Age Of Onset In Patients Research Articles

A Novel Homozygote Pathogenic Variant in the DIAPH1 Gene Associated With Seizures, Cortical Blindness, and Microcephaly Syndrome (SCBMS): Report of a Family and Literature Review.

Mammalian Diaphanous-Related Formin (mDia1), which is encoded by the DIAPH1 gene, serves as essential for the regulation of cell morphology and cytoskeletal organization. The role of DIAPH1 in brain development has been extensively established. This study aims to evaluate the clinical, neuroradiological, and genetic characteristics of patients with DIAPH1-related disease and determine probable genotype-phenotype relationships. In the current study, exome sequencing was performed to identify the genetic basis of the clinical presentation in an Iranian 7-year-old boy. Validation of the detected variant was done by Sanger sequencing. Furthermore, we performed a comprehensive review of the literature. Here, we detected a novel homozygous c.1285C> T (p.Gln429*) pathogenic variant in the patient. In silico analysis with prediction software tools identified this variant as a probable source of damage. Twenty cases from seven studies were found after a review of the literature. The patients' main symptoms were a developmental delay, microcephaly, and seizures. The mean age of onset for patients in the group of 20 patients with a known age of onset was 2.3 months (SD = 1.6). Of the variants identified, c.2769del, c.684+1G>A, and c.2332C> T were identified in 72% of the patients. Considering the variant's position in the gene and the encoding protein, a pathogenic effect is predicted for the variant. So, the patient's clinical manifestation is probably caused by this pathogenic variant. Moreover, by studying clinical manifestations in all molecularly confirmed reported cases, provided a comprehensive overview of clinical presentation, and attempted to find a genotype-phenotype correlation.

Differential Diagnosis of Pathological Type of Peripheral Lung Cancer with Multimodal Contrast-Enhanced Ultrasound

ObjectiveThe goal of the work described here was to investigate the role of multimodal contrast-enhanced ultrasound in the differential diagnosis of peripheral lung cancer. MethodsFrom April 2017 to July 2021, 109 patients with confirmed pulmonary malignant lesions who underwent CEUS examination were involved in our study. Seven patients were excluded because of the short duration of CEUS video or unsatisfactory imaging. Finally,102 patients with peripheral lung cancer were enrolled in this study. The maximum diameter of the lesions ranged from 1.6 to 13.0 cm (mean 6.2 ± 2.3 cm). On the basis of the pathological results, the patients were divided into the small cell lung cancer (SCLC) group and non-small cell lung cancer (NSCLC) group (including adenocarcinoma, lung squamous cell carcinoma and large cell neuroendocrine carcinoma). A Logiq E9 ultrasonic machine equipped with a 3.5 to 5.0 MHz C5-1 probe was used. Patient clinical information, CEUS features, CPI patterns and TIC parameters were analyzed and compared between different groups. Statistical analyses were performed with SPSS software and MedCalc software. The receiver operating characteristic curve was plotted. ResultsIn the differential diagnosis of SCLC and NSCLC, color parametric imaging indicated great performance. NSCLC exhibited a centripetal enhancement pattern more frequently (72.7%), while SCLC exhibited an eccentric enhancement pattern more frequently (92.9%) (p < 0.001). In the differential diagnosis of adenocarcinoma and squamous cell carcinoma, logistic regression analysis revealed that patient age of onset ≤60 y, difference in arrival time between lung and tumor ≤3.8 s, drop time of the time–intensity curve >23.2 s and absence of internal necrosis on CEUS were independent predictors for adenocarcinoma (area under the curve = 0.861). ConclusionIn our study, multimodal contrast-enhanced ultrasound provided useful information in the differential diagnosis between small cell lung cancer and non-small cell lung cancer, especially between adenocarcinoma and squamous cell carcinoma.

Inverse correlation between age of onset and myocardial amyloid deposition quantified by 99mTc-PYP scintigraphy in patients with wild-type transthyretin amyloid cardiomyopathy.

Wild-type transthyretin amyloidosis cardiomyopathy (ATTRwt-CM) is increasingly recognized as a contributing factor to cardiac insufficiency in the elderly population. We aimed to identify the factors affecting age of onset of ATTRwt-CM, encompassing the assessment of amyloid deposition in myocardial tissue through the use of 99mTc-pyrophosphate (PYP) and clinical parameters. A retrospective investigation involving a consecutive cohort of 107 cases, each having been diagnosed with ATTRwt-CM confirmed through histopathological and genetic analysis, was performed. All patients underwent PYP scintigraphy, and the heart-to-contralateral (H/CL) ratio was calculated to measure amyloid deposition in the myocardium. Univariate and multivariate analyses were performed to identify independent predictors of the age of onset of ATTRwt-CM, considering the H/CL ratio and various clinical risk factors for heart failure. Gender (p = 0.03), Creatinine (Cr) (r = 0.32, p < 0.01), hemoglobin (Hb) (r = - 0.44, p < 0.01), albumin (Alb) (r = - 0.32, p < 0.01), brain natriuretic peptide (BNP) (r = 0.21, p = 0.03), low-density lipoprotein-cholesterol (LDL-C) (r = - 0.27, p < 0.01), and H/CL ratio (r = - 0.44, p < 0.01) were all significantly associated with the onset age. In multiple regression analysis, the independent predictive factors for the onset age of ATTRwt-CM were identified as the H/CL ratio (p < 0.01), Hb (p < 0.01), and Cr (p < 0.01). The H/CL ratio, Hb, and Cr independently affect age of onset in patients with ATTRwt-CM. The H/CL ratio is inversely correlated with age of onset, and may be the sole factor in the development of heart failure in early onset patients, while it may have a synergistic effect on heart failure with anemia and renal dysfunction in late-onset patients.

