account for the relationship between gestation length (GL) and DCU and their association with early lactation disease, milk production, pregnancy and culling outcomes. The effect of stocking density, the number of days from a pen filling event to calving and the calving density experienced by a cow in her week of calving was also evaluated. Causal inference was used to correct for confounding bias due to farm identity. The odds of disease in the first 30 DIM increased with stocking density before calving. A quadratic association was found between the first principal component (PC1), representing the combined effect of GL and DCU, and the odds of disease in multiparous cows only. Early lactation milk production and 305 d milk production in multiparous cows increased with PC1 score. Quadratic relationships were found between stocking density at d 8 to 2 before calving with both early lactation and 305 d milk production in multiparous cows but no associations were found in primiparous cows. Calving density showed a quadratic association with 305 d milk production in primiparous cows. The number of days from the last pen filling event to calving was not associated with changes in milk production. Disease occurrence was negatively associated with both early lactation and 305 d milk yield in multiparous cows but only with early lactation milk production in primiparous cows. The occurrence of disease was associated with a delayed time to pregnancy only in primiparous cows while both disease and being in lactation group ≥ 3 were negatively associated with time to pregnancy in multiparous cows. Week 4 milk (W4MK) was positively associated with reduced time to pregnancy in multiparous cows. For primiparous cows, increasing age at calving was associated with increased culling risk, while being in lactation group ≥ 3 was associated with increased culling risk in multiparous cows. Culling risk decreased with increasing W4MK in all cows. These results suggest that gestation length, time spent in close-up and stocking density are important factors influencing disease incidence in early lactation and subsequent lactation performance but had differing effects on primiparous versus multiparous cows. A better understanding of how pre-partum management factors influence postpartum health and milk production can help farms to plan facilities and organize the day-to-day management of cows and will assist in improving cow welfare and productivity.
ABSTRACT
BACKGROUND: Anaplastic sarcoma of the kidney (ASK) is a DICER1-related neoplasm first identified as a distinctive tumor type through the evaluation of unusual cases of putative anaplastic Wilms tumors. Subsequent case reports identified the presence of biallelic DICER1 variants as well as progression from cystic nephroma, a benign DICER1-related neoplasm. Despite increasing recognition of ASK as a distinct entity, the optimal treatment remains unclear. METHODS: Individuals with known or suspected DICER1-related tumors including ASK were enrolled in the International Pleuropulmonary Blastoma/DICER1 Registry. Additionally, a comprehensive review of reported cases of ASK was undertaken, and data were aggregated for analysis with the aim to identify prognostic factors and clinical characteristics to guide decisions regarding genetic testing, treatment, and surveillance. RESULTS: Ten cases of ASK were identified in the Registry along with 37 previously published cases. Staging data, per Children's Oncology Group guidelines, was available for 40 patients: 13 were stage I, 12 were stage II, 10 were stage III, and five were stage IV. Outcome data were available for 37 patients. Most (38 of 46) patients received upfront chemotherapy and 14 patients received upfront radiation. Two-year event-free survival (EFS) for stage I-II ASK was 81.8% (95% confidence interval [CI]: 67.2%-99.6%), compared with 46.6% EFS (95% CI: 24.7%-87.8%) for stage III-IV (p = .07). Two-year overall survival (OS) for stage I-II ASK was 88.9% (95% CI: 75.5%-100.0%), compared with 70.0% (95% CI: 46.7%-100.0%) for stage III-IV (p = .20). Chemotherapy was associated with improved EFS and OS with hazard ratios of 0.09 (95% CI: 0.02-0.31) and 0.08 (95% CI: 0.02-0.42), respectively. CONCLUSION: ASK is a rare DICER1-related renal neoplasm. In the current report, we identify clinical and treatment-related factors associated with outcome including the importance of chemotherapy in treating ASK. Ongoing data collection and genomic analysis are indicated to optimize outcomes for children and adults with these rare tumors.
