An extra-erythrocyte role of haemoglobin body in chondrocyte hypoxia adaption.

Although haemoglobin is a known carrier of oxygen in erythrocytes that functions to transport oxygen over a long range, its physiological roles outside erythrocytes are largely elusive1,2. Here we found that chondrocytes produced massive amounts of haemoglobin to form eosin-positive bodies in their cytoplasm. The haemoglobin body (Hedy) is a membraneless condensate characterized by phase separation. Production of haemoglobin in chondrocytes is controlled by hypoxia and is dependent on KLF1 rather than the HIF1/2α pathway. Deletion of haemoglobin in chondrocytes leads to Hedy loss along with severe hypoxia, enhanced glycolysis and extensive cell death in the centre of cartilaginous tissue, which is attributed to the loss of the Hedy-controlled oxygen supply under hypoxic conditions. These results demonstrate an extra-erythrocyte role of haemoglobin in chondrocytes, and uncover a heretofore unrecognized mechanism in which chondrocytes survive a hypoxic environment through Hedy.

A high-fat diet promotes cancer progression by inducing gut microbiota-mediated leucine production and PMN-MDSC differentiation.

A high-fat diet (HFD) is a high-risk factor for the malignant progression of cancers through the disruption of the intestinal microbiota. However, the role of the HFD-related gut microbiota in cancer development remains unclear. This study found that obesity and obesity-related gut microbiota were associated with poor prognosis and advanced clinicopathological status in female patients with breast cancer. To investigate the impact of HFD-associated gut microbiota on cancer progression, we established various models, including HFD feeding, fecal microbiota transplantation, antibiotic feeding, and bacterial gavage, in tumor-bearing mice. HFD-related microbiota promotes cancer progression by generating polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs). Mechanistically, the HFD microbiota released abundant leucine, which activated the mTORC1 signaling pathway in myeloid progenitors for PMN-MDSC differentiation. Clinically, the elevated leucine level in the peripheral blood induced by the HFD microbiota was correlated with abundant tumoral PMN-MDSC infiltration and poor clinical outcomes in female patients with breast cancer. These findings revealed that the "gut-bone marrow-tumor" axis is involved in HFD-mediated cancer progression and opens a broad avenue for anticancer therapeutic strategies by targeting the aberrant metabolism of the gut microbiota.

A Population-Based Study of Genes Previously Implicated in Breast Cancer.

BACKGROUND: Population-based estimates of the risk of breast cancer associated with germline pathogenic variants in cancer-predisposition genes are critically needed for risk assessment and management in women with inherited pathogenic variants. METHODS: In a population-based case-control study, we performed sequencing using a custom multigene amplicon-based panel to identify germline pathogenic variants in 28 cancer-predisposition genes among 32,247 women with breast cancer (case patients) and 32,544 unaffected women (controls) from population-based studies in the Cancer Risk Estimates Related to Susceptibility (CARRIERS) consortium. Associations between pathogenic variants in each gene and the risk of breast cancer were assessed. RESULTS: Pathogenic variants in 12 established breast cancer-predisposition genes were detected in 5.03% of case patients and in 1.63% of controls. Pathogenic variants in BRCA1 and BRCA2 were associated with a high risk of breast cancer, with odds ratios of 7.62 (95% confidence interval [CI], 5.33 to 11.27) and 5.23 (95% CI, 4.09 to 6.77), respectively. Pathogenic variants in PALB2 were associated with a moderate risk (odds ratio, 3.83; 95% CI, 2.68 to 5.63). Pathogenic variants in BARD1, RAD51C, and RAD51D were associated with increased risks of estrogen receptor-negative breast cancer and triple-negative breast cancer, whereas pathogenic variants in ATM, CDH1, and CHEK2 were associated with an increased risk of estrogen receptor-positive breast cancer. Pathogenic variants in 16 candidate breast cancer-predisposition genes, including the c.657_661del5 founder pathogenic variant in NBN, were not associated with an increased risk of breast cancer. CONCLUSIONS: This study provides estimates of the prevalence and risk of breast cancer associated with pathogenic variants in known breast cancer-predisposition genes in the U.S. population. These estimates can inform cancer testing and screening and improve clinical management strategies for women in the general population with inherited pathogenic variants in these genes. (Funded by the National Institutes of Health and the Breast Cancer Research Foundation.).