Smoking and pathogenic germline variants in patients with lung cancer.

8040 Background: Few studies have investigated the correlation of smoking history with pathogenic germline variants (PGVs) in patients diagnosed with lung cancer. With emerging opportunities for PGVs in DNA damage-repair (DDR) genes to inform precision therapies, we investigated the prevalence of PGVs in patients with lung cancer, stratified by smoking status. Methods: Germline genetic testing (GGT) (Invitae Corp.) and insurance claims (Komodo Healthcare MapTM) data were reviewed for 14,317 patients with an ICD code for lung cancer from 2015-2023 and hereditary cancer GGT of ≥ 10 genes. PGV rates were assessed overall, in DDR genes and in lung cancer related genes. Smoking history was defined by ICD codes. Number of genes tested varied per ordering clinician preference. Clinically actionable PGVs were defined as those associated with clinical management recommendations or trial eligibility per current standard of care guidelines. Chi-square tests were used with significance set to p &lt; 0.05. Results: The cohort was predominantly female (70.9%), white (65.7%), and over half had a history of smoking (57.1%). PGVs in 73 known cancer-risk genes were identified in 1,804/14,317 (12.6%) patients. Frequencies of PGV were 12.6% (1,026/8,175) in patients with smoking history compared to 12.7% (778/6,142) in those with no reported smoking history. There was no statistically significant difference in DDR gene, TP53, or EGFR PGV rates for patients with or without smoking history (p &gt; 0.05). Mean (SD) age of lung cancer diagnosis was significantly younger for patients with a history of smoking and DDR PGVs (61 (11)) compared to those with negative results (62 (12), p = 0.005). There was no significant difference in age of diagnosis between patients with no smoking history and DDR PGVs (60 (12)) and those with negative results (59 (13), p = 0.888). PGV rates by clinician-reported ancestry: Black/African-American, 9%; Asian or Pacific Islander, 11%; Hispanic, 12%; White, 13%. Among genes with &gt; 1,000 patients tested, PGVs were most common in BRCA2 (2.2%), CHEK2 (2.0%), ATM (1.6%), SPINK1 (1.6%), and BRCA1 (1.2%). Conclusions: In 14,317 patients with lung cancer, 12.6% had PGVs. There was no significant difference in enrichment of PGVs in DDR genes when patients were stratified by reported smoking history, suggesting the enrichment of these genes is independently associated with lung cancer. The age of onset for patients with DDR gene PGVs varied with smoking history, suggesting that risk conferred by these PGVs could be additive to smoking risk. These data reinforce prior studies supporting consideration of GGT for all patients with lung cancer, independent of age or reported smoking history.

Clinical features and mutational spectrum of Chinese patients with primary hyperoxaluria type 2.

Primary hyperoxaluria type 2 (PH2) is a rare hereditary disease that causes nephrolithiasis, nephrocalcinosis and kidney failure. This study aimed to investigate the clinical features and mutational spectrum of Chinese patients with PH2. A retrospective cohort study was performed on PH2 patients admitted to our center over seven years. We also systematically reviewed all the articles on Chinese PH2 patients published from January 2000 to May 2023 and conducted a meta-analysis. A total of 25 PH2 patients (10 from our center and 15 from published studies) were included in this study. The median age of onset in patients from our center was 8.50 (1.00, 24.00) years, and 50% were male. Among the full cohort of 25 Chinese patients, the median age of onset was 8.00 (0.40, 26.00) years, and 64% of them were male. Seven patients progressed to end-stage kidney disease, with a median age of 27.50 (12, 31) years. The cumulative renal survival rates were 100%, 91.67%, 45.83% and 30.56% at 10, 20, 30 and 40 years of age, respectively. A total of 18 different variants were identified, and c.864_865del was the dominant variant, accounting for 57.69% of the total alleles. Patients who were heterozygous for c.864_865del were more susceptible to nephrocalcinosis than those who were homozygous for c.864_865del and those harboring other mutations (83.33% versus 33.3% and 0%, respectively) (p = 0.025). The clinical features and mutational spectrum of Chinese PH2 patients were described. This study helps to expand awareness of the phenotypes and genotypes of Chinese PH2 patients and contributes to the improvement of diagnostic and treatment strategies for PH2 patients.

