De novo missense variants in HDAC3 leading to epigenetic machinery dysfunction are associated with a variable neurodevelopmental disorder.

Histone deacetylase 3 (HDAC3) is a crucial epigenetic modulator essential for various developmental and physiological functions. Although its dysfunction is increasingly recognized in abnormal phenotypes, to our knowledge, there have been no established reports of human diseases directly linked to HDAC3 dysfunction. Using trio exome sequencing and extensive phenotypic analysis, we correlated heterozygous de novo variants in HDAC3 with a neurodevelopmental disorder having variable clinical presentations, frequently associated with intellectual disability, developmental delay, epilepsy, and musculoskeletal abnormalities. In a cohort of six individuals, we identified missense variants in HDAC3 (c.277G>A [p.Asp93Asn], c.328G>A [p.Ala110Thr], c.601C>T [p.Pro201Ser], c. 797T>C [p.Leu266Ser], c.799G>A [p.Gly267Ser], and c.1075C>T [p.Arg359Cys]), all located in evolutionarily conserved sites and confirmed as de novo. Experimental studies identified defective deacetylation activity in the p.Asp93Asn, p.Pro201Ser, p.Leu266Ser, and p.Gly267Ser variants, positioned near the enzymatic pocket. In addition, proteomic analysis employing co-immunoprecipitation revealed that the disrupted interactions with molecules involved in the CoREST and NCoR complexes, particularly in the p.Ala110Thr variant, consist of a central pathogenic mechanism. Moreover, immunofluorescence analysis showed diminished nuclear to cytoplasmic fluorescence ratio in the p.Ala110Thr, p.Gly267Ser, and p.Arg359Cys variants, indicating impaired nuclear localization. Taken together, our study highlights that de novo missense variants in HDAC3 are associated with a broad spectrum of neurodevelopmental disorders, which emphasizes the complex role of HDAC3 in histone deacetylase activity, multi-protein complex interactions, and nuclear localization for proper physiological functions. These insights open new avenues for understanding the molecular mechanisms of HDAC3-related disorders and may inform future therapeutic strategies.

Problem Solving MRI to Reduce False-Positive Biopsy Related to Breast US: Conductivity vs. DWI vs. Abbreviated Contrast-Enhanced MRI.

BACKGROUND: While breast ultrasound (US) is a useful tool for diagnosing breast masses, it can entail false-positive biopsy results because of some overlapping features between benign and malignant breast masses and subjective interpretation. PURPOSE: To evaluate the performance of conductivity imaging for reducing false-positive biopsy results related to breast US, as compared to diffusion-weighted imaging (DWI) and abbreviated MRI consisting of one pre- and one post-contrast T1-weighted imaging. STUDY TYPE: Prospective. SUBJECTS: Seventy-nine women (median age, 44 years) with 86 Breast Imaging Reporting and Data System (BI-RADS) category 4 masses as detected by breast US. FIELD STRENGTH/SEQUENCE: 3-T, T2-weighted turbo spin echo sequence, DWI, and abbreviated contrast-enhanced MRI (T1-weighted gradient echo sequence). ASSESSMENT: US-guided biopsy (reference standard) was obtained on the same day as MRI. The maximum and mean conductivity parameters from whole and single regions of interest (ROIs) were measured. Apparent diffusion coefficient (ADC) values were obtained from an area with the lowest signal within a lesion on the ADC map. The performance of conductivity, ADC, and abbreviated MRI for reducing false-positive biopsies was evaluated using the following criteria: lowest conductivity and highest ADC values among malignant breast lesions and BI-RADS categories 2 or 3 on abbreviated MRI. STATISTICAL TESTS: One conductivity parameter with the maximum area under the curve (AUC) from receiver operating characteristics was selected. A P-value <0.05 was considered statistically significant. RESULTS: US-guided biopsy revealed 65 benign lesions and 21 malignant lesions. The mean conductivity parameter of the single ROI method was selected (AUC = 0.74). Considering conductivity (≤0.10 S/m), ADC (≥1.60 × 10-3 mm2 /sec), and BI-RADS categories 2 or 3 reduced false-positive biopsies by 23% (15 of 65), 38% (25 of 65), and 43% (28 of 65), respectively, without missing malignant lesions. DATA CONCLUSION: Conductivity imaging may show lower performance than DWI and abbreviated MRI in reducing unnecessary biopsies. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 2.