Phenotypic and mutational spectrum of 17 Chinese patients with Menkes Disease.

BACKGROUND: Menkes Disease (MD) is a fatal X-linked recessive disorder caused by mutations in the ATP7A gene. Severe cases typically die before the age of three. Mild MD and occipital horn syndrome are variants of MD characterized by a less severe phenotype and longer survival. OBJECTIVE: This case series aims to validate previous findings, expand the clinical phenotype, identify novel ATP7A mutations of MD patients. METHODS: Observational data with follow-up were collected from 17 genetically diagnosed Chinese MD patients. RESULTS: All 17 patients exhibited neurological symptoms, including delayed motor milestones (100%) and seizures (58.8%). Unspecific pregnancy or delivery complications occurred in 9 patients (52.9%). The most prevalent connective tissue problems were abnormal hair (76.5%), followed by skeletal and dental abnormalities (52.9%), skin problems (41.2%) and hernia (35.3%). Sensorineural hearing loss (17.6%) was previously unreported. Coronary artery aneurysm and patent foramen ovale (5.9%) were infrequent. One 16-year-old boy carries pathological exon 3-4 deletion, presents novel mild phenotype including short stature and cerebellar ataxia. Out of 13 patients with follow-up (median: 24 months), 7 patients (53.8%) died with median survival of 40 months (range: 21-48 months), 3 patients (23.1%) show severe motor development delay and 2 (15.4%) have refractory epilepsy, only the mild MD patient shows improved cerebellar ataxia. Sixteen ATP7A mutations were identified including 6 small indels (37.5%), 5 nonsense mutations (31.2%), 2 missense mutations (12.5%), 2 exon deletions (12.5%), and 1 splice site mutation (6.25%). Fourteen mutations were novel. CONCLUSIONS: Our study further broadens the phenotypic and genotypic spectrums of Menkes disease.

Association of meat consumption with the risk of gastrointestinal cancers: a systematic review and meta-analysis.

BACKGROUND: The association between gastrointestinal cancer and types of meat consumption, including red meat, processed meat, or a combination of both, remains disputable. Therefore, we performed a systematic review and meta-analysis of prospective cohort studies to estimate the association between meat consumption and gastrointestinal cancer risk. METHODS: PubMed, EmBase, and the Cochrane library databases were searched systematically for eligible studies that investigated the relation between meat consumption and the risk of developing gastrointestinal cancers, including esophageal cancer (EC), gastric cancer (GC), colorectal cancer (CRC), colon cancer (CC), rectal cancer (RC), pancreatic cancer (PC), and hepatocellular carcinoma (HCC) throughout February, 2023. The pooled relative risk (RR) with 95% confidence interval (CI) was assigned as an effect estimate and calculated using a random-effects model with inverse variance weighting. RESULTS: Forty cohorts comprising 3,780,590 individuals were selected for the final quantitative analysis. The summary results indicated that a higher red meat consumption was associated with an increased risk of CRC (RR: 1.09; 95% CI: 1.02-1.16; P = 0.007) and CC (RR: 1.13; 95% CI: 1.03-1.25; P = 0.011). Moreover, a higher processed meat consumption was associated with an increased risk of CRC (RR: 1.19; 95% CI: 1.13-1.26; P < 0.001), CC (RR: 1.24; 95% CI: 1.13-1.26; P < 0.001), and RC (RR: 1.24; 95% CI: 1.08-1.42; P = 0.002). Furthermore, a higher total consumption of red and processed meat was associated with an increased risk of CRC (RR: 1.13; 95% CI: 1.06-1.20; P < 0.001), CC (RR: 1.17; 95% CI: 1.04-1.33; P = 0.012), and RC (RR: 1.20; 95% CI: 1.04-1.39; P = 0.016). Finally, the strength of higher consumption of total red and processed meat with the risk of GC, and higher consumption of red meat with the risk of RC in subgroup of high adjusted level was lower than subgroup of moderate adjusted level, while the strength of higher consumption of processed meat with the risk of RC and HCC in subgroup of follow-up ≥ 10.0 years was higher than subgroup of follow-up < 10.0 years. CONCLUSIONS: This study found that meat consumption was associated with an increased risk of CRC, CC, and RC, and dietary intervention could be considered an effective strategy in preventing CRC.