Cortical Microhemorrhage Presentation of Small Vessel Primary Angiitis of the Central Nervous System.

Primary angiitis of the central nervous system (PACNS) is a rare vasculitis restricted to the brain, spinal cord, and leptomeninges. This study aimed to describe the imaging characteristics of patients with small vessel PACNS (SV-PACNS) using 7 T magnetic resonance imaging (MRI). This ongoing prospective observational cohort study included patients who met the Calabrese and Mallek criteria and underwent 7 T MRI scan. The MRI protocol includes T1-weighted magnetization-prepared rapid gradient echo imaging, T2 star weighted imaging, and susceptibility-weighted imaging. Two experienced readers independently reviewed the neuroimages. Clinical data were extracted from the electronic patient records. The findings were then applied to a cohort of patients with large vessel central nervous system (CNS) vasculitis. We included 21 patients with SV-PACNS from December 2021 to November 2023. Of these, 12 (57.14%) had cerebral cortical microhemorrhages with atrophy. The pattern with microhemorrhages was described in detail based on the gradient echo sequence, leading to the identification of what we have termed the "coral-like sign." The onset age of patients with coral-like sign (33.83 ± 9.93 years) appeared younger than that of patients without coral-like sign (42.11 ± 14.18 years) (P = 0.131). Furthermore, the cerebral lesions in patients with cortical microhemorrhagic SV-PACNS showed greater propensity toward bilateral lesions (P = 0.03). The coral-like sign was not observed in patients with large vessel CNS vasculitis. The key characteristics of the coral-like sign represent cerebral cortical diffuse microhemorrhages with atrophy, which may be an important MRI pattern of SV-PACNS. ANN NEUROL 2024;96:194-203.

Analysis of characteristics of movement disorders in patients with anti-N-methyl-D-aspartate receptor encephalitis.

Movement disorders (MDs) are common in anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis but are poorly studied. This study aimed to investigate the clinical characteristics of MDs and the clinical differences between patients with and without MDs in anti-NMDAR encephalitis. A retrospective study was conducted on patients with anti-NMDAR encephalitis who were first diagnosed and treated in the First People's Hospital of Yunnan Province from January 2017 to September 2022. According to the presence or absence of MDs, all patients were divided into two groups, and the clinical manifestations, auxiliary examinations, and prognosis of the two groups were compared. Patients in the MDs group were further subgrouped by different ages (<12 years, 12-17 years, and ≥ 18 years) and genders, and the prevalence of each MD was compared in different age and gender groups. (1) In our study there were 64 patients, of whom 76.6% (49/64) presented with MDs; the median age of onset in patients with MDs was 21 (15,35) years and 65.3% (32/49) were female. The three most common MDs were orofacial dyskinesia (OFLD) (67.3%), dystonia (55.1%), and stereotypies (34.7%). Patients <12 years were more likely to experience chorea than patients in other age groups (p = 0.003). (2) Compared with the non-MDs group, patients in the MDs group showed higher rates of prodromal manifestations, autonomic dysfunction, consciousness disorders, as well as pulmonary infection and gastrointestinal dysfunction (all p < 0.05). Peripheral blood neutrophil to lymphocyte ratio (NLR) (p = 0.014), the proportion of cerebrospinal fluid (CSF) NMDAR antibody titers ≥1:32 (p = 0.047), ICU admission rate (p = 0.04), length of stay (p = 0.007), maximum mRS score in the course of disease (p = 0.001) and mRS score at discharge (p = 0.006) in the MDs group were significantly higher than the non-MDs group. MDs associated with anti-NMDAR encephalitis were predominantly hyperkinetic. Chorea occurred more commonly in patients aged <12 years. Patients with MDs were prone to autonomic dysfunction, consciousness disorders, pulmonary infection, and gastrointestinal dysfunction; they had more intense inflammation, more severe disease, and a poorer short-term prognosis.

Cancer-associated neuromyelitis optica spectrum disorder: a case report with literature review.

Neuromyelitis optica spectrum disorders (NMOSD) is one of autoimmune inflammatory diseases and is characterized by area postrema syndrome, brainstem syndrome, optic neuritis, and/or myelitis. Typical myelitis is longitudinally extended transverse myelitis (LETM) which extends over three vertebral bodies. Several previous case reports have suggested association between cancer and NMOSD. A 50-year-old woman had breast cancer and underwent mastectomy and, 10 months later, she had developed acutely progressive dysbasia. Spine MRI showed LETM in 13 vertebrae length and blood test revealed positive anti-aquaporin 4 (anti-AQP4) antibody based on enzyme-linked immunosorbent assay with index of over 40. She was treated by intravenous methylprednisolone, plasma exchange, and intravenous immunoglobulin, followed by oral prednisolone. The condition had mostly recovered after the treatment. A small population of NMOSD has the aspect of paraneoplastic neurological syndrome. The age of onset in patients with cancer-associated NMOSD tends to be higher than that in individuals with NMOSD due to any causes of NMOSD.