SYNGAP1-related developmental and epileptic encephalopathy: Genotypic and phenotypic characteristics and longitudinal insights.

The clinical and genetic characteristics of SYNGAP1 mutations in Korean pediatric patients are not well understood. We retrospectively analyzed 13 individuals with SYNGAP1 mutations from a longitudinal aspect. Clinical data, genetic profiles, and electroencephalography (EEG) patterns were examined. Genotypic analyses included gene panels and whole-exome sequencing. All patients exhibited global developmental delay from early infancy, with motor development eventually reaching independent ambulation by 3 years of age. Language developmental delay varied significantly from nonverbal to simple sentences, which plateaued in all patients. Patients with the best language outcomes typically managed 2-3-word sentences, corresponding to a developmental age of 2-3 years. Epilepsy developed in 77% of patients, with onset consistently following developmental delays at a median age of 31 months. Longitudinal EEG data revealed a shift from occipital to frontal epileptiform discharges with age, suggesting a correlation with synaptic maturation. These findings suggest that the critical developmental plateau occurs between the ages of 2 and 5 years and is potentially influenced by epilepsy. By analyzing longitudinal data, our study contributes to a deeper understanding of SYNGAP1-related DEE, provides potential EEG biomarkers, and underlines the importance of early diagnosis and intervention to address this complex disorder.

Orphan Nuclear Receptor ERRα Controls Macrophage Metabolic Signaling and A20 Expression to Negatively Regulate TLR-Induced Inflammation.

The orphan nuclear receptor estrogen-related receptor α (ERRα; NR3B1) is a key metabolic regulator, but its function in regulating inflammation remains largely unknown. Here, we demonstrate that ERRα negatively regulates Toll-like receptor (TLR)-induced inflammation by promoting Tnfaip3 transcription and fine-tuning of metabolic reprogramming in macrophages. ERRα-deficient (Esrra(-/-)) mice showed increased susceptibility to endotoxin-induced septic shock, leading to more severe pro-inflammatory responses than control mice. ERRα regulated macrophage inflammatory responses by directly binding the promoter region of Tnfaip3, a deubiquitinating enzyme in TLR signaling. In addition, Esrra(-/-) macrophages showed an increased glycolysis, but impaired mitochondrial respiratory function and biogenesis. Further, ERRα was required for the regulation of NF-κB signaling by controlling p65 acetylation via maintenance of NAD(+) levels and sirtuin 1 activation. These findings unravel a previously unappreciated role for ERRα as a negative regulator of TLR-induced inflammatory responses through inducing Tnfaip3 transcription and controlling the metabolic reprogramming.

Pulmonary function characteristics in children with suspected asthma: implications for asthma diagnosis.

BACKGROUND: In children suspected of asthma, diagnosis is confirmed via variable expiratory airflow limitation. However, there is no single gold standard test for diagnosing asthma. OBJECTIVE: This study aimed to evaluate the pulmonary function characteristics in children suspected of asthma without bronchodilator response (BDR) and bronchial hyperresponsiveness (BHR). METHODS: We utilized two separate real-world retrospective observational cohorts of children who underwent both spirometry and bronchial provocation testing for asthma. Spirometry parameters were collected and compared between definite asthma, probable asthma, and non-asthma groups. The original cohort comprised 1199 children who visited the Severance Hospital (Seoul, Korea) between January 2017 and December 2019. The external cohort included 105 children who visited the Gangnam Severance Hospital between January 2019 and December 2019. RESULTS: Probable asthma accounted for 16.8% and 32.4% of the original and external cohorts, respectively. This group showed a significantly higher FeNO level and prevalence of allergic sensitization. Baseline forced expiratory volume in 1 second (FEV1), FEV1/forced vital capacity (FVC), forced expiratory flow at 25-75% of FVC (FEF25-75), and FEF75 showed stepwise decrements from non-asthma, probable asthma, to definite asthma patients (P < 0.001). The probable asthma group showed significantly higher odds of abnormal FEV1/FVC (OR, 2.24 [95%CI, 1.43-3.52])and FEF25-75 (2.05 [1.13-3.73]) than the non-asthma group and lower odds of abnormal FEV1(0.05 [0.01-0.19]),FEV1 /FVC (0.27 [0.18-0.41]), FEF25-75 (0.17 [0.11-0.28]), and FEF75 (0.14 [0.08-0.24]) compared to the definite asthma group. The external cohort was consistent with the original cohort. CONCLUSION: We show evidence of airway dysfunction in children for whom a high clinical suspicion of asthma exists without evidence of BDR and BHR. Repeated pulmonary function tests that closely monitor for subtle lung function impairments and active utilization of additional tests, such as allergic screening and FeNO, should be considered to close the gap in diagnosing asthma.