Subject(s)
DEAD-box RNA Helicases , Kidney Neoplasms , Pulmonary Blastoma , Registries , Ribonuclease III , Sarcoma , Humans , DEAD-box RNA Helicases/genetics , Ribonuclease III/genetics , Pulmonary Blastoma/pathology , Pulmonary Blastoma/therapy , Pulmonary Blastoma/genetics , Pulmonary Blastoma/mortality , Male , Female , Kidney Neoplasms/pathology , Kidney Neoplasms/genetics , Kidney Neoplasms/therapy , Kidney Neoplasms/mortality , Child, Preschool , Child , Infant , Sarcoma/genetics , Sarcoma/pathology , Sarcoma/therapy , Survival Rate , Prognosis , Adolescent , Follow-Up StudiesABSTRACT
OBJECTIVE: Sertoli-Leydig cell tumors (SLCTs) are rare sex cord-stromal tumors, representing <0.5% of all ovarian tumors. We sought to describe prognostic factors, treatment and outcomes for individuals with ovarian SLCT. METHODS: Individuals with SLCT were enrolled in the International Pleuropulmonary Blastoma/DICER1 Registry and/or the International Ovarian and Testicular Stromal Tumor Registry. Medical records were systematically abstracted, and pathology was centrally reviewed when available. RESULTS: In total, 191 participants with ovarian SLCT enrolled, with most (92%, 175/191) presenting with FIGO stage I disease. Germline DICER1 results were available for 156 patients; of these 58% had a pathogenic or likely pathogenic germline variant. Somatic (tumor) DICER1 testing showed RNase IIIb hotspot variants in 97% (88/91) of intermediately and poorly differentiated tumors. Adjuvant chemotherapy was administered in 40% (77/191) of cases, and among these, nearly all patients received platinum-based regimens (95%, 73/77), and 30% (23/77) received regimens that included an alkylating agent. Three-year recurrence-free survival for patients with stage IA tumors was 93.6% (95% CI: 88.2-99.3%) compared to 67.1% (95% CI: 55.2-81.6%) for all stage IC and 60.6% (95% CI: 40.3-91.0%) for stage II-IV (p < .001) tumors. Among patients with FIGO stage I tumors, those with mesenchymal heterologous elements treated with surgery alone were at higher risk for recurrence (HR: 74.18, 95% CI: 17.99-305.85). CONCLUSION: Most individuals with SLCT fare well, though specific risk factors such as mesenchymal heterologous elements are associated with poor prognosis. We also highlight the role of DICER1 surveillance in early detection of SLCT, facilitating stage IA resection.
Subject(s)
DEAD-box RNA Helicases , Ovarian Neoplasms , Pulmonary Blastoma , Registries , Ribonuclease III , Sertoli-Leydig Cell Tumor , Humans , Sertoli-Leydig Cell Tumor/pathology , Sertoli-Leydig Cell Tumor/surgery , Female , Ovarian Neoplasms/pathology , Ovarian Neoplasms/surgery , DEAD-box RNA Helicases/genetics , Pulmonary Blastoma/pathology , Adult , Ribonuclease III/genetics , Middle Aged , Young Adult , Aged , Male , Adolescent , Chemotherapy, Adjuvant , Sex Cord-Gonadal Stromal Tumors/pathology , Sex Cord-Gonadal Stromal Tumors/surgery , Sex Cord-Gonadal Stromal Tumors/diagnosis , Testicular Neoplasms/pathology , Testicular Neoplasms/surgery , Lung Neoplasms/pathology , Lung Neoplasms/surgeryABSTRACT
BACKGROUND: Pleuropulmonary blastoma (PPB), the hallmark tumour associated with DICER1-related tumour predisposition, is characterised by an age-related progression from a cystic lesion (type I) to a high-grade sarcoma with mixed cystic and solid features (type II) or purely solid lesion (type III). Not all cystic PPBs progress; type Ir (regressed), hypothesised to represent regressed or non-progressed type I PPB, is an air-filled, cystic lesion lacking a primitive sarcomatous component. This study aims to evaluate the prevalence of non-progressed lung cysts detected by CT scan in adolescents and adults with germline DICER1 pathogenic/likely pathogenic (P/LP) variants. METHODS: Individuals were enrolled in the National Cancer Institute Natural History of DICER1 Syndrome study, the International PPB/DICER1 Registry and/or the International Ovarian and Testicular Stromal Tumor Registry. Individuals with a germline DICER1 P/LP variant with first chest CT at 12 years of age or older were selected for this analysis. RESULTS: In the combined databases, 110 individuals with a germline DICER1 P/LP variant who underwent first chest CT at or after the age of 12 were identified. Cystic lung lesions were identified in 38% (42/110) with a total of 72 cystic lesions detected. No demographic differences were noted between those with lung cysts and those without lung cysts. Five cysts were resected with four centrally reviewed as type Ir PPB. CONCLUSION: Lung cysts are common in adolescents and adults with germline DICER1 variation. Further study is needed to understand the mechanism of non-progression or regression of lung cysts in childhood to guide judicious intervention.