Potential Modifying Effect of the APOEε4 Allele on Age of Onset and Clinical Manifestations in Patients with Early-Onset Alzheimer's Disease with and without a Pathogenic Variant in PSEN1 in a Sample of the Mexican Population.

In Alzheimer's disease (AD), the age of onset (AoO) exhibits considerable variability, spanning from 40 to 90 years. Specifically, individuals diagnosed with AD and exhibiting symptoms prior to the age of 65 are typically classified as early onset (EOAD) cases. Notably, the apolipoprotein E (APOE) ε4 allele represents the most extensively studied genetic risk factor associated with AD. We clinically characterized and genotyped the APOEε4 allele from 101 individuals with a diagnosis of EOAD, and 69 of them were affected carriers of the autosomal dominant fully penetrant PSEN1 variant c.1292C>A (rs63750083, A431E) (PSEN1+ group), while there were 32 patients in which the genetic cause was unknown (PSEN1- group). We found a correlation between the AoO and the APOEε4 allele; patients carrying at least one APOEε4 allele showed delays, in AoO in patients in the PSEN1+ and PSEN1- groups, of 3.9 (p = 0.001) and 8.6 years (p = 0.012), respectively. The PSEN1+ group presented higher frequencies of gait disorders compared to PSEN1- group, and apraxia was more frequent with PSEN1+/APOE4+ than in the rest of the subgroup. This study shows what appears to be an inverse effect of APOEε4 in EOAD patients, as it delays AoO and modifies clinical manifestations.

Clinical features and prognostic factors in 49 patients with follicular lymphoma at a single center: A retrospective analysis

Follicular lymphoma (FL) is a type of B-cell lymphoma that originates at the germinal center and has a low malignancy rate. FL has become the most common inert lymphoma in Europe and America but has a relatively low incidence in Asia. To explore the clinical features, curative effects, and prognostic factors of FL. Completed medical records of 49 patients with FL who were admitted to the Ningbo First Hospital from June 2010 to June 2021 were examined. These patients were definitively diagnosed by pathological biopsy or immunohistochemical staining. The diagnostic criteria were based on the 2008 World Health Organization classification of lymphomas. Ann Arbor staging was performed according to the imaging and bone marrow examination results. Risk stratification of all patients was performed based on the International Prognostic Index (IPI), age-adjusted IPI, Follicular Lymphoma International Prognosis Index (FLIPI), and FLIPI2 to compare the efficacy of different treatment regimens and analyze the related prognostic factors. The age of onset in patients ranged from 24 to 76 years, with a median age of 51 years. Most patients developed the disease at 40-59 years of age, and the male:female ratio was 1.6:1. No significant difference was noted in the curative effect between the non-chemotherapy, combined chemotherapy, and other chemotherapy regimens (P > 0.05). Hemoglobin (Hb) level < 120 g/L, Ki-67 value > 50%, bone marrow involvement, and clinical stages III-IV were associated with a poor prognosis of FL (P < 0.05). However, the influence of other indicators was not statistically significant. Risk grouping was performed using the FLIPI, and the results showed that 24.5%, 40.8%, and 34.7% of patients were in the low-, moderate-, and high-risk groups, respectively. According to the survival analysis results, the survival rate of patients was lower in the high-risk group than in the other low-risk and moderate-risk groups (P < 0.05). FL mainly occurs in middle-aged and elderly men, primarily affecting lymph nodes and bone marrow. Hb level, Ki-67 value, bone marrow involvement, and clinical staging were used to evaluate prognosis.

Worldwide epidemiologic factors in pemphigus vulgaris and bullous pemphigoid.

Autoimmune blistering diseases such as bullous pemphigoid (BP) and pemphigus vulgaris (PV) are complex, multifactorial, and polygenic diseases, whose exact pathogenesis is difficult to pinpoint. Research aimed at elucidating the associated epidemiologic risk factors of these two diseases has been hampered by their rare disease status. Further, a lack of centralization and standardization of available data makes the practical application of this information challenging. In order to collate and clarify the available literature we comprehensively reviewed 61 PV articles from 37 different countries and 35 BP articles from 16 different countries addressing a range of disease relevant clinical parameters including age of onset, sex, incidence, prevalence, and HLA allele association. The reported incidence of PV ranged from 0.098 to 5 patients per 100,000 people, while BP ranged from 0.21 to 7.63 patients per 100,000. Prevalence of PV ranged from 0.38 to 30 per 100,000 people and BP ranged from 1.46 to 47.99 per 100,000. The mean age of onset in patients ranged from 36.5 to 71 years for PV and 64 to 82.6 years for BP. Female-to-male ratios ranged from 0.46 to 4.4 in PV and 1.01 to 5.1 in BP. Our analysis provides support for the reported linkage disequilibrium of HLA DRB1*0402 (an allele previously shown to be associated with PV) and DQB1*0302 alleles in Europe, North America, and South America. Our data also highlight that HLA DQB1*0503 (also known to be associated with PV) appears in linkage disequilibrium with DRB1*1404 and DRB1*1401, mainly in Europe, the Middle East, and Asian countries. The HLA DRB1*0804 allele was only associated with PV in patients of Brazilian and Egyptian descent. Only two HLA alleles were reported as associated with BP more than twice in our review, DQB1*0301 and DQA1*0505. Collectively, our findings provide detailed insights into the variation of disease parameters relevant to PV and BP that can be expected to inform future work aimed at unraveling the complex pathogenesis of these conditions across the globe.