Adjustment to "new normal" after cancer among non-small cell lung cancer survivors: A qualitative study.

OBJECTIVES: Cancer is a life-changing experience, and side effects from treatment can make it difficult for survivors to return to their pre-cancer "normal life." We explored the "new normal" and barriers to achieving it among lung cancer survivors who underwent surgery. METHODS: Semi-structured interviews were conducted with 32 recurrence-free non-small cell lung cancer survivors. We asked survivors how life had changed; how they defined the "new normal"; barriers that prevent them from achieving a "normal" life; and unmet needs or support for normalcy. Thematic analysis was performed. RESULTS: Defining "new normal" subjectively depends on an individual's expectation of recovery: (1) being able to do what they want without pain or discomfort; (2) being able to do activities they could accomplish before their surgery; and (3) being able to work, earn money, and support their family. We found that (1) persistent symptoms, (2) fear of cancer recurrence, (3) high expectations in recovery, and (4) psychosocial stress and guilty feelings were barriers to achieving a "new normal." The needs and support for normalcy were information on expected trajectories, postoperative management, and support from family and society. SIGNIFICANCE OF RESULTS: Survivors defined the "new normal" differently, depending on their expectations for recovery. Informing survivors about the "new normal" so they could expect possible changes and set realistic goals for their life after cancer. Health professionals need to communicate with survivors about expectations for "normality" from the beginning of treatment, and it should be included in comprehensive survivorship care.

Use of imaging prediction model for omission of axillary surgery in early-stage breast cancer patients.

PURPOSE: To develop a prediction model incorporating clinicopathological information, US, and MRI to diagnose axillary lymph node (LN) metastasis with acceptable false negative rate (FNR) in patients with early stage, clinically node-negative breast cancers. METHODS: In this single center retrospective study, the inclusion criteria comprised women with clinical T1 or T2 and N0 breast cancers who underwent preoperative US and MRI between January 2017 and July 2018. Patients were temporally divided into the development and validation cohorts. Clinicopathological information, US, and MRI findings were collected. Two prediction models (US model and combined US and MRI model) were created using logistic regression analysis from the development cohort. FNRs of the two models were compared using the McNemar test. RESULTS: A total of 964 women comprised the development (603 women, 54 ± 11 years) and validation (361 women, 53 ± 10 years) cohorts with 107 (18%) and 77 (21%) axillary LN metastases in each cohort, respectively. The US model consisted of tumor size and morphology of LN on US. The combined US and MRI model consisted of asymmetry of LN number, long diameter of LN, tumor type, and multiplicity of breast cancers on MRI, in addition to tumor size and morphology of LN on US. The combined model showed significantly lower FNR than the US model in both development (5% vs. 32%, P < .001) and validation (9% vs. 35%, P < .001) cohorts. CONCLUSION: Our prediction model combining US and MRI characteristics of index cancer and LN lowered FNR compared to using US alone, and could potentially lead to avoid unnecessary SLNB in early stage, clinically node-negative breast cancers.

Background Parenchymal Enhancement at Postoperative Surveillance Breast MRI: Association with Future Second Breast Cancer Risk.