An S-like curve relationship between systemic inflammation response index (SIRI) and respiratory failure in GBS patients.

BACKGROUND: Our study examined the association between the initial systemic inflammation response index (SIRI) and respiratory failure in patients with Guillain-Barré syndrome (GBS). METHODS: The weighted linear regression model, weighted chi-square test, logistic regression models, smooth curve fittings, and the two-piece linear regression model were utilized for data analysis. RESULTS: Among the 443 GBS patients, 75 (6.9%) had experienced respiratory failure. According to logistic regression models, there existed no consistent linear relationship between respiratory failure and SIRI in model 1 (OR = 1.2, p < 0.001), model 2 (OR = 1.2, p < 0.001), and model 3 (OR = 1.3, p = 0.017). However, smooth curve fittings found an S-like curve relationship between SIRI and respiratory failure. Furthermore, when SIRI was < 6.4, there existed a positive correlation between SIRI and respiratory failure in model 1 (OR = 1.5, 95% CI = (1.3, 1.8), p < 0.0001), higher correlation in model 2 (OR = 1.6, 95% CI = (1.3, 1.8), p < 0.0001), and highest correlation in model 3 (OR = 1.6, 95% CI = (1.3, 2.5), p < 0.0001). CONCLUSIONS: SIRI can be used as a predictor of respiratory failure in GBS, and an S-like relationship exists between SIRI and respiratory failure at an infliction point of 6.4. When the SIRI was less than 6.4 and increased, SIRI was associated with a higher occurrence of respiratory failure. The risk of respiratory failure was no longer increased when the SIRI was over 6.4.

Clinical features and reclassification of essential tremor with NOTCH2NLC GGC repeat expansions based on a long-term follow-up.

BACKGROUND AND PURPOSE: NOTCH2NLC GGC repeat expansions have been identified to be associated with essential tremor (ET). Our aim was to characterize ET patients with NOTCH2NLC repeat expansions versus non-expansions and describe distinctive clinical features of repeat expanded patients with long-term follow-up according to the new tremor classification. METHODS: Participants included 597 ET pedigrees, 412 sporadic cases and 1085 healthy controls. Repeat expansions of GGC in NOTCH2NLC were screened, and comprehensive clinical features were investigated. A longitudinal clinical assessment and reclassification were performed in NOTCH2NLC expanded patients. RESULTS: In total, 27 ET pedigrees (27/597) and three sporadic patients (3/412) were identified with pathogenic NOTCH2NLC GGC repeat expansions (≥60 repeats). Intermediate-length GGC repeats (41-59 repeats) were found in four sporadic ET cases and one control subject, and the frequency was higher than that in control participants (4/412 vs. 1/1085, p = 0.022). About 46 ET patients (43 familial cases from 27 pedigrees and three sporadic cases) with NOTCH2NLC GGC repeat expansions had higher Essential Tremor Rating Assessment Scale I, Essential Tremor Rating Assessment Scale II and Non-Motor Symptoms Scale scores and lower Mini-Mental State Examination scores than the patients without expansions. Patients with pathogenic GGC repeats were reclassified as pure ET (25/46), ET-plus (11/46) and ET-neuronal intranuclear inclusion disease (10/46) subgroups at 2-8 years of follow-up. CONCLUSION: Our results further supported that NOTCH2NLC GGC repeat expansions were associated with ET. Patients with pathogenic GGC repeats presented with more severe motor and non-motor symptoms. Further long-term follow-up and subtype studies will help to define the role of NOTCH2NLC in ET.

Prevalence and associated factors of frailty and sarcopenia in multiple system atrophy and progressive supranuclear palsy: a cross-sectional study.