The articular and the craniocervical abnormalities are of confusing age of onset in patients with Maroteaux-Lamy disease (MPS VI).

Maroteaux-Lamy disease (MPS Type VI) is an autosomal recessive lysosomal storage disorder. Skeletal abnormalities are vast. Early recognition may facilitate timely diagnosis and intervention, leading to improved patient outcomes. The most challenging is when patients manifest a constellation of craniocervical and articular deformities with variable age of onset. We collected 15 patients with MPS VI (aged from 6 years-58 years). From within our practice in Pediatric Orthopedics, we present patients with MPS type VI who were found to manifest a diverse and confusing clinical presentation of hip deformities and cervical cord compression. Stem cell transplants were proposed as treatment tool and enzyme replacement therapy has been instituted in some patients. The spectrum of the clinical involvement in our group of patients was supported firstly via the clinical phenotype followed by assessment of the biochemical defect, which has been detected through the deficiency of N-acetylgalactosamine-4-sulfatase (arylsulphatase B) leading to increased excretion of dermatan sulphate. Secondly, through the molecular genetic results, which showed homozygous or compound heterozygous mutation in the ARSB gene on chromosome 5q14. Hip replacements and decompression operations have been performed to restore function and to alleviate pain in the former and life saving procedure in the latter. The efforts in searching for the etiological diagnosis in patients with skeletal dysplasia/MPSs has not been rewarding as many had anticipated. This emerged from several facts such as improper clinical documentation, missing diagnostic pointers in radiographic interpretations, limited knowledge in skeletal dysplasia and its variants, and the reliance on underpowered studies. Physicians and radiologists are required to appreciate and assess the diverse phenotypic and the radiographic variability of MPS VI. The importance of considering MPS in the differential diagnosis of other forms skeletal dysplasia is mandatory. Finally, we stress that the value of early diagnosis is to overcome dreadful complications.

Cerebral cortical thinning in Parkinson's disease depends on the age of onset.

Patients with older-onset Parkinson's disease (PD) have more severe motor symptoms, faster progression, and a worse prognosis. The thinning of the cerebral cortex is one of the causes of these issues. Patients with older-onset PD manifest more extended neurodegeneration associated with α-synuclein deposition in the cerebral cortex; however, the cortical regions that undergo thinning are unclear. We aimed to identify cortical regions with different thinning depending on the age of onset in patients with PD. Sixty-two patients with PD were included in this study. Patients with PD onset at <63 years old were included in the early or middle-onset PD group, and those with PD onset at >63 years old were included in the late-onset PD (LOPD) group. Brain magnetic resonance imaging data of these patients were processed using FreeSurfer to measure their cortical thickness. The LOPD group displayed less cortical thickness in the superior frontal gyrus, middle frontal gyrus, precentral gyrus, postcentral gyrus, superior temporal gyrus, temporal pole, paracentral lobule, superior parietal lobule, precuneus, and occipital lobe than the early or middle-onset PD group. Compared with patients with early and middle-onset PD, elderly patients displayed extended cortical thinning with disease progression. Differences in the clinical manifestations of PD according to the age of onset were partly due to variations in the morphological changes in the brain.

Recurrent Benign Paroxysmal Positional Vertigo in DFNB16 Patients with Biallelic STRC Gene Deletions.

Deletions of STRC gene (DFNB16) account for 12% of isolated congenital mild to moderate hearing loss (HL). In mice, the stereocilin protein, encoded by STRC , is present in the vestibular kinocilium embedded in the otoconial membrane of the utricular macula. Despite this, effects on vestibular function have not been widely investigated. The aim of this study was to investigate the prevalence of benign paroxysmal positional vertigo (BPPV) in a cohort of DFNB16 patients. Observational descriptive epidemiological study. Single-center study, in a tertiary referral center. Older than 5 years, with a genetic diagnosis of HL related to biallelic STRC gene deletions, diagnosed between 2015 and 2021. Patients or their parents were interviewed to determine whether they had experienced vertigo or episodes of BPPV. Criteria were at least five acute episodes of rotatory vertigo, each lasting less than 1 minute, episodes triggered by changes in specific head position, and an absence of neurological symptoms. Sixty-four patients having mild (33%) to moderate (66%) HL were included. Median age was 15 years (range, 6-48 yr). Prevalence of BPPV was 39% (25 of 64). Median age of first onset was 13 years (range, 3-18 yr). This study showed recurrent BPPV and early age of onset in patients with biallelic STRC gene deletions. BPPV may be associated with the HL phenotype in patients with STRC gene deletions. It is important to inform patients and families of this potential risk such that appropriate management can be proposed.

Maternal family history of urolithiasis is associated with earlier age of onset of stone disease.

To evaluate the impact of detailed family history on the severity of disease and age of onset in patients with urolithiasis. Prospectively collected data from a single institution between October 2015 and December 2020 were analyzed. Our primary endpoint was the number of patients experiencing at least one recurrent stone during the follow-up period. Of 1566 patients analyzed, 603 (39%) reported at least one family member with a history of stones. The percentage of patients experiencing at least one recurrent stone event was higher in patients with a family history of stones (38%) compared to those without a family history of stones (28%) over a median follow-up period of 8months (p = 0.001). On multivariate analysis, the presence of any family history of urolithiasis increased risk of recurrent stone events (odds ratio [OR] 1.62, p < 0.001). The presence of both a first- and a second-degree relative with urolithiasis was associated with higher odds for a recurrent stone event (OR 2.17; p = 0.003) and a younger age of onset for stones, (OR 3.32; < 0.001). A maternal-side relative with stones conferred a higher odds ratio for younger age of first onset of stones (OR 2.93; p < 0.001). Any family history of kidney stone disease imparts an increased risk of recurrent stone event and an earlier age of onset for urolithiasis. The presence of both first- and second-degree relatives or a maternal-side relative with kidney stones may be a predictor for an earlier age of onset for urolithiasis.

Association of podocyte injury with clinical features and prognosis in patients with mesangial proliferative lupus nephritis.

The aim of this study is to explore the association of podocyte injury with clinical features and outcomes in mesangial proliferative (Class II) lupus nephritis (LN). We conducted a retrospective and clinicopathologic analysis with 576 LN patients with renal biopsy and screened 58 patients with Class II LN. Then, the 58 cases were divided into 4 groups based on the degree of podocyte damage and immune complex (IC) deposits on light microscope (histological and immunofluorescence) and electron microscope: Podocyte Injury Group, IC deposits Group, Podocyte Injury and IC Group, and Less-lesion Group. Clinical and pathologic information was collected from the patients' medical records at the time of the kidney biopsy and at follow-up. The data of demography, clinical parameters, therapy, remission, and relapse rates were analyzed and compared across groups. A significant difference was observed in the ages of patients among four Class II LN groups. The onset age of patients with FPE ≥ 50% was significant later. The frequency of thrombocytopenia was statistically different among the four groups and the patients with FPE ≥ 50% had lower frequency of thrombocytopenia. Patients with FPE ≥ 50% had lower serum albumin, eGFR, and elevated proteinuria and serum lipids. In this study, most patients received glucocorticoids in combination with immunosuppressants. Among the 4 groups, the use of ACEI/ARBs was highest in the podocyte injury group. There was a statistical difference in the renal relapse rates among the 4 Class II LN groups. Moreover, the recurrence rate was higher in the FPE ≥ 50% group. Our data identified Class II LN patients with podocyte injury (FPE ≥ 50%) present prominent renal damage and higher rate of renal relapse, suggesting more aggressive treatment and close follow-up for these patients.

HLA Class I Allele-Specific Pathology Defines Clinical Manifestations of Immune Aplastic Anemia