Background Background parenchymal enhancement (BPE) is a known risk factor for breast cancer. However, studies on the association between BPE and second breast cancer risk are still lacking. Purpose To investigate whether BPE at surveillance breast MRI is associated with subsequent second breast cancer risk in women with a personal history of breast cancer. Materials and Methods A retrospective search of the imaging database of an academic medical center identified consecutive surveillance breast MRI examinations performed between January 2008 and December 2017 in women who underwent surgery for primary breast cancer and had no prior diagnosis of second breast cancer. BPE at surveillance breast MRI was qualitatively assessed using a four-category classification of minimal, mild, moderate, or marked. Future second breast cancer was defined as ipsilateral breast tumor recurrence or contralateral breast cancer diagnosed at least 1 year after each surveillance breast MRI examination. Factors associated with future second breast cancer risk were evaluated using the multivariable Fine-Gray subdistribution hazard model. Results Among the 2668 women (mean age at baseline surveillance breast MRI, 49 years ± 8 [SD]), 109 developed a second breast cancer (49 ipsilateral, 58 contralateral, and two ipsilateral and contralateral) at a median follow-up of 5.8 years. Mild, moderate, or marked BPE at surveillance breast MRI (hazard ratio [HR], 2.1 [95% CI: 1.4, 3.1]; P < .001), young age (<45 years) at initial breast cancer diagnosis (HR, 3.4 [95% CI: 1.7, 6.4]; P < .001), positive results from a BRCA1/2 genetic test (HR, 6.5 [95% CI: 3.5, 12.0]; P < .001), and negative hormone receptor expression in the initial breast cancer (HR, 1.6 [95% CI: 1.1, 2.6]; P = .02) were independently associated with an increased risk of future second breast cancer. Conclusion Background parenchymal enhancement at surveillance breast MRI was associated with future second breast cancer risk in women with a personal history of breast cancer. © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by Niell in this issue.

Transcriptome-based variant calling and aberrant mRNA discovery enhance diagnostic efficiency for neuromuscular diseases.

BACKGROUND: Whole-exome sequencing-based diagnosis of rare diseases typically yields 40%-50% of success rate. Precise diagnosis of the patients with neuromuscular disorders (NMDs) has been hampered by locus heterogeneity or phenotypic heterogeneity. We evaluated the utility of transcriptome sequencing as an independent approach in diagnosing NMDs. METHODS: The RNA sequencing (RNA-Seq) of muscle tissues from 117 Korean patients with suspected Mendelian NMD was performed to evaluate the ability to detect pathogenic variants. Aberrant splicing and CNVs were inspected to identify additional causal genetic factors for NMD. Aberrant splicing events in Dystrophin (DMD) were investigated by using antisense oligonucleotides (ASOs). A non-negative matrix factorisation analysis of the transcriptome data followed by cell type deconvolution was performed to cluster samples by expression-based signatures and identify cluster-specific gene ontologies. RESULTS: Our pipeline called 38.1% of pathogenic variants exclusively from the muscle transcriptomes, demonstrating a higher diagnostic rate than that achieved via exome analysis (34.9%). The discovery of variants causing aberrant splicing allowed the application of ASOs to the patient-derived cells, providing a therapeutic approach tailored to individual patients. RNA-Seq data further enabled sample clustering by distinct gene expression profiles that corresponded to clinical parameters, conferring additional advantages over exome sequencing. CONCLUSION: The RNA-Seq-based diagnosis of NMDs achieves an increased diagnostic rate and provided pathogenic status information, which is not easily accessible through exome analysis.

TEV/FEV3 as a coherent metric of small airway dysfunction in childhood asthma.

Background: Spirometry is an unrivalled tool for determining asthma and asthma severity. The ratio of forced expiratory volume (FEV) in 1 second (FEV1) to forced vital capacity (FVC) and the forced expiratory flow between 25% and 75% of FVC (FEF25-75) are well-known markers of airway obstruction, but they are limited by low reproducibility, particularly in children. In this study, we defined terminal expiration volume (TEV) as FEV in 3 seconds forced expiratory volume in 3 seconds (FEV3) minus forced expiratory volume in 1 seconds (FEV1) and investigate whether TEV/FEV3 can function as a coherent marker to compensate for existing markers. Methods: This retrospective study comprised 980 children ages ≤ 18 years who underwent spirometry and the bronchial provocation testing. TEV/FEV3 was compared with regard to asthma presence and severity. The findings were verified with an external validation group (n = 105). Results: FEV3 was obtained in 837 children (85.4%). TEV/FEV3 was significantly higher in patients with asthma than in patients who did not have asthma (17.1 ± 5.5 versus 12.0 ± 4.4, p < 0.001). External validation with 73 patients showed similar results (18.0 ± 5.9 in asthma versus 10.2 ± 5.1 in non-asthma, p < 0.001). The discriminatory power of TEV/FEV3 for asthma was comparable with that of FEF25-75 (p = 0.804). TEV/FEV3 significantly increased with asthma severity (mild, 16.1 ± 5.4; moderate, 17.7 ± 5.4; severe, 22.0 ± 5.3; p < 0.001). For patients who could not achieve FEV3, FEF25-75 demonstrated no significant difference between mild and moderate asthma, and could not discriminate asthma or asthma severity. Conclusion: TEV/FEV3 is a new metric that may help diagnose and determine asthma severity by using conventional spirometry by assessing small airway dysfunction. TEV/FEV3 promotes a reassessment of the reliability of other spirometric parameters, particularly in young children. Caution is needed in interpreting the result of spirometry in children who cannot achieve FEV3.

Metabolomic profiling revealed altered lipid metabolite levels in childhood food allergy.

BACKGROUND: The pathophysiology of childhood food allergy (FA) and its natural history are poorly understood. Clarification of the underlying mechanism may help identify novel biomarkers and strategies for clinical intervention in children with FA. OBJECTIVE: This study aimed to identify metabolites associated with the development and resolution of FA. METHODS: The metabolomic profiles of 20 children with FA and 20 healthy controls were assessed by liquid chromatography-tandem mass spectrometry. Comparative analysis was performed to identify metabolites associated with FA and FA resolution. For subjects with FA, serum samples were collected at the time of diagnosis and after resolution to identify the changes in metabolite levels. The selected metabolites were then quantified in a quantification cohort to validate the results. Finally, genome-wide association analysis of the metabolite levels was performed. RESULTS: The study demonstrated a significantly higher level of sphingolipid metabolites and a lower level of acylcarnitine metabolites in children with FA than those in healthy controls. At diagnosis, subjects with resolving FA had a significantly high level of omega-3 metabolites and a low level of platelet-activating factors compared to persistent FA. However, the level of omega-3 metabolites decreased in children with resolving FA but increased in children with persistent FA during the same time. The quantification data of omega-3-derived resolvins, platelet-activating factor, and platelet-activating factor acetylhydrolase activity further supported these results. CONCLUSION: The lipid metabolite profile is closely related to childhood FA and FA resolution. This study suggests potential predictive biomarkers and provides insight into the mechanisms underlying childhood FA.

Psychosocial Stressors of COVID-19- and Non-COVID-19-Dedicated Nurses: A Comparative Study.

The current comparative study sought to identify psychosocial stressors of corona-virus disease 2019 (COVID-19)-dedicated (n = 110) and non-COVID-19-dedicated (n = 118) nurses (herein referred to as COVID nurses and non-COVID nurses, respectively). Data were collected online from October 20, 2020, to April 1, 2021. Significant predictors of mental health for COVID nurses were purpose/meaning (ß = -0.32, p < 0.001), perceived stigma (ß = 0.25, p = 0.001), perceived work environment improvement (ß = -0.22, p = 0.004), and absolute work intensity (ß = 0.26, p = 0.004). For non-COVID nurses, predictors were purpose/meaning (ß = -0.34, p < 0.001) and absolute work intensity (ß = 0.26, p = 0.003). It is necessary to develop programs and policies that support the mental health of nursing staff. Administrative efforts should be made to create a work environment that allows nurses to focus on their work during health crises, such as the COVID-19 pandemic. Nursing staff should be supported so that appropriate working hours are maintained and breaks are guaranteed. [Journal of Psychosocial Nursing and Mental Health Services, 61(1), 39-46.].

US Evaluation of Axillary Lymphadenopathy Following COVID-19 Vaccination: A Prospective Longitudinal Study.

Background Both temporal changes in imaging characteristics of lymphadenopathy on US scans after COVID-19 vaccination and expected duration of radiologically evident lymphadenopathy remain uncertain. Purpose To longitudinally evaluate COVID-19 vaccine-associated lymphadenopathy on axillary US scans at various time intervals in both messenger (mRNA) and vector vaccine recipients. Materials and Methods This prospective cohort study was conducted between March 2021 and January 2022. The participants were asymptomatic women without breast cancer who had received COVID-19 vaccination. Serial follow-up US was performed in women with lymphadenopathy. The following variables were assessed: cortical thickness, number of lymph nodes, morphologic characteristics, and Doppler signal. Temporal changes in cortical thickness and number of lymph nodes during follow-up were assessed using a linear mixed model. Results Ninety-one women with lymphadenopathy in the vaccinated arm had undergone a total of 215 serial US examinations (mean age, 44 years ± 13 [SD]). Fifty-one participants had received a vector vaccine (ChAdOx1 nCoV-19 vaccine) and 40 had received an mRNA vaccine (BNT162b2 vaccine [n = 37] and mRNA-1273 vaccine [n = 3]). Three of the 91 women were lost to follow-up; thus, 88 women underwent serial US. Complete resolution of axillary lymphadenopathy was observed at a median of 6 weeks after vaccination (range, 4-7 weeks) in 26% of women (23 of 88). Among 49 women with follow-up US at a median of 12 weeks after vaccination (range, 8-14 weeks), persistent lymphadenopathy was observed in 25 (51%). During the follow-up period, the cortical thickness gradually decreased (P < .001) over time regardless of vaccine type; however, values were higher in recipients of the mRNA vaccine than in recipients of the vector vaccine (P = .02). Conclusion COVID-19 vaccine-associated axillary lymphadenopathy frequently persisted for more than 6 weeks on US scans. Lymphadenopathy should be interpreted considering vaccine type and time elapsed since vaccination. Follow-up US examination at least 12 weeks after vaccination may be reasonable, particularly for recipients of the messenger RNA vaccine. © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by Moy and Kim in this issue.

Abbreviated Screening MRI for Women with a History of Breast Cancer: Comparison with Full-Protocol Breast MRI.

Background Few studies have compared abbreviated breast MRI with full-protocol MRI in women with a personal history of breast cancer (PHBC), and they have not adjusted for confounding variables. Purpose To compare abbreviated breast MRI with full-protocol MRI in women with PHBC by using propensity score matching to adjust for confounding variables. Materials and Methods In this single-center retrospective study, women with PHBC who underwent full-protocol MRI (January 2008-August 2017) or abbreviated MRI (September 2017-April 2019) were identified. With use of a propensity score-matched cohort, screening performances were compared between the two MRI groups with the McNemar test or a propensity score-adjusted generalized estimating equation. The coprimary analyses were sensitivity and specificity. The secondary analyses were the cancer detection rate, interval cancer rate, positive predictive value for biopsies performed (PPV3), and Breast Imaging Reporting and Data System (BI-RADS) category 3 short-term follow-up rate. Results There were 726 women allocated to each MRI group (mean age ± SD, 50 years ± 8 for both groups). Abbreviated MRI and full-protocol MRI showed comparable sensitivity (15 of 15 cancers [100%; 95% CI: 78, 100] vs nine of 13 cancers [69%; 95% CI: 39, 91], respectively; P = .17). Abbreviated MRI showed higher specificity than full-protocol MRI (660 of 711 examinations [93%; 95% CI: 91, 95] vs 612 of 713 examinations [86%; 95% CI: 83, 88], respectively; P < .001). The cancer detection rate (21 vs 12 per 1000 examinations), interval cancer rate (0 vs five per 1000 examinations), and PPV3 (61% [14 of 23 examinations] vs 41% [nine of 22 examinations]) were comparable (all P < .05). The BI-RADS category 3 short-term follow-up rate of abbreviated MRI was less than half that of full-protocol MRI (5% [36 of 726 examinations] vs 12% [84 of 726 examinations], respectively; P < .001). Ninety-three percent (14 of 15) of cancers detected at abbreviated MRI were node-negative T1-invasive cancers (n = 6) or ductal carcinoma in situ (n = 8). Conclusion Abbreviated breast MRI showed comparable sensitivity and superior specificity to full-protocol MRI in breast cancer detection in women with a personal history of breast cancer. © RSNA, 2022 Online supplemental material is available for this article.

Microcalcifications and Peritumoral Edema Predict Survival Outcome in Luminal Breast Cancer Treated with Neoadjuvant Chemotherapy.