OBJECTIVE: To investigate the prevalence of, and clinicodemographic factors associated with, frailty and sarcopenia in patients with multiple system atrophy or progressive supranuclear palsy. METHODS: A total of 264 participants were recruited in this study. Demographic and clinical data were collected through structured interviews. Frailty was assessed with the clinical frailty scale (CFS), and sarcopenia was assessed with the simple five-item scoring questionnaire (SARC-F). RESULTS: The prevalence of frailty and sarcopenia was 48.57% and 35.71% in multiple system atrophy, and 51.09% and 39.13% in progressive supranuclear palsy. Multiple system atrophy patients with frailty or sarcopenia were more likely to be female and have longer disease duration, greater motor impairment, greater non-motor burden, and lower life quality. In multiple system atrophy, frailty was associated with reduced motor function and sarcopenia was associated with female sex, reduced motor function, and orthostatic hypotension. Progressive supranuclear palsy patients with frailty or sarcopenia had more severe motor impairment and non-motor burden, longer disease duration, and lower life quality. In progressive supranuclear palsy, frailty was associated with mentation and gait/midline symptoms, while sarcopenia was associated with reduced daily activity and severe gait/midline symptoms. CONCLUSION: Frailty and sarcopenia may be more common among patients with multiple system atrophy or progressive supranuclear palsy than among the general population, and they are associated with more severe forms of the two diseases. Prospective studies are necessary to clarify causal relationships between frailty/sarcopenia and clinical manifestations of multiple system atrophy and progressive supranuclear palsy.

Correction: Large-scale genome-wide meta-analysis of polycystic ovary syndrome suggests shared genetic architecture for different diagnosis criteria.

[This corrects the article DOI: 10.1371/journal.pgen.1007813.].

[Genetic analysis of a Chinese pedigree affected with Becker muscular dystrophy with myalgia as the main feature].

OBJECTIVE: To explore the genetic basis of a Chinese pedigree affected with Becker muscular dystrophy (BMD) with myalgia as the main feature. METHODS: Clinical data of the patients and results of auxiliary examinations were retrospectively analyzed. Multiplex ligation-dependent probe amplification and high-throughput sequencing were used to detect potential variants. Sanger sequencing was used to verify the results. RESULTS: The clinical manifestations of the proband included myalgia and elevated serum creatine kinase, which is similar to another patient from the pedigree. Genetic testing revealed that the two patients both harbored hemizygous deletions of exons 10 to 29 of the DMD gene, for which the mother was a carrier. The same deletion was not found in his father. Based on the guidelines from American College of Medical Genetics and Genomics, the deletion was predicted to be pathogenic (PVS1+PM2+PP1). CONCLUSION: Myalgia with elevated serum CK may be atypical clinical manifestations of BMD and may be associated with variants in the rod domain of the DMD gene. The deletion of exons 10 to 29 of the DMD gene probably underlay the BMD in this pedigree.

Leveraging sequence-based faecal microbial community survey data to identify alterations in gut microbiota among patients with Parkinson's disease.

Parkinson's disease is a common degenerative disease of the elderly. Although the majority of studies have focused on the central nervous system (CNS) features of Parkinson's disease, recent findings suggest there is a functional link between the gut microbiome and the hallmarks of the disease. PubMed, Web of Science, EMBASE and other Chinese and English databases were searched for relevant literature. Studies on changes to intestinal microbiota in Parkinson's patients were retrieved and systematically reviewed. Quality filtering, clustering and species annotation were performed on 16s sequencing raw data from retrieved studies to achieve comparability across studies. Alpha-diversity indices and a random effect model were used to analyse significantly altered microbiota. A total of nine studies were included in this retrospective analysis, four of which contained raw data. Alpha diversity was significantly different between control and Parkinson's disease patients in two of the four studies. Using the raw data from four individual studies, we observed differences in the phlya Bacteroidetes and Actinobacteria. Additionally, differences were observed between control and Parkinson's disease patients at the level of family (Prevotellacaea and Lactobacillaceae) and genus (Bifidobacterium and Clostridium). This study confirmed that changes in the microbiome are a consistent feature of Parkinson's disease patients and, therefore, may contribute to the onset of disease.

Fatigue prevalence and associated factors in patients with multiple system atrophy.