Leukocytes that have lost the cell surface expression of an HLA class I allele due to somatic HLA gene mutations or 6p loss of heterozygosity (LOH) are often present in patients with immune aplastic anemia (AA), consistent with T cell-mediated bone marrow cell destruction. A recent NIH study suggested that the clinical significance and underlying pathology of HLA loss may differ according to the type of HLA allele affected (Zaimoku et al. Blood 2021) because (1) the significant correlation of HLA loss with clonal evolution was primarily attributed to patients who lost HLA-B*14:02 and A*02:01; (2) all patients who lost B*40:02 and A*02:06 achieved a hematologic response to immunosuppressive therapy (IST), though HLA loss in general was not correlated with the IST response; (3) loss of B*07:02 and B*40:01 was associated with older age of onset; (4) patients who retained B*14:02, B*07:02, and B*40:01 also showed clinical features of patients who lost respective HLA alleles. We aimed to confirm the HLA class I allele-related clinical manifestations in Japanese AA patients. HLA loss was assessed by SNP array, HLA flow cytometry, digital PCR, or deep nucleotide sequencing. An HLA allele was classified as "affected by loss" in individual patients when the single allele was lost or inactivated by somatic mutations or when both HLA-A and HLA-B alleles in a haplotype were lost due to 6p LOH with no evidence of loss or inactivation of a single HLA allele. Clinical characteristics were compared according to the affected HLA alleles. In 496 Japanese patients with AA (severe, n = 368; non-severe, n = 128; median age, 59 [range, 1-89] years), there were 146 (29%) patients with HLA loss. HLA-B*40:02, A*02:06, A*31:01, and B*54:01 were more frequently affected in our cohort than in the NIH cohort, where B*14:02, A*02:01, B*08:01, and B*07:02 held the majority of lost alleles (Figure 1). The median age of patients with B*40:01 loss (75 years) was highest among the groups of patients with HLA allele loss, consistent with the NIH study. The prevalence of ≥0.003% paroxysmal nocturnal hemoglobinuria (PNH) clones was significantly reduced in patients with B*40:02 loss but not in others. Sex and severity of AA were not markedly different across the groups of patients with HLA allele loss. Outcomes after anti-thymocyte globulin (ATG)-based IST were evaluable in 263 of the 496 patients. Although HLA loss was correlated with the IST response at 6 months (as reported by our group), loss of HLA-A*02:01 did not contribute to the high response, consistent with the NIH study. Loss of frequently affected HLA alleles in Japanese patients (B*40:02, A*02:06, B*54:01, etc.) was generally correlated with the IST-response. Further, patients who carried 5 HLA-B alleles (B*40:01, B*40:02, B*44:03, B*54:01, and B*56:01) without loss still displayed higher response rates than other patients. In contrast, the favorable effect of A*02:06 loss was not seen in patients who carried A*02:06 without loss. A*02:06 loss, the presence of the 5 HLA-B alleles (irrespective of loss), and previously reported HLA class II alleles (DRB1*13 and DRB1*15) were independently correlated with the IST response. The incidence of clonal evolution to myeloid neoplasms after ATG-based IST was significantly higher in patients with HLA-A*02:01 loss than other patients (Figure 2), as observed in the NIH study; A*02:01 was affected in 4 of 7 patients showing both HLA loss and clonal evolution in our cohort; B*40:02, B*44:02, and B*52:01 were affected in other 3 patients. In summary, our study in Japanese AA patients broadly confirmed the associations of loss of specific HLA alleles with clinical manifestations observed in American patients, including older age of onset in patients with HLA-B*40:01 loss, high IST response rates in patients who lost B*40:02 and A*02:06 but not in patients with A*02:01 loss, and frequent clonal evolution in patients with A*02:01 loss. We also revealed the correlation of 5 HLA-B alleles with IST response, irrespective of loss, similar to the relationship of B*14:02 to clonal evolution in the United States, and the reduced prevalence of PNH clones in patients with B*40:02 loss. These findings strongly suggest that the heterogeneous pathology of AA can be classified by affected HLA alleles. This should be useful for studies to unravel the pathophysiology and improve the outcomes of patients with immune AA. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Correlation study between multiplanar reconstruction trigeminal nerve angulation and trigeminal neuralgia

ObjectivesNeurovascular compression (NVC) produces morphological changes on the trigeminal nerve root is considered the cause of trigeminal neuralgia (TN), but there were some patients with TN found no NVC, and also NVC was found in asymptomatic individuals. Many studies found tight relationships of TN and morphological structures of trigeminal nerve. We designed this study to explore the correlation between multiplanar reconstruction (MPR) trigeminal nerve angulation (TNA) and TN.MethodsPatients with classical symptoms of TN were recruited as observation group (OG) in this study, 50 healthy controls were enrolled as control group (CG), the OG was further subtyped into young patients (YP), middle-aged patients (MP) and old patients (OP) based to the onset age of symptoms, and also divided into patients with or without trigger maneuvers (TM) based on the presence of TM or not. All the participants underwent magnetic resonance (MR) examinations in same device, bilateral TNA measurements were carried out in OG and CG, then TNA was compared between different groups or subgroups. All images were interpreted by two radiologists who were blinded to the study, diagnosis of TN was made by two senior neurosurgery professors.ResultUltimately, 95 patients with primary TN were recruited in OG, aged from 25 to 84 (61.15 ± 12.70) years with a course of 0.5 to 30 (5.03 ± 5.41) years, their onset age ranged from 24 to 82 (56.13 ± 11.98) years. There were 34 males and 61 females in OG, and 58 cases involved right side. The CG aged from 22 to 85 (61.86 ± 13.03) years. No statistical difference was found between the age of OG and CG(p = 0.76), and also the bilateral TNA of CG (154.92 ± 16.90° vs 155.55 ± 17.03°, p > 0.05), while TNA of OG was significantly smaller than CG (150.78 ± 11.29° vs 155.24 ± 16.88°, p = 0.019). In OG, TNA on the affected side was significantly smaller than the unaffected side (149.29 ± 12.44° vs 152.27 ± 9.85°, p = 0.014). TNA showed a positive correlation with onset age of patients with TN, as TNA on the affected side of YP was significantly smaller than MP and OP (139.00 ± 11.64° vs 148.86 ± 11.54°, 139.00 ± 11.64° vs 152.18 ± 12.61°, p = 0.004 and 0.026). Furthermore, patients with TM showed smaller TNA than those without TM (147.05 ± 11.30° vs 164.75 ± 8.39°, p < 0.001).ConclusionsThis study suggested that TNA might play a role in TN, small TNA could be a risk factor of TN. Furthermore, patients with small TNA are more likely to combine with TM, but more studies are needed to explore the exact role of TNA in TN.

Mutations in protein kinase Cγ promote spinocerebellar ataxia type 14 by impairing kinase autoinhibition.