Background Little is known regarding findings at imaging associated with survival in patients with luminal breast cancer treated with neoadjuvant chemotherapy (NAC). Purpose To determine the relationship between imaging (MRI, US, and mammography) and clinical-pathologic variables in predicting distant metastasis-free survival (DMFS) and overall survival (OS) in patients with luminal breast cancer treated with NAC. Materials and Methods In this retrospective study, consecutive women with luminal breast cancer who underwent NAC followed by surgery were identified from the breast cancer registries of two hospitals. Women from one hospital between January 2003 and July 2015 were classified into the development cohort, and women from the other hospital between January 2007 and July 2015 were classified into the validation cohort. MRI scans, US scans, and mammograms before and after NAC (hereafter, referred to as pre- and post-NAC, respectively) and clinical-pathologic data were reviewed. Peritumoral edema was defined as the water-like high signal intensity surrounding the tumor on T2-weighted MRI scans. The prediction model was developed in the development cohort by using Cox regression and then tested in the validation cohort. Results The development cohort consisted of 318 women (68 distant metastases, 54 deaths) and the validation cohort consisted of 165 women (37 distant metastases, 14 deaths) (median age, 46 years in both cohorts). Post-NAC MRI peritumoral edema, age younger than 40 years, clinical N2 or N3, and lymphovascular invasion were associated with worse DMFS (all, P < .05). Pre-NAC mammographic microcalcifications, post-NAC MRI peritumoral edema, age older than 60 years, and clinical T3 or T4 were associated with worse OS (all, P < .05). The prediction model showed good discrimination ability (C index, 0.67-0.75 for DMFS and 0.70-0.77 for OS) and stratified prognosis into low-risk and high-risk groups (10-year DMFS rates, 79% vs 21%, respectively; and 10-year OS rates, 95%-96% vs 63%-67%, respectively) in the validation cohort. Conclusion MRI features and clinical-pathologic variables were identified that were associated with prolonged survival of patients with luminal breast cancer treated with neoadjuvant chemotherapy. © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by Kataoka in this issue.

Dominant KPNA3 Mutations Cause Infantile-Onset Hereditary Spastic Paraplegia.

OBJECTIVE: Hereditary spastic paraplegia (HSP) is a highly heterogeneous neurologic disorder characterized by lower-extremity spasticity. Here, we set out to determine the genetic basis of an autosomal dominant, pure, and infantile-onset form of HSP in a cohort of 8 patients with a uniform clinical presentation. METHODS: Trio whole-exome sequencing was used in 5 index patients with infantile-onset pure HSP to determine the genetic cause of disease. The functional impact of identified genetic variants was verified using bioinformatics and complementary cellular and biochemical assays. RESULTS: Distinct heterozygous KPNA3 missense variants were found to segregate with the clinical phenotype in 8 patients; in 4 of them KPNA3 variants had occurred de novo. Mutant karyopherin-α3 proteins exhibited a variable pattern of altered expression level, subcellular distribution, and protein interaction. INTERPRETATION: Our genetic findings implicate heterozygous variants in KPNA3 as a novel cause for autosomal dominant, early-onset, and pure HSP. Mutant karyopherin-α3 proteins display varying deficits in molecular and cellular functions, thus, for the first time, implicating dysfunctional nucleocytoplasmic shuttling as a novel pathomechanism causing HSP. ANN NEUROL 2021;90:738-750.

The Role of Decreased Cortical Thickness and Volume of Medial Temporal Lobe Structures in Predicting Incident Psychosis in Patients With Alzheimer's Disease: A Prospective Longitudinal MRI Study.

OBJECTIVE: To investigate the effect of decreased cortical thickness or volume of medial temporal lobe structures on the risk of incident psychosis in patients with AD. DESIGN, SETTING, AND PARTICIPANTS: This hospital-based prospective longitudinal study enrolled 109 patients with AD. All patients with AD were evaluated at 3-month intervals to investigate the effect of decreased cortical thickness or volume of medial temporal lobe structures on the risk of incident psychosis in patients with AD. OUTCOME MEASURE: The main outcome measure was time-to-progression from AD to incident psychosis. The thickness or volume of medial temporal lobe structures (i.e., the hippocampus, entorhinal cortex, and parahippocampus) were measured using magnetic resonance imaging and the Freesurfer automated segmentation pipeline at baseline. RESULTS: Multivariate Cox proportional hazards regression analysis revealed that a decreased cortical thickness or volume of medial temporal region was associated with a higher risk of incident psychosis in patients with AD. The hazard ratios for decreased cortical thickness of the left entorhinal cortex and decreased cortical volume of the right hippocampus were 4.291 (95% confidence interval [CI], 1.196-15.384) and 2.680 [(CI, 1.003-1.196]), respectively. CONCLUSION: Our study revealed that decreased cortical thickness or volume of medial temporal sub-regions is a risk factor for incident psychosis in patients with AD. A careful assessment of the thickness or volume of the medial temporal lobe structures in AD may improve early detection and intervention of psychosis in AD.

Usefulness of extended nitric oxide analysis in children with allergic rhinitis.