Subject(s)
Cysts , DEAD-box RNA Helicases , Germ-Line Mutation , Pulmonary Blastoma , Registries , Ribonuclease III , Adolescent , Adult , Child , Female , Humans , Male , Middle Aged , Young Adult , Cysts/genetics , Cysts/pathology , Cysts/diagnostic imaging , DEAD-box RNA Helicases/genetics , Lung Diseases/genetics , Lung Diseases/pathology , Lung Diseases/diagnostic imaging , Lung Diseases/epidemiology , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Lung Neoplasms/diagnostic imaging , Prevalence , Pulmonary Blastoma/genetics , Pulmonary Blastoma/pathology , Ribonuclease III/genetics , Tomography, X-Ray Computed , United States/epidemiology , AgedABSTRACT
INTRODUCTION: Controversy exists around which distal tibial fractures are pilon fractures. We evaluated views to define a pilon fracture and support the development of standards of care. METHODS: Views regarding the characteristics of a pilon fracture and acute soft tissue management were determined through a questionnaire. This was trialled, approved by the British Orthopaedic Foot and Ankle Society and distributed to its members. This was also distributed nationally as part of the ENFORCE study. RESULTS: In total, 282 consultants from 27 units responded, of whom 24% (69/282) were foot and ankle specialists. Some 58% (163/282) agreed that a pilon fracture is primarily a soft tissue injury, 81% (228/282) that pilon fractures occur though high-energy transfer, 81% (228/282) that pilon fractures are sustained through an axial compression mechanism and 93% (265/282) that they are a potentially limb-threatening injury. Overall, 83% (234/282) agreed that in a length-unstable pilon fracture it is not possible to maintain the talus near anatomically under the tibial plafond without rigid fixation to control length - with 87% (246/282) agreeing that the acute first-line management should be a spanning external fixator. Opinions were that the time frame between diagnosis and intervention should be: less than 6h (63%; 154/246), 6-12h (31%; 77/246) and 12-24h (6%; 15/246). CONCLUSION: Consensus supports defining a pilon fracture as a potentially limb-threatening high-energy axial compression injury, and a spanning external fixator as the first-line management of a length-unstable injury less than 12h from diagnosis.
ABSTRACT
Germline pathogenic loss-of-function (pLOF) variants in DICER1 are associated with a predisposition for a variety of solid neoplasms, including pleuropulmonary blastoma and Sertoli-Leydig cell tumor (SLCT). The most common DICER1 pLOF variants include small insertions or deletions leading to frameshifts, and base substitutions leading to nonsense codons or altered splice sites. Larger deletions and pathogenic missense variants occur less frequently. Identifying these variants can trigger surveillance algorithms with potential for early detection of DICER1-related cancers and cascade testing of family members. However, some patients with DICER1-associated tumors have no pLOF variants detected by germline or tumor testing. Here, we present two patients with SLCT whose tumor sequencing showed only a somatic missense DICER1 RNase IIIb variant. Conventional exon-directed germline sequencing revealed no pLOF variants. Using a custom capture panel, we discovered novel intronic variants, ENST00000343455.7: c.1752+213A>G and c.1509+16A>G, that appear to interfere with normal splicing. We suggest that when no DICER1 pLOF variants or large deletions are discovered in exonic regions despite strong clinical suspicion, intron sequencing and splicing analysis should be performed.
Subject(s)
Ovarian Neoplasms , Sertoli-Leydig Cell Tumor , Male , Female , Humans , Sertoli-Leydig Cell Tumor/genetics , Sertoli-Leydig Cell Tumor/pathology , Ovarian Neoplasms/genetics , Introns/genetics , Germ-Line Mutation/genetics , Mutation , Ribonuclease III/genetics , DEAD-box RNA Helicases/geneticsABSTRACT
Prenatal alcohol exposure (PAE), the leading known cause of childhood developmental disability, has long-lasting effects extending throughout the lifespan. It is well documented that children prenatally exposed to alcohol have difficulties inhibiting behavior and sustaining attention. Thus, the Sustained Attention to Response Task (SART), a Go/No-go paradigm, is especially well suited to assess the behavioral and neural functioning characteristics of children with PAE. In this study, we utilized neuropsychological assessment, parent/guardian questionnaires, and magnetoencephalography during SART random and fixed orders to assess characteristics of children 8-12 years old prenatally exposed to alcohol compared to typically developing children. Compared to neurotypical control children, children with a Fetal Alcohol Spectrum Disorder (FASD) diagnosis had significantly decreased performance on neuropsychological measures, had deficiencies in task-based performance, were rated as having increased Attention-Deficit/Hyperactivity Disorder (ADHD) behaviors and as having lower cognitive functioning by their caretakers, and had decreased peak amplitudes in Broadmann's Area 44 (BA44) during SART. Further, MEG peak amplitude in BA44 was found to be significantly associated with neuropsychological test results, parent/guardian questionnaires, and task-based performance such that decreased amplitude was associated with poorer performance. In exploratory analyses, we also found significant correlations between total cortical volume and MEG peak amplitude indicating that the reduced amplitude is likely related in part to reduced overall brain volume often reported in children with PAE. These findings show that children 8-12 years old with an FASD diagnosis have decreased amplitudes in BA44 during SART random order, and that these deficits are associated with multiple behavioral measures.
Subject(s)
Attention Deficit Disorder with Hyperactivity , Fetal Alcohol Spectrum Disorders , Prenatal Exposure Delayed Effects , Humans , Child , Female , Pregnancy , Fetal Alcohol Spectrum Disorders/diagnostic imaging , Fetal Alcohol Spectrum Disorders/psychology , Prenatal Exposure Delayed Effects/psychology , Neuropsychological Tests , Attention Deficit Disorder with Hyperactivity/etiology , Attention Deficit Disorder with Hyperactivity/psychology , EthanolABSTRACT
Topological magnetic charges, arising due to the non-vanishing magnetic flux on spin ice vertices, serve as the origin of magnetic monopoles that traverse the underlying lattice effortlessly. Unlike spin ice materials of atomic origin, the dynamic state in artificial honeycomb spin ice is conventionally described in terms of finite size domain wall kinetics that require magnetic field or current application. Contrary to this common understanding, here we show that a thermally tunable artificial permalloy honeycomb lattice exhibits a perpetual dynamic state due to self-propelled magnetic charge defect relaxation in the absence of any external tuning agent. Quantitative investigation of magnetic charge defect dynamics using neutron spin echo spectroscopy reveals sub-ns relaxation times that are comparable to the relaxation of monopoles in bulk spin ices. Most importantly, the kinetic process remains unabated at low temperature where thermal fluctuation is negligible. This suggests that dynamic phenomena in honeycomb spin ice are mediated by quasi-particle type entities, also confirmed by dynamic Monte-Carlo simulations that replicate the kinetic behavior. Our research unveils a macroscopic magnetic particle that shares many known traits of quantum particles, namely magnetic monopole and magnon.