Spinocerebellar ataxia type 14 (SCA14) is a neurodegenerative disease caused by germline variants in the diacylglycerol (DAG)/Ca2+-regulated protein kinase Cγ (PKCγ), leading to Purkinje cell degeneration and progressive cerebellar dysfunction. Most of the identified mutations cluster in the DAG-sensing C1 domains. Here, we found with a FRET-based activity reporter that SCA14-associated PKCγ mutations, including a previously undescribed variant, D115Y, enhanced the basal activity of the kinase by compromising its autoinhibition. Unlike other mutations in PKC that impair its autoinhibition but lead to its degradation, the C1 domain mutations protected PKCγ from such down-regulation. This enhanced basal signaling rewired the brain phosphoproteome, as revealed by phosphoproteomic analysis of cerebella from mice expressing a human SCA14-associated H101Y mutant PKCγ transgene. Mutations that induced a high basal activity in vitro were associated with earlier average age of onset in patients. Furthermore, the extent of disrupted autoinhibition, but not agonist-stimulated activity, correlated with disease severity. Molecular modeling indicated that almost all SCA14 variants not within the C1 domain were located at interfaces with the C1B domain, suggesting that mutations in and proximal to the C1B domain are a susceptibility for SCA14 because they uniquely enhance PKCγ basal activity while protecting the enzyme from down-regulation. These results provide insight into how PKCγ activation is modulated and how deregulation of the cerebellar phosphoproteome by SCA14-associated mutations affects disease progression.

Risk factors and resistance patterns of invasive Acinetobacter Baumannii infection in Children

Objective: To understand the risk factors and antibiotics-resistant patterns of invasive Acinetobacter baumannii infection in Children. Methods: This retrospective study was conducted in 6 tertiary hospitals from January 2016 to December 2018. The basic information, clinical data and the results of antimicrobial susceptibility testing were collected from the 98 pediatric inpatients with Acinetobacter baumannii isolated from blood or cerebrospinal fluid and analyzed. According to the susceptibility of the infected strains to carbapenems, they were divided into carbapenem-sensitive Acinetobacter baumannii (CSAB) group and carbapenem-resistant Acinetobacter baumannii (CRAB) group. According to the possible sources of infection, they were divided into nosocomial infection group and community infection group. Chi-square test or Fisher exact test were used to analyze categorical variables and rank sum test were used to analyze continuous variables. The risk factors of invasive CRAB infection in children were analyzed by Logistic regression. Result: There were 56 males and 42 females in 98 cases. The onset age of patients was 8 (2, 24) months. There were 62 cases (63%) from rural area. A total of 87 cases (89%) were confirmed with bloodstream infection, and 12 cases (12%) confirmed with meningitis (1 case was accompanied with bloodstream infection). In these patients, 66 cases (67%) received invasive medical procedures or surgery, 54 cases (55%) received carbapenems-containing therapy. Twenty-four cases were infected with CRAB, and 74 cases with CSAB. The onset age of cases in CRAB group was lower than that in CSAB group (4 (1, 9) vs. 10 (4, 24) months, Z=-2.16, P=0.031). The proportions of hospitalization in intensive care unit, carbapenem antibiotics using, pneumonia and adverse prognosis in CRAB group were higher than those in CSAB group (6 cases (25%) vs. 4 cases (5%), 18 cases (75%) vs. 36 cases (49%), 17 cases (71%) vs. 17 cases (23%), 6 cases (25%) vs. 4 cases (5%), χ2=5.61, 5.09, 18.32, 5.61, all P<0.05). Seventy-seven cases were nosocomial infection and 21 cases were hospital-acquired infection. The proportion of children hospitalized in high-risk wards for nosocomial infections, length of hospitalization, number of antimicrobial therapy received and duration of antimicrobial therapy were higher in the hospital associated infection group than those in the community acquired infection group (all P<0.05). Logistic regression analysis showed that children from rural area (OR=8.42, 95%CI 1.45-48.88), prior mechanical ventilation (OR=12.62, 95%CI 1.31-121.76), and prior antibiotic therapy (OR=4.90, 95%CI 1.35-17.72) were independent risk factors for CRAB infection. The resistance percentage of CSAB isolates to many classes of antibiotics was <6% except to gentamicin, which was as high as 20% (13/65). All CRAB isolates of resistant to ampicillin-sulbactam (20/20), cefepime (23/23), piperacillin (17/17), meropenem (23/23) and imipenem (24/24) were 100%. The resistance percentage to other antibiotics were up to 42%-96%. Conclusions: Most of invasive Acinetobacter baumannii infection in children in China are hospital-acquired. The outcome of invasive CRAB infection was poorer than that of CSAB infection. The drug resistance rate of CRAB strains isolated is high. Living in rural area, prior invasive mechanical ventilation and prior antibiotic therapy were independent risk factors for invasive CRAB infection. The prevention and control of nosocomial infection and appropriate use of antibiotics to reduce Acinetobacter baumannii infection.