OBJECTIVE: Fatigue was reported a determinant of poor quality of life in multiple system atrophy (MSA) patients. This study aimed to determine fatigue prevalence and associated demographic, motor, and non-motor symptoms in MSA patients. MATERIALS AND METHODS: A total of 174 MSA patients met "Probable" diagnostic criteria were included in this cross-sectional study. Fatigue Severity Scale (FSS) was used to measure fatigue prevalence. Unified MSA Rating Scale (UMSARS), Non-Motor Symptoms Scale (NMSS), Hamilton Depression Rating Scale-17 (HDRS-17), Hamilton Anxiety Scale (HAMA), Pittsburgh Sleep Quality Index (PSQI), Epworth Sleepiness Scale (ESS), REM Sleep Behavior Disorder Screening Questionnaire (RBDSQ), and Mini-Mental State Exam (MMSE) were used for comprehensive clinical assessments. Nonparametric Mann-Whitney or Pearson's chi-square test was used to compare the patient score with or without fatigue (defined as a mean FSS score≥4). Binary logistic regression analysis was performed to determine features independently associated with the presence of fatigue. RESULTS: Fifty (28.7%) patients enrolled reported fatigue. Results of multivariate analysis revealed that anxiety (OR = 3.01, 95% CI = 1.43-6.31), excessive daytime sleepiness (OR = 2.70, 95% CI = 1.23-5.90), and use of sleep medicine (OR = 3.58, 95% CI = 1.39-9.24) were significantly associated with fatigue in MSA patients. CONCLUSIONS: Fatigue is common in our MSA patients. Anxiety, excessive daytime sleepiness, and current sleep medicine use may be associated with an increased risk of fatigue. However, the severity of motor symptoms may not be associated with fatigue. Our findings highlight the need to identify, investigate, and treat fatigue in MSA.

Clinical value of C-reactive protein/albumin ratio in Guillain-Barré syndrome.

BACKGROUND: Respiratory failure in patients with Guillain-Barré syndrome (GBS) can lead to serious complications and dysfunctions, emphasizing the importance of early detection. The C-reactive protein-to-albumin ratio (CAR) is emerging as a novel inflammatory marker for predicting neurological outcome. We aimed to identify the association of CAR with respiratory failure and short-term outcome in GBS patients. METHODS: A total of 200 patients diagnosed with GBS were retrospectively analyzed. Data were collected from an electronic database. The associations of C-reactive protein (CRP), albumin, and CAR at admission with outcomes were evaluated by logistic regression analysis. Using receiver operating characteristic curves, we calculated the cutoff value for the CAR and compared its discriminatory power with that of C-reactive protein alone. RESULTS: Fifty-two (26%) patients showed poor short-term outcome, and 50 (25%) developed respiratory failure. CAR > 0.21 was an independent predictor of respiratory failure, and CAR > 0.19 was an independent predictor of poor short-term outcome. CAR showed a better predictive value than CRP alone. In addition, the c-index of the predictive nomogram for respiratory failure was higher when it included CAR (0.962) than when it did not (0.958). A similar result was observed for the predictive nomogram for poor short-term outcome (0.953 vs 0.947). CONCLUSION: CAR > 0.21, a novel inflammatory biomarker, is independently associated with the occurrence of respiratory failure in GBS patients, while CAR > 0.19 is independently associated with poor short-term outcome. CAR may help identify GBS patients at high risk of poor prognosis.

Large-scale genome-wide meta-analysis of polycystic ovary syndrome suggests shared genetic architecture for different diagnosis criteria.