ABSTRACT
Congenital cystic pulmonary lesions (CCPLs) are represented by the following entities: congenital pulmonary airway malformation (CPAM), formerly congenital cystic adenomatoid malformation, extra- and intralobar sequestration (EIS), congenital lobar emphysema (overexpansion), and bronchogenic cyst. The developmental model of CPAM histogenesis by Stocker proposed perturbations designated as CPAM type 0 to type 4 without known or specific pathogenetic mechanisms along the airway from the bronchus to the alveolus. This review highlights mutational events either at the somatic level in KRAS (CPAM types 1 and possibly 3) or germline variants in congenital acinar dysplasia, formerly CPAM type 0, and pleuropulmonary blastoma (PPB), type I, formerly CPAM type 4. The potential for overt malignant progression exists in the case of PPB type I and CPAM type 1 in some cases to well-differentiated mucinous adenocarcinoma. On the other hand, CPAM type 2 is an acquired lesion resulting from interruption in lung development secondary to bronchial atresia. The latter is also regarded as the etiology of EIS whose pathologic features are similar, if not identical, to CPAM type 2. These observations have provided important insights into the pathogenetic mechanisms in the development of the CPAMs since the Stocker classification.
Subject(s)
Bronchopulmonary Sequestration , Cystic Adenomatoid Malformation of Lung, Congenital , Lung Neoplasms , Pulmonary Blastoma , Respiratory System Abnormalities , Humans , Cystic Adenomatoid Malformation of Lung, Congenital/diagnosis , Cystic Adenomatoid Malformation of Lung, Congenital/genetics , Lung/pathology , Pulmonary Blastoma/diagnosis , Pulmonary Blastoma/genetics , Lung Neoplasms/congenital , Respiratory System Abnormalities/diagnosis , Respiratory System Abnormalities/genetics , Bronchopulmonary Sequestration/pathologyABSTRACT
BACKGROUND: Pleuropulmonary blastoma (PPB) is the most common lung cancer of infancy and early childhood. Type I PPB is a purely cystic lesion that has a microscopic population of primitive small cells with or without rhabdomyoblastic features and may progress to type II or III PPB, whereas type Ir lacks primitive small cells. METHODS: Children with suspected PPB were enrolled in the International PPB/DICER1 Registry. Pathology was centrally reviewed, and follow-up was ascertained annually. RESULTS: Between 2006 and 2022, 205 children had centrally reviewed type I or Ir PPB; 39% of children with type I and 5% of children with type Ir PPB received chemotherapy. Outcomes were favorable, although 11 children (nine with type I and two with type Ir PPB) experienced progression to type II/III (n = 8) or regrowth of type I PPB at the surgical site (n = 3), none of whom received chemotherapy before progression. Age and cyst size in combination were more suitable than either factor alone in predicting whether a particular lesion was type I or Ir PPB. CONCLUSIONS: For young children with type I PPB, outcomes are favorable, but complete resection is indicated because of the risk for progression. Chemotherapy may be useful in a subset of children at increased risk for recurrence/progression. Efforts to risk stratify children with type I PPB to optimize outcomes while reducing treatment-related side effects are underway.
Subject(s)
Drug-Related Side Effects and Adverse Reactions , Lung Neoplasms , Pulmonary Blastoma , Child , Humans , Child, Preschool , Pulmonary Blastoma/drug therapy , Lung Neoplasms/drug therapy , Registries , Ribonuclease III , DEAD-box RNA HelicasesABSTRACT
Purpose: The purpose was to determine the effect of a single-dose prophylactic ibuprofen use before a 164-km road cycling event in high ambient temperature on the circulating cytokine and leukocyte responses. Methods: Twenty-three men (53 ± 8 y, 172.0 ± 22.0 cm, 85.1 ± 12.8 kg, 19.6 ± 4.4% body fat) completed a 164-km self-paced recreational road cycling event in a hot, humid, sunny environment (WBGT = 29.0 ± 2.9°C) after consuming 600 mg of ibuprofen (n = 13) or a placebo (n = 10). Blood samples were obtained one to two hours before (PRE) and immediately after (POST) the event, and analyzed for concentrations of circulating cytokines interleukins (IL)-1ß, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12, IL-13, GM-CSF, IFN-γ, and TNF-α and leukocytes (total leukocytes, granulocytes, monocytes, and lymphocytes). Results: Event completion time was 400.2 ± 74.8 min. Concentrations of all cytokines (except IL-1ß, IL-2, IL-5, IL-12, GM-CSF, and IFN-γ) and of all leukocyte subsets increased from PRE to POST. Ibuprofen ingestion attenuated the increase in IL-10 (86% increase with Ibuprofen; 270% increase with placebo). Conclusions: Consuming 600 mg of Ibuprofen prior to a 164-km road cycling event in a hot-humid environment attenuates exercise-induced increases in the concentration of the anti-inflammatory cytokine IL-10, but does not alter the effect of the exercise event on concentrations of other circulating cytokines or leukocyte subset concentrations.
Subject(s)
Granulocyte-Macrophage Colony-Stimulating Factor , Ibuprofen , Male , Humans , Ibuprofen/pharmacology , Ibuprofen/therapeutic use , Interleukin-10 , Hot Temperature , Bicycling/physiology , Interleukin-2 , Interleukin-5 , Cytokines , Interleukin-12ABSTRACT
PURPOSE: Pleuropulmonary blastoma (PPB) is the most common primary lung neoplasm of infancy and early childhood. Type II and type III PPB have historically been associated with a poor prognosis. METHODS: Patients with known or suspected PPB were enrolled in the International PPB/DICER1 Registry. Medical records were abstracted with follow-up ascertained annually. All PPB diagnoses were confirmed by central pathology review. Beginning in 2007, the IVADo regimen (ifosfamide, vincristine, actinomycin-D, and doxorubicin) was recommended as a potential treatment regimen for children with type II and type III PPB. This regimen was compared with a historical control cohort. RESULTS: From 1987 to 2021, 314 children with centrally confirmed type II and type III PPB who received upfront chemotherapy were enrolled; 132 children (75 with type II and 57 with type III) received IVADo chemotherapy. Adjusted analyses suggest improved overall survival for children treated with IVADo in comparison with historical controls with an estimated hazard ratio of 0.65 (95% CI, 0.39 to 1.08). Compared with localized disease, distant metastasis at diagnosis was associated with worse PPB event-free survival and overall survival with hazard ratio of 4.23 (95% CI, 2.42 to 7.38) and 4.69 (95% CI, 2.50 to 8.80), respectively. CONCLUSION: The use of IVADo in children with type II and type III PPB resulted in similar-to-improved outcomes compared with historical controls. Inferior outcomes with metastatic disease suggest the need for novel therapies. This large cohort of uniformly treated children with advanced PPB serves as a benchmark for future multicenter therapeutic studies for this rare pediatric tumor.
Subject(s)
Lung Neoplasms , Pulmonary Blastoma , Child , Humans , DEAD-box RNA Helicases , Doxorubicin/therapeutic use , Lung Neoplasms/pathology , Pulmonary Blastoma/drug therapy , Registries , Ribonuclease IIIABSTRACT
BACKGROUND: COVID-19 can cause some individuals to experience chronic symptoms. Rates and predictors of chronic COVID-19 symptoms are not fully elucidated. OBJECTIVE: To examine occurrence and patterns of post-acute sequelae of SARS-CoV2 infection (PASC) symptomatology and their relationship with demographics, acute COVID-19 symptoms and anti-SARS-CoV-2 IgG antibody responses. METHODS: A multi-stage observational study was performed of adults (≥18 years) from 5 US states. Participants completed two rounds of electronic surveys (May-July 2020; April-May 2021) and underwent testing to anti-SARS-CoV-2 nucleocapsid protein IgG antibody testing. Latent Class Analysis was used to identify clusters of chronic COVID-19 symptoms. RESULTS: Overall, 390 adults (median [25%ile, 75%ile] age: 42 [31, 54] years) with positive SARS-CoV-2 antibodies completed the follow-up survey; 92 (24.7%) had ≥1 chronic COVID-19 symptom, with 11-month median duration of persistent symptoms (range: 1-12 months). The most common chronic COVID-19 symptoms were fatigue (11.3%), change in smell (9.5%) or taste (5.6%), muscle or joint aches (5.4%) and weakness (4.6%). There were significantly higher proportions of ≥1 persistent COVID-19 symptom (31.5% vs. 18.6%; Chi-square, P = 0.004), and particularly fatigue (15.8% vs. 7.3%, P = 0.008) and headaches (5.4% vs. 1.0%, P = 0.011) in females compared to males. Chronic COVID-19 symptoms were also increased in individuals with ≥6 acute COVID-19 symptoms, Latent class analysis revealed 4 classes of symptoms. Latent class-1 (change of smell and taste) was associated with lower anti-SARS-CoV-2 antibody levels; class-2 and 3 (multiple chronic symptoms) were associated with higher anti-SARS-CoV-2 antibody levels and more severe acute COVID-19 infection. LIMITATIONS: Ambulatory cohort with less severe acute disease. CONCLUSION: Individuals with SARS-CoV-2 infection commonly experience chronic symptoms, most commonly fatigue, changes in smell or taste and muscle/joint aches. Female sex, severity of acute COVID-19 infection, and higher anti-SARS-CoV-2 IgG levels were associated with the highest risk of having chronic COVID-19 symptoms.
Subject(s)
COVID-19 , Adult , Antibodies, Viral , Fatigue , Female , Humans , Immunoglobulin G , Male , Pain , RNA, Viral , SARS-CoV-2ABSTRACT
The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors' suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in the Journal of Clinical Oncology, to patients seen in their own clinical practice.
Subject(s)
Medical Oncology , Wilms Tumor , Humans , Referral and Consultation , Wilms Tumor/genetics , Wilms Tumor/therapyABSTRACT
Variants of concern (VOC) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), including alpha, beta, gamma, delta, and omicron, threaten to prolong the pandemic, leading to more global morbidity and mortality. Genome sequencing is the mainstay of tracking the evolution of the virus, but is costly, slow, and not easily accessible. Multiplex quantitative RT-PCR assays for SARS-CoV-2 have been developed that identify all VOCs as well as other mutations of interest in the viral genome, nine mutations in total, using single-nucleotide discriminating molecular beacons. The presented variant molecular beacon assays showed a limit of detection of 50 copies of viral RNA, with 100% specificity. Twenty-six SARS-CoV-2-positive patient samples were blinded and tested using a two-tube assay. When testing patient samples, the assay was in full agreement with results from deep sequencing with a sensitivity and specificity of 100% (26 of 26). We have used our design methodology to rapidly design an assay that detects the new omicron variant. This omicron assay was used to accurately identify this variant in 17 of 33 additional patient samples. These quantitative RT-PCR assays identify all currently circulating VOCs of SARS-CoV-2, as well as other important mutations in the spike protein coding sequence. These assays can be easily implemented on broadly available five-color thermal cyclers and will help track the spread of these variants.
Subject(s)
COVID-19 , SARS-CoV-2 , COVID-19/diagnosis , Humans , Multiplex Polymerase Chain Reaction , Mutation , SARS-CoV-2/geneticsABSTRACT
Extrapulmonary DICER1-associated sarcomas (DS) can harbor morphological features overlapping with pleuropulmonary blastoma. We report three children with intracranial and genital tract sarcomas, suspected to have DS based on a heterogeneous yet defining combination of spindle-cell sarcomatous and blastemal morphology, with rhabdomyomatous differentiation. Foci of immature cartilage at diagnosis (n = 2/3) and increased neuroepithelial differentiation at recurrence (n = 1) were noted. Morphological suspicion prompted somatic testing at reference centers, confirming likely biallelic, loss-of-function, and "hotspot" missense DICER1 variants in all three tumors. This can serve as a model for this diagnosis in resource-limited settings and has implications for germline testing, surveillance, and tumor management.
Subject(s)
Pulmonary Blastoma , Sarcoma , Soft Tissue Neoplasms , Child , DEAD-box RNA Helicases/genetics , Developing Countries , Germ-Line Mutation , Humans , Pulmonary Blastoma/diagnosis , Pulmonary Blastoma/genetics , Pulmonary Blastoma/pathology , Ribonuclease III/genetics , Sarcoma/diagnosis , Sarcoma/genetics , Sarcoma/pathologyABSTRACT
This report documents a unique multicystic neoplasm of the liver in an 8-month-old boy with a heterozygous germline pathogenic DICER1 variant. This neoplasm, initially considered most likely a mesenchymal hamartoma based on imaging, demonstrated the characteristic histologic pattern of embryonal rhabdomyosarcoma residing in the subepithelial or cambium layer-like zone of the epithelial-lined cysts. Thus, although the differential diagnosis includes mesenchymal hamartoma, a young child with a multicystic mass lesion in the liver, lung, or kidney should both raise the possibility of a germline pathogenic DICER1 variant and also not be mistaken for one of the other hepatic neoplasms of childhood.
Subject(s)
Hamartoma , Liver Neoplasms , Lung Neoplasms , Pulmonary Blastoma , Child , DEAD-box RNA Helicases/genetics , Humans , Infant , Liver Neoplasms/diagnosis , Liver Neoplasms/genetics , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Male , Pulmonary Blastoma/complications , Pulmonary Blastoma/diagnosis , Pulmonary Blastoma/genetics , Ribonuclease III/geneticsABSTRACT
Pediatric tumors are uncommon, yet are the leading cause of cancer-related death in childhood. Tumor types, molecular characteristics, and pathogenesis are unique, often originating from a single genetic driver event. The specific diagnostic challenges of childhood tumors led to the development of the first World Health Organization (WHO) Classification of Pediatric Tumors. The classification is rooted in a multilayered approach, incorporating morphology, IHC, and molecular characteristics. The volume is organized according to organ sites and provides a single, state-of-the-art compendium of pediatric tumor types. A special emphasis was placed on "blastomas," which variably recapitulate the morphologic maturation of organs from which they originate. SIGNIFICANCE: In this review, we briefly summarize the main features and updates of each chapter of the inaugural WHO Classification of Pediatric Tumors, including its rapid transition from a mostly microscopic into a molecularly driven classification systematically taking recent discoveries in pediatric tumor genomics into account.
Subject(s)
Brain Neoplasms/classification , Child , Genomics , Humans , World Health OrganizationABSTRACT
OBJECTIVE: We aimed to explore: (i) the association of sedentary time (ST) and physical activity (PA) during pregnancy with the placental expression of genes related to glucose and lipid metabolism in pregnant women who are obese; (ii) maternal metabolic factors mediating changes in these placental transcripts; and (iii) cord blood markers related to the mRNAs mediating neonatal adiposity. DESIGN: Multicentre randomised controlled trial. SETTING: Hospitals in nine European countries. POPULATION: A cohort of 112 pregnant women with placental tissue. METHODS: Both ST and moderate-to-vigorous PA (MVPA) levels were measured objectively using accelerometry at three time periods during pregnancy. MAIN OUTCOME MEASURES: Placental mRNAs (FATP2, FATP3, FABP4, GLUT1 and PPAR-γ) were measured with NanoString technology. Maternal and fetal metabolic markers and neonatal adiposity were assessed. RESULTS: Longer periods of ST, especially in early to middle pregnancy, was associated with lower placental FATP2 and FATP3 expression (P < 0.05), whereas MVPA at baseline was inversely associated with GLUT1 mRNA (P = 0.02). Although placental FATP2 and FATP3 expression were regulated by the insulin-glucose axis (P < 0.05), no maternal metabolic marker mediated the association of ST/MVPA with placental mRNAs (P > 0.05). Additionally, placental FATP2 expression was inversely associated with cord blood triglycerides and free fatty acids (FFAs; P < 0.01). No cord blood marker mediated neonatal adiposity except for cord blood leptin, which mediated the effects of PPAR-γ on neonatal sum of skinfolds (P < 0.05). CONCLUSIONS: In early to middle pregnancy, ST is associated with the expression of placental genes linked to lipid transport. PA is hardly related to transporter mRNAs. Strategies aimed at reducing sedentary behaviour during pregnancy could modulate placental gene expression, which may help to prevent unfavourable fetal and maternal pregnancy outcomes. TWEETABLE ABSTRACT: Reducing sedentary behaviour in pregnancy might modulate placental expression of genes related to lipid metabolism in women who are obese.