OBJECTIVE: Evaluation of airway inflammation and dysfunction is important in management of allergic rhinitis (AR) since AR is a risk factor for developing asthma. Theoretical nonlinear modeling of exhaled nitric oxide (NO) has revealed extended flow-independent NO parameters that could explain where or how NO metabolism was altered. We aimed to evaluate the association between extended NO parameters and bronchial hyperresponsiveness (BHR) in children with AR. METHODS: Exhaled NO was measured in 74 children with AR on the same day they underwent the provocholine challenge test (PCT). Extended NO was measured in three different exhaled flow rates (30, 100, 200 mL/s) and calculated using the Högman-Meriläinen model. We compared the extended NO parameters including bronchial NO (JawNO), airway tissue NO (CawNO), alveolar tissue NO (CaNO), and diffusing capacity of NO (DawNO) between AR with and without BHR groups, and analyzed the correlation between extended NO parameters and the response-dose ratio (RDR) of the PCT. We additionally evaluated 49 respiratory healthy controls. RESULTS: Among the 74 children with AR, nine showed BHR. JawNO increased more in children with AR than the control group. In children with AR, JawNO was higher in the AR with BHR than without BHR group, and was correlated positively with log RDR (r = 0.373, p = .001). CONCLUSIONS: Extended NO analysis including JawNO can be a useful tool for assessing BHR in AR.

Safety and efficacy of high-intensity focused ultrasound for treatment of periorbital, perioral, and neck wrinkles: Prospective open single-center single-arm confirmatory clinical trial.

Periorbital, perioral, and neck wrinkles are one of the most common concerns of aging skin. We evaluated the efficacy and safety of high-intensity focused ultrasound (HIFU) device with a 5.5-MHz transducer and a 2.0-mm focal depth for improving periorbital, perioral, and neck wrinkles. A total of 102 participants were enrolled, and 34 each were assigned to the periorbital, perioral, and neck groups. All subjects were treated with HIFU three times at 2-week intervals at the corresponding treatment site. Objective measurements and clinical evaluations were performed at 10 and 16 weeks after treatment. Based on the primary efficacy evaluation, the mean Cutometer R7 value was significantly increased at 10 weeks post-treatment compared to baseline in all treated groups. In addition, all other Cutometer values, PRIMOS and Antera 3D camera evaluation results, classification of wrinkle assessment results, and Subject Global Aesthetic Improvement Scale also showed that the periorbital, perioral, and neck wrinkles were significantly improved at 10 and 16 weeks post-treatment. No permanent adverse effects were observed during the follow-up period. HIFU treatment using 5.5-MHz transducers (2.0-mm focal depth) could be an effective and safe treatment modality for the treatment of periorbital, perioral, and neck wrinkles.

Cryolipolysis for abdominal subcutaneous fat reduction: A prospective, multicenter, single arm, clinical study.

Various treatment methods are used for noninvasive body contouring. To evaluate the efficacy and safety of a newly designed cryolipolysis device using a three-dimensional cooling method for abdominal fat reduction. Twenty-five participants with clinically apparent abdominal fat tissue participated in the study. The thickness of fat tissue below the umbilicus level was measured using a caliper at baseline and 12 weeks after the first treatment. The height of abdominal subcutaneous fat tissue on ultrasonography and participant satisfaction were assessed at every visit for 16 weeks. All adverse events (AEs) during the study period were recorded. p values <0.05 were considered statistically significant. Twenty-four participants completed this study; the mean BMI of participants was 29.34 ± 2.36 kg/m2 . The mean thickness of abdominal subcutaneous fat was significantly lower at 12 weeks (40.4 ± 6.8 mm, p < 0.001) than at baseline (49.3 ± 8.5 mm). Differences in the height of abdominal subcutaneous fat compared to that at baseline were 1.02 ± 0.41 cm (12 weeks, p < 0.001) and 1.13 ± 0.44 cm (16 weeks, p < 0.001). Rates of abdominal subcutaneous fat reduction at 12 and 16 weeks compared to that at baseline were 28.45% and 31.13%, respectively. The ratio of abdominal circumference to hip circumference at 12 and 16 weeks was significantly decreased compared to that at baseline. Most participants (95.8%) reported improvement in satisfaction scores at 16 weeks. There were no serious AEs during the entire study period. The study demonstrated the efficacy of a noninvasive cryolipolysis device using a three-dimensional cooling method for reducing abdominal subcutaneous fat.