Polycystic ovary syndrome (PCOS) is a disorder characterized by hyperandrogenism, ovulatory dysfunction and polycystic ovarian morphology. Affected women frequently have metabolic disturbances including insulin resistance and dysregulation of glucose homeostasis. PCOS is diagnosed with two different sets of diagnostic criteria, resulting in a phenotypic spectrum of PCOS cases. The genetic similarities between cases diagnosed based on the two criteria have been largely unknown. Previous studies in Chinese and European subjects have identified 16 loci associated with risk of PCOS. We report a fixed-effect, inverse-weighted-variance meta-analysis from 10,074 PCOS cases and 103,164 controls of European ancestry and characterisation of PCOS related traits. We identified 3 novel loci (near PLGRKT, ZBTB16 and MAPRE1), and provide replication of 11 previously reported loci. Only one locus differed significantly in its association by diagnostic criteria; otherwise the genetic architecture was similar between PCOS diagnosed by self-report and PCOS diagnosed by NIH or non-NIH Rotterdam criteria across common variants at 13 loci. Identified variants were associated with hyperandrogenism, gonadotropin regulation and testosterone levels in affected women. Linkage disequilibrium score regression analysis revealed genetic correlations with obesity, fasting insulin, type 2 diabetes, lipid levels and coronary artery disease, indicating shared genetic architecture between metabolic traits and PCOS. Mendelian randomization analyses suggested variants associated with body mass index, fasting insulin, menopause timing, depression and male-pattern balding play a causal role in PCOS. The data thus demonstrate 3 novel loci associated with PCOS and similar genetic architecture for all diagnostic criteria. The data also provide the first genetic evidence for a male phenotype for PCOS and a causal link to depression, a previously hypothesized comorbid disease. Thus, the genetics provide a comprehensive view of PCOS that encompasses multiple diagnostic criteria, gender, reproductive potential and mental health.

Forensic effectiveness and genetic distribution of 20 non-CODIS STRs and D3S1358 in Guangdong Han population.

In this study, Guangdong Han population was analyzed with Goldeneye™ DNA ID 22NC Kit containing 20 non-CODIS STR loci and a CODIS STR locus. In 503 unrelated individuals, a total of 232 alleles and 813 genotypes were observed. The values of polymorphism information content (PIC), expected heterozygosity (He), and observed heterozygosity (Ho) ranged from 0.6678 to 0.8618, 0.7197 to 0.8757, and 0.6938 to 0.8767, respectively. No deviation from Hardy-Weinberg equilibrium was observed at all loci after the Bonferroni correction. The combined power of discrimination and the combined power of exclusion were 0.999999999999999999999999937051 and 0.999999998467033, respectively. Population comparison revealed that Guangdong Han population was relatively close to Huadong Han population. These results suggested that the 21 STR loci are highly polymorphic and Goldeneye™ DNA ID 22NC Kit is suitable for individual identification and paternity testing in Guangdong Han population.

A nomogram to predict mechanical ventilation in Guillain-Barré syndrome patients.

INTRODUCTION: Guillain-Barré syndrome (GBS) is one of the most common causes of acute flaccid paralysis, with up to 20%-30% of patients requiring mechanical ventilation. The aim of our study was to develop and validate a mechanical ventilation risk nomogram in a Chinese population of patients with GBS. METHODS: A total of 312 GBS patients were recruited from January 1, 2015, to June 31, 2018, of whom 17% received mechanical ventilation. The least absolute shrinkage and selection operator (LASSO) regression model was used to select clinicodemographic characteristics and blood markers that were then incorporated, using multivariate logistic regression, into a risk model to predict the need for mechanical ventilation. The model was characterized and assessed using the C-index, calibration plot, and decision curve analysis. The model was validated using bootstrap resampling in a prospective study of 114 patients recruited from July 1, 2018, to July 10, 2019. RESULTS: The predictive model included hospital stay, glossopharyngeal and vagal nerve deficits, Hughes functional grading scale scores at admission, and neutrophil/lymphocyte ratio (NLR). The model showed good discrimination with a C-index value of 0.938 and good calibration. A high C-index value of 0.856 was reached in the validation group. Decision curve analysis demonstrated the clinical utility of the mechanical ventilation nomogram. CONCLUSIONS: A nomogram incorporating hospital stay, glossopharyngeal and vagal nerve deficits, Hughes functional grading scale scores at admission, and NLR may reliably predict the probability of requiring mechanical ventilation in GBS patients.

Clinical characteristics of patients with essential tremor or essential tremor plus.

BACKGROUND: The International Parkinson and Movement Disorder Society introduced the category of essential tremor (ET)-plus in its new ET classification scheme, but how the clinical correlates of ET-plus differ from those of "pure" ET is unclear. By comparing the clinical characteristics of ET and ET-plus patients, we expect to better understand the impact and invoked questions of the new classification on clinical practice. METHