Clinical features and outcomes of small airway disease in ANCA-associated vasculitis.

BACKGROUND AND OBJECTIVE: To clarify the prevalence, features and outcomes of small airway disease (SAD) in a Chinese cohort with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) related pulmonary involvement. METHODS: SAD was recorded when the manifestations of either centrilobular nodules or air trapping were observed according to CT scans, except for infection or other airway-related comorbidities. Baseline and follow-up data were collected retrospectively. RESULTS: Of the 359 newly diagnosed AAV patients with pulmonary involvement, 92 (25.6%) had SAD, including 79 (85.9%) cases of anti-MPO-ANCA positive, 9 (9.8%) cases of anti-PR3-ANCA positive and 2 (2.2%) cases of double positive. Patients with SAD were more likely to be younger, female, non-smokers, have more ear-nose-throat (ENT) involvement, and have higher baseline Birmingham Vasculitis Activity Score (BVAS) compared to patients without SAD. Several AAV-related SAD patients have improved lung function and CT scans after immunosuppressive therapy. Patients with SAD had a better prognosis compared to those without SAD. When dividing all patients into three groups: isolated SAD (only small airway involvements), SAD with other lower airway involvements, and non-SAD, patients in the SAD with other lower airway involvements group had the highest risk of infection, while patients in the non-SAD group had the worst long-term outcomes. Similar results were observed in anti-MPO-ANCA positive patients when performing subgroup analyses. CONCLUSION: SAD is a unique manifestation of AAV-related lung involvement and exhibits distinct clinical features. It is vital to focus on SAD because of its association with prognosis and infection in AAV patients, especially in anti-MPO-ANCA positive patients. Moreover, SAD might represent a better response to immunosuppressors.

Patterns of Interstitial Lung Disease and Prognosis in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis.

BACKGROUND: Interstitial lung disease (ILD) is a common pulmonary manifestation of antineutrophil cytoplasmic antibody-associated vasculitis (AAV). OBJECTIVES: We aimed to clarify the clinical predictors of mortality in a cohort of patients with AAV-related ILD (AAV-ILD). METHOD: We retrospectively identified AAV-ILD patients seen at Peking University First Hospital from January 2010 to June 2020 and manually screened for study inclusion. Baseline computed tomography (CT) images were further classified as nonspecific interstitial pneumonia (NSIP), usual interstitial pneumonia (UIP), organizing pneumonia (OP), and unclassified ILD. Disease characteristics and other pulmonary findings including pulmonary function test and bronchoalveolar lavage (BAL) were also evaluated. Multivariable Cox regression analysis was performed to identify clinical predictors of mortality. RESULTS: The cohort included 204 patients with AAV-ILD, 152 had UIP on CT (AAV-UIP), 39 had NSIP on CT (AAV-NSIP), 3 had OP, and 10 had unclassified ILD. Microscopic polyangiitis was more prevalent in patients with UIP, while granulomatosis with polyangiitis was more common in the NSIP and OP groups, and eosinophilic granulomatosis with polyangiitis was more frequent in patients with unclassified ILD. ILD diagnosis before AAV was more common in patients with either UIP or NSIP patterns. During the median follow-up of 40 months, 44 (21.6%) patients died. One- and 5-year overall survival rates were 88.2% (95% CI, 83.7-92.7%) and 81.0% (95% CI, 74.9-87.1%) for the entire cohort. Patients with UIP patterns had the worst prognosis, while those with NSIP patterns had the best long-term outcome. Specifically, patients with UIP patterns had an approximately 5-fold risk of death compared to those with NSIP. After controlling for potential confounding factors, we observed that each 10% increase in the BAL fluid neutrophil percentage was associated with nearly a 20% increased risk of death (HR 1.195, 95% CI 1.018-1.404). CONCLUSIONS: Clinical characteristics and survival differ between subgroups defined by CT patterns. BAL fluid neutrophilia is an independent predictor of mortality among AAV-ILD patients, and therefore, the clinical utility of BAL at the time of AAV diagnosis should be considered.

Characteristics and feasibility of ambulatory respiratory assessment of paediatric neuromuscular disease: an observational retrospective study.

PURPOSE: To investigate the characteristics of respiratory involvement in Chinese paediatric neuromuscular disease (NMD) at early stage and to explore convenient monitoring methods. MATERIALS AND METHODS: Children with NMD (age < 18) diagnosed at a multidisciplinary joint NMD clinic at Peking University First Hospital from January 2016 to April 2021 were included. Overnight polysomnography (PSG) and pulmonary function test (PFT) data were analysed, and the characteristics of four groups: congenital muscular dystrophy (CMD), congenital myopathy, spinal muscular atrophy, and Duchenne muscular dystrophy (DMD) were compared. RESULTS: A total of 83 children with NMD were referred for respiratory assessment, of who 80 children underwent PSG; 41 performed spirometry and 38, both. The duration of pulse oxygen saturation (SpO2) <90% over apnoea and hypopnoea index (AHI) was lowest in DMD and significantly different from CMD (p = 0.033). AHI was positively correlated with the oxygen desaturation index (ODI) (r = 0.929, p = 0.000). The peak expiratory flow (PEF) were positively correlated with forced vital capacity (FVC), both as actual values and percent pred, respectively (r = 0.820, 0.719, p = 0.000). ROC derived sensitivity and specificity of prediction of AHI > 15/h or duration of SpO2<90% ≥ 60 min from FVC <51% pred was 75.8% and 85.7%, respectively. CONCLUSIONS: AHI and hypoxia burden were independent factors in children with NMD in PSG and attention needed to be paid in both. FVC might be a daytime predictor for significant sleep-disordered breathing or hypoxia. Nocturnal consecutive oximetry with diurnal peak flow measurement may be convenient and effective for home monitoring at early stage of respiratory involvement.

Thigh MRI in antisynthetase syndrome, and comparisons with dermatomyositis and immune-mediated necrotizing myopathy.

OBJECTIVES: To evaluate MRI changes to define muscle-lesion specific patterns in patients with antisynthetase syndrome (ASS), and compare them with those in other common idiopathic inflammatory myopathy subtypes. METHODS: Qualitative and semi-quantitative thigh MRI evaluations were conducted in patients with ASS, DM and immune-mediated necrotizing myopathy (IMNM). RESULTS: This study included 51 patients with ASS, 56 with DM and 61 with IMNM. Thigh MRI revealed muscle oedema (62.7%), myofascial oedema (90.2%), subcutaneous-tissue oedema (60.8%) and fatty infiltration of muscles (68.6%) in patients with ASS. Compared with IMNM, ASS and DM were associated with more frequent adductor-muscle relative sparing (40.6% vs 3.6%, P<0.001, and 25.6% vs 3.6%, P<0.001) and subcutaneous-tissue oedema (60.8% vs 23.0%, P<0.001, and 57.1% vs 23.0%, P<0.001). Although ASS and DM exhibited similar oedema patterns, there were certain subtle differences between them. The ASS group was less frequently symmetric (60.6% vs 88.4%, P=0.005, and 60.6% vs 80.0%, P=0.048), but more frequently showed myofascial oedema of the tensor fasciae latae (80.4% vs 48.2%, P<0.001, and 80.4% vs 31.1%, P<0.001) than either the DM or IMNM groups. The receiver operating characteristic curve analysis showed an optimal combination of thigh MRI findings had an area under the curve with 0.893 for diagnosing ASS. CONCLUSION: Thigh MRI in ASS exhibited frequent myofascial oedema. ASS oedema patterns resembled those of DM more than those of IMNM. Bilateral asymmetry, adductor-muscle relative sparing and remarkable myofascial oedema of tensor fasciae latae were the most characteristic ASS imaging findings.

Pro-thrombotic changes associated with exposure to ambient ultrafine particles in patients with chronic obstructive pulmonary disease: roles of lipid peroxidation and systemic inflammation.

BACKGROUND: Exposure to particulate matter air pollution is associated with an increased risk of cardiovascular mortality in patients with chronic obstructive pulmonary disease (COPD), but the underlying mechanisms are not yet understood. Enhanced platelet and pro-thrombotic activity in COPD patients may explain their increased cardiovascular risk. We aim to explore whether short-term exposure to ambient particulate matter is associated with pro-thrombotic changes in adults with and without COPD, and investigate the underlying biological mechanisms in a longitudinal panel study. Serum concentration of thromboxane (Tx)B2 was measured to reflect platelet and pro-thrombotic activity. Lipoxygenase-mediated lipid peroxidation products (hydroxyeicosatetraenoic acids [HETEs]) and inflammatory biomarkers (interleukins [ILs], monocyte chemoattractant protein-1 [MCP-1], tumour necrosis factor alpha [TNF-α], and macrophage inflammatory proteins [MIPs]) were measured as potential mediating determinants of particle-associated pro-thrombotic changes. RESULTS: 53 COPD and 82 non-COPD individuals were followed-up on a maximum of four visits conducted from August 2016 to September 2017 in Beijing, China. Compared to non-COPD individuals, the association between exposure to ambient ultrafine particles (UFPs) during the 3-8 days preceding clinical visits and the TxB2 serum concentration was significantly stronger in COPD patients. For example, a 103/cm3 increase in the 6-day average UFP level was associated with a 25.4% increase in the TxB2 level in the COPD group but only an 11.2% increase in the non-COPD group. The association in the COPD group remained robust after adjustment for the levels of fine particulate matter and gaseous pollutants. Compared to the non-COPD group, the COPD group also showed greater increases in the serum concentrations of 12-HETE (16.6% vs. 6.5%) and 15-HETE (9.3% vs. 4.5%) per 103/cm3 increase in the 6-day UFP average. The two lipid peroxidation products mediated 35% and 33% of the UFP-associated increase in the TxB2 level of COPD patients. UFP exposure was also associated with the increased levels of IL-8, MCP-1, MIP-1α, MIP-1ß, TNF-α, and IL-1ß in COPD patients, but these inflammatory biomarkers did not mediate the TxB2 increase. CONCLUSIONS: Short-term exposure to ambient UFPs was associated with a greater pro-thrombotic change among patients with COPD, at least partially driven by lipoxygenase-mediated pathways following exposure. Trial registration ChiCTR1900023692 . Date of registration June 7, 2019, i.e. retrospectively registered.

Pulmonary involvement of ANCA-associated vasculitis in adult Chinese patients.

OBJECTIVE: The aim of this study was to clarify the clinical characteristics and long-term outcomes of ANCA-associated vasculitis (AAV) patients with pulmonary involvement from a single Chinese cohort. METHODS: Newly diagnosed AAV patients with pulmonary involvement, as defined by CT, were recruited from January 2010 to June 2020. Clinical data and CT images were collected retrospectively. Baseline CTs were evaluated and re-classified into four categories: interstitial lung disease (ILD), airway involvement (AI), alveolar hemorrhage (AH), and pulmonary granuloma (PG). RESULTS: A total of 719 patients were newly diagnosed with AAV, 366 (50.9%) of whom combined with pulmonary involvement at baseline. Among the AAV cases with pulmonary involvement, 55.7% (204/366) had ILD, 16.7% (61/366) had AI alone, 14.8% (54/366) had PG, and 12.8% (47/366) had AH alone. During follow-up of a median duration of 42.0 months, 66/366 (18.0%) patients died, mainly died from infections. Survival, relapse, and infection were all significantly different based on the radiological features. Specifically, the ILD group tends to have a poor long-term prognosis, the PG group is prone to relapse, and the AI group is apt to infection. The AH group has a high risk of both early infection and relapse, thus a poor short-term prognosis. CONCLUSION: AAV patients with diverse radiological features have different clinical characteristics and outcomes. Therefore, the intensity of immunosuppressive therapy must be carefully valued by considering the baseline CT findings among AAV patients with pulmonary involvement.

Diffuse large B-cell lymphoma presenting as reversible intrapulmonary arteriovenous shunts with hypoxia, fever and progressive jaundice: a case report and literature review.

BACKGROUND: Intrapulmonary arteriovenous shunts is rare seen in a patient without lung involvement. CASE PRESENTATION: This is the first report of reversible intrapulmonary arteriovenous shunts secondary to extrapulmonary lymphoma as one initial symptom. The patient presented as fever of unknown origin and dyspnea, and examinations of infection were negative. Diagnosis of DLBCL was finally confirmed through bone marrow and splenic biopsies. Intrapulmonary arteriovenous shunts were diagnosed through 100% oxygen inhalation test and transthoracic contrast echocardiography (TTCE). After the treatment of lymphoma, his respiratory failure was relieved. We rechecked the 100% oxygen inhalation test and TTCE, which both indicated that his intrapulmonary arteriovenous shunts had resolved. CONCLUSIONS: We speculated the prominent inflammation from active DLBCL was the most possible mechanism associated with the reversible intrapulmonary shunt in this patient. These findings will assist us to better understand the mechanism of intrapulmonary shunts.

Renal involvement in a silicosis patient - case report and literature review.

A 43-year-old Chinese man with a silicosis history was admitted to our hospital due to bilateral lower extremity edema for 1 year, exacerbating with hematuria for 2 months. He started working as a coal miner 30 years ago, and was diagnosed as silicosis 3 months ago. Lab tests revealed hematuria 3+, proteinuria 3+, and a serum creatinine value 2.47 mg/dl on routine check. He was diagnosed with focal proliferative IgA nephropathy (IgAN) and acute tubulo-interstitial nephritis by renal biopsy. He was treated with corticosteroids and got a remission 4 months later. Immunohistochemical staining showed the deposition of macrophage receptor with collagenous structure (MARCO), nod-like receptor pyrin domain-containing-3 (NLRP3), Caspase-1, apoptosis-associated speck (ASC), interleukin (IL)-1ß, and IL-18 in both glomerular and tubulo-interstitial areas. We proposed that the silicon exposure could be related to his kidney disease in the patient and NLRP3 mediated inflammation might be involved in its pathogenesis which needs further explorations.

Outcomes and prognostic factors of non-HIV patients with pneumocystis jirovecii pneumonia and pulmonary CMV co-infection: A Retrospective Cohort Study.

BACKGROUND: Pneumocystis jirovecii pneumonia (PJP) and pulmonary cytomegalovirus (CMV) infection are common opportunistic infections among immunocompromised patients. However, few studies have evaluated their co-infection, especially among non-HIV patients. Therefore, we aimed to evaluate the outcomes and prognostic factors among non-HIV patients with PJP according to their CMV infection status. METHODS: This retrospective study evaluated non-HIV patients who were diagnosed with PJP between January 2009 and January2016.The patients were classified and compared according to their pulmonary CMV infection status (positive infection: bronchoalveolar lavage fluid [BALF] CMV DNA loads of >500copies/mL). RESULTS: Among 70 non-HIV patients with PJP, we identified 38 patients (54.3%) with pulmonary CMV infection. There was no significant difference in the mortality rates for the two groups (p = 0.15). Pulmonary CMV infection was significantly more common among patients who were receiving glucocorticoids and immunosuppressants, compared to corticosteroids only (p = 0.02). Pulmonary CMV infection was also significantly associated with severe dyspnea, a lower PaO2/FiO2, and the presence of centrilobular nodules (p = 0.008). Higher CMV DNA loads in the BALF were positively associated with mortality (p = 0.012). CONCLUSIONS: Combined therapy using corticosteroids and other immunosuppressants may be a risk factor for pulmonary CMV co-infection among patients with PJP. In addition, CMV pneumonia should be considered when centrilobular nodules and/or severe hypoxemia are observed in non-HIV patients with PJP. Furthermore, antiviral treatment should be promptly initiated for patients with a high CMV DNA load in BALF, based on their poor prognosis.

Severe pneumonia caused by adenovirus 7 in pregnant woman: Case report and review of the literature.

We report a rare case of adenoviral pneumonia in a previously healthy pregnant woman at 26(+4) weeks' gestation. She presented with persistent high fever, cough for 5 days, and developed progressive dyspnea with hypoxemic respiratory failure and bilateral pulmonary infiltrates with pleural effusions. Aggressive supportive care and timely obstetrical management saved the mother and prevented preterm delivery and fetal anomaly.

Quantitative Real-Time PCR and Platelia Galactomannan Assay for the Diagnosis of Invasive Pulmonary Aspergillosis: Bronchoalveolar Lavage Fluid Performs Better Than Serum in Non-neutropaenic Patients.

The diagnosis of invasive pulmonary aspergillosis (IPA) is still in challenge in clinical practice, particularly for those patients without an obvious neutropaenia. In this study, a well-validated qPCR method and Platelia galactomannan (GM) assay were compared for their diagnostic performance using paired samples of bronchoalveolar lavage (BAL) fluid and serum from predominantly non-neutropaenic patients. In the serum samples, qPCR showed a comparable performance with GM assay in terms of sensitivity and specificity. In the BAL samples, qPCR and GM assay both demonstrated a good sensitivity (90 vs. 90 %); however, the specificity of qPCR was higher than that of GM assay (92.5 vs. 68.8 %, P < 0.001) in these samples. A better sensitivity was obtained with BAL compared with serum samples for both GM assay (90 vs. 50 %) and qPCR (90 vs. 60 %). In conclusion, in non-neutropaenic patients, BAL appears to provide improved sensitivity for both GM and qPCR assays. BAL qPCR offers a better diagnostic value for IPA compared with BAL GM assay, significantly increasing the specificity without affecting the sensitivity.

Clinical and GAA gene mutation analysis in mainland Chinese patients with late-onset Pompe disease: identifying c.2238G > C as the most common mutation.

BACKGROUND: Pompe disease is an autosomal recessive lysosomal glycogen storage disorder that has been reported in different ethnic populations which carry different common mutations of the acid alpha-glucosidase (GAA) gene. The GAA mutation pattern in mainland Chinese patients with late-onset Pompe disease is still not well understood. METHODS: We presented the clinical and genetic characteristics of 27 mainland Chinese late-onset Pompe patients from 24 families. RESULTS: GAA mutation analysis revealed 26 different mutations, including 10 that were novel. The allelic frequency of c.2238G > C (p.W746C) was found to be 27.08% in this patient group. Respiratory dysfunction was diagnosed in 10 of 11 patients who underwent pulmonary function evaluation, although only four required ventilator support at night. CONCLUSIONS: Our findings indicate that c.2238G > C (p.W746C) is the most common mutation in mainland Chinese late-onset Pompe patients, as observed in Taiwanese patients. The novel mutations identified in this study expand the genetic spectrum of late-onset Pompe disease, and the prevalence of respiratory dysfunction highlights the importance of monitoring pulmonary function in late-onset Pompe patients.

Use of 6-minute walk test for assessing severity of interstitial lung disease: an observational study.

BACKGROUND: The 6-minute walk test (6MWT) is a potential tool for assessing the severity of interstitial lung disease (ILD). OBJECTIVES: To explore the relationship between 6MWT results and traditional measures including pulmonary function and chest computed tomography(CT) and to determine factors that might influence the 6-minute walk distance (6MWD). METHODS: Seventy-three patients with ILD were enrolled at Peking University First Hospital. All patients underwent 6MWT, pulmonary CT, and pulmonary function tests and their correlations were analyzed. Multivariate regression analysis was used to identify factors that might impact 6MWD.  Results: Thirty (41.4%) of the patients were female and the mean age was 66.1 ± 9.6 years. 6MWD was correlated with forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), total lung capacity (TLC), diffusing capacity for carbon monoxide (DLCO) and DLCO%pred. The decrease in oxygen saturation (SpO2) after the test was correlated with FEV1%pred, FVC%pred, TLC, TLC%pred, DLCO, DLCO%pred and the percentage of normal lung calculated by quantitative CT. The increase in Borg dyspnea scale was correlated with FEV1, DLCO and the percentage of normal lung. The backward multivariate model (F = 15.257, P < 0.001, adjusted R2 = 0.498) indicated that 6MWD was predicted by age, height, body weight, increase in heart rate, and DLCO. CONCLUSIONS: The 6MWT results were closely correlated with pulmonary function and quantitative CT in patients with ILD. However, in addition to disease severity, 6MWD was also influenced by individual characteristics and the degree of patient effort, which should thus be considered by clinicians when interpreting 6WMT results.

Severe pigeon paramyxovirus 1 infection in a human case with probable post-COVID-19 condition.

Pigeon paramyxovirus 1 (PPMV-1) is an antigenic host variant of avian paramyxovirus 1. Sporadic outbreaks of PPMV-1 infection have occurred in pigeons in China; however, few cases of human PPMV-1 infection have been reported. The purpose of this article is to report a case of severe human PPMV-1 infection in an individual with probable post-COVID-19 syndrome (long COVID) who presented with rapidly progressing pulmonary infection. The patient was a 66-year-old man who was admitted to the intensive care unit 11 days after onset of pneumonia and recovered 64 days after onset. PPMV-1 was isolated from the patient's sputum and in cloacal smear samples from domesticated pigeons belonging to the patient's neighbour. Residual severe acute respiratory syndrome coronavirus 2 was detected in respiratory and anal swab samples from the patient. Sequencing analyses revealed that the PPMV-1 genome belonged to genotype VI.2.1.1.2.2 and had the 112RRQKRF117 motif in the cleavage site of the fusion protein, which is indicative of high virulence. This case of cross-species transmission of PPMV-1 from a pigeon to a human highlights the risk of severe PPMV-1 infection in immunocompromised patients, especially those with long COVID. Enhanced surveillance for increased risk of severe viral infection is warranted in this population.

[Retrospective analysis of relationship between radiological features and prognoses of pneumocystis pneumonia in non-AIDS immunocompromised patients].

OBJECTIVE: To elucidate the relationship between the radiological features and prognoses of pneumocystis pneumonia (PCP) in non-acquired immunodeficiency syndrome (non-AIDS) immunocompromised patients. METHODS: Retrospective analyses were performed for the radiological features and prognoses of 36 non-AIDS immunocompromised PCP patients hospitalized at Peking University First Hospital from April 2006 to April 2010. There were 24 males and 12 females with an average age of (51.7 ± 18.9) years. RESULTS: All patients underwent chest photographic examinations and chest computed tomography (CT) was performed on 29 of them. The overall case fatality rate (CFR) of 36 patients was 33.3% (12/36). At the start of anti-PCP treatment, there were normal chest radiography (n = 7), bilateral diffuse infiltration (n = 21), bilateral diffuse consolidation (n = 8), aerothorax, mediastinal emphysema or pneumohypoderma (n = 6) and numbers of deceased patients (n = 0, 8, 5 and 5 respectively). The CFRs of the patients with normal chest radiography and aerothorax, mediastinal emphysema or pneumohypoderma were both statistically significant as compared with the overall rate (P < 0.05). At the start of anti-PCP treatment, there were bilateral diffuse ground glass opacities (GGO) (n = 29), "mosaic sign" (n = 19), air bronchogram (n = 19), pulmonary consolidation (n = 17), bilateral pleural effusion (n = 7), thickened lobular septa (n = 6), cystic lesions (n = 5), aerothorax, mediastinal emphysema or pneumohypoderma (n = 4) and numbers of deceased patients (n = 8, 5, 5, 5, 2, 2, 2 and 4 respectively). The CFRs of the patients with aerothorax, mediastinal emphysema or pneumohypoderma were statistically significant as compared with the overall rate (P < 0.05). CONCLUSIONS: The major radiological features of PCP in non-AIDS immunocompromised patients are bilateral diffuse infiltration. And bilateral diffuse GGO on chest CT scans are usually accompanied with "mosaic" sign, air bronchogram or pulmonary consolidation. The prognoses are excellent for the patients with normal chest radiograph and poor for those with aerothorax, mediastinal emphysema or pneumohypoderma.

A 44-Year-Old Man With Right Limb Convulsion and Cavitary Lung Lesion With Diffuse Interstitial Abnormalities.

CASE PRESENTATION: A 44-year-old man with a history of asthma presented with intermittent convulsion of the right limb, fever in the late afternoon, and decreased exercise tolerance over 2 months. Occasional productive cough, no hemoptysis, and weight loss of nearly 6 kg were observed during this period. Neither chemotherapy nor oral immunosuppressive drugs had been administered, and no exposure to toxic substances was known. He was a cook and had smoked approximately one pack of cigarettes per day for the past 20 years. The living environment was relatively humid. The patient presented to a local hospital, where the workup was notable for low-density shadows in the left parieto-occipital lobe and a cavity in the right upper lobe of the lung with bilateral diffuse interlobular septal thickening and multiple patchy ground-glass opacities. The brain and lung lesions were 18F-fluorodeoxyglucose avid on PET/CT scan. Bronchoscopy with BAL and transbronchial biopsy were nondiagnostic. While preparing for another diagnostic procedure, the patient gradually developed increasing dyspnea and more frequent convulsions with the progression of lesions on the follow-up chest CT scan. The patient was transferred to our hospital.

Scoliosis Orthopedic Surgery Combined With Nusinersen Intrathecal Injection Significantly Improved the Outcome of Spinal Muscular Atrophy Patient: A Case Report.

Background: Spinal muscular atrophy (SMA) is an autosomal recessive disorder caused by pathogenic variation of the survival motor neuron (SMN) 1 gene. Symptoms of SMA include progressive limb muscle weakness, atrophy, and severe scoliosis. Nusinersen is an antisense oligonucleotide that can enhance the production of the SMN protein. Here, we report a case with scoliosis who received orthopedic surgery combined with Nusinersen intrathecal injections. Case Presentation: Scoliosis orthopedic surgery followed by Nusinersen intrathecal injections was given to a 16-year-old girl who had thoracic and lumbar scoliosis and type 3 SMA. Surgery was performed for T3-S2 posterolateral fusion (PLF), with a channel left on the vertebral laminae of L3-L4. The balance of the spine and pelvis was significantly improved and the height increased by 9 cm. Lumbar puncture was conducted with local anesthesia under ultrasound and CT guidance through the laminae channel and Nusinersen was successfully injected. Comparing the two approaches, real-time ultrasound guidance for intrathecal Nusinersen injections after spinal surgery is preferred, however, CT guidance is an alternative if the initial puncture procedure is difficult. After the aforementioned multidisciplinary treatment, a good outcome was achieved, as demonstrated by a 2-point increase in RULM and MFM32 scores 2 months later. Conclusion: Scoliosis orthopedic surgery combined with Nusinersen intrathecal injection is an effective treatment for SMA patients with scoliosis.

Novel SEPN1 Mutations in Exon 1 Are Common in Rigid Spine With Muscular Dystrophy Type 1 in Chinese Patients.

Congenital muscular dystrophy with early rigid spine, also known as the rigid spine with muscular dystrophy type 1 (RSMD1), is caused by SEPN1 mutation. We investigated the clinical manifestations, pathological features, and genetic characteristics of 8 Chinese RSMD1 patients in order to improve diagnosis and management of the disease. Eight patients presented with delayed motor development, muscle weakness, hypotonia, and a myopathic face with high palatine arches. All patients could walk independently, though with poor running and jumping, and most had a rigid spine, lordosis, or scoliosis. The symptoms of respiratory involvement were present early, and upper respiratory tract infections and pneumonia often occurred. Five patients had severe pneumonia, pulmonary hypertension, and respiratory failure. Lung function tests showed variable restrictive ventilation dysfunction. Polysomnography suggested hypoxia and hypoventilation. The serum creatine kinase (CK) level was normal or mildly increased. Muscle biopsy indicated chronic myopathic changes and minicores. Muscle magnetic resonance imaging (MRI) showed diffuse fatty infiltration of the gluteus maximus and thigh muscle. SEPN1 gene analysis revealed 16 compound heterozygous variants, 81.3% of which are unreported, including 7 exon 1 variants. Our study expands the spectrum of clinical and genetic findings in RSMD1 to improve diagnosis, management, and standards of care. SEPN1 mutations in exon 1 are common and easily missed, and exon 1 should be carefully analyzed when RSMD1 is suspected, which will provide valuable genetic counseling for the family and useful information for future natural history studies and clinical trials.

Ceramide metabolism mediates the impaired glucose homeostasis following short-term black carbon exposure: A targeted lipidomic analysis.

BACKGROUND: Ambient particulate matter (PM), especially its carbonaceous composition black carbon (BC) increases cardiometabolic risks, yet the underlying mechanisms are incompletely understood. Ceramides (Cer; a class of sphingolipids) are biological intermediates in glucose metabolism. OBJECTIVES: To explore whether Cer metabolism mediates impaired glucose homeostasis following short-term PM exposure. METHODS: In a panel study in Beijing, China, 112 participants were followed-up between 2016 and 2017. Targeted lipidomic analyses quantified 26 sphingolipids in 387 plasma samples. Ambient BC and PM with aerodynamic diameter ≤ 2.5 µm (PM2.5) were continuously monitored in a station. We examined the associations of sphingolipid levels with average BC and PM2.5 concentrations 1-14 days before clinical visits using linear mixed-effects models, and explored the mediation effects of sphingolipids on PM-associated fasting blood glucose (FBG) difference using mediation analyses. RESULTS: Increased levels of FBG and multiple sphingolipids in Cer metabolic pathways were associated with BC exposure in 1-14-day time window, but not with PM2.5 exposure. For each 10 µg/m3 increase in the average BC concentration 1-14 days before the clinical visits, species in the Cer C24:1 pathway (Cer, dihydroceramide, hexosylceramide, lactosylceramide, and sphingomyelin C24:1) increased in levels ranging from 11.8% (95% confidence interval [CI]: -6.2-33.2) to 48.7% (95% CI: 8.8-103.4), as did the Cer C16:0, C18:0, and C20:0 metabolic pathway species, ranging from 3.2% (95% CI: -5.6-12.9) to 32.4% (95% CI: 7.0-63.8), respectively. The Cer C24:1 metabolic pathway species mediated 6.5-25.5% of the FBG increase associated with BC exposure in 9-day time window. The Cer C16:0, C18:0, and C20:0 metabolic pathway species mediated 5.4-26.2% of the BC-associated FBG difference. CONCLUSIONS: In conclusion, Cer metabolism may mediate impaired glucose homeostasis following short-term BC exposure. The current findings are preliminary, which need to be corroborated by further studies.

Transcriptional pathways of elevated fasting blood glucose associated with short-term exposure to ultrafine particles: A panel study in Beijing, China.

There is growing concern about the strong health effects of ultrafine particles (UFPs). However, less is known about the biological mechanisms. The objective of this study is to examine the association between short-term exposure to UFPs and fasting blood glucose (FBG) levels, and explore the potential physiological mechanisms at transcriptional levels. In a panel study of 135 participants, we measured FBG and the whole blood transcriptome repeatedly. The concentrations of ambient air pollutants were monitored continuously at a station. Linear mixed-effects models coupled with a mediating effect model were used to discriminate transcripts associated with air pollutant exposure and ln-transformed FBG levels. We found that FBG was significantly associated with interquartile range increase in the average UFPs concentrations 1-13 d prior to the clinical visits (ranging from 5.1% [95% CI 2.0-8.1%] in the 1-d time-window to 12.1% [95% CI 6.5-17.8%] in the 13-d time-window). Top 1000 transcripts associated with FBG increase following UFPs exposure were enriched into some biological pathways, such as pro-opiomelanocortin processing, negative regulation of hypoxia-inducible factor 1 A function, ubiquinone metabolism, and antigen presentation by major histocompatibility complex class I, classical pathway. These results suggest that elevated FBG associated with UFPs exposure may be related to regulation of metabolism, immune response, DNA damage, and apoptosis and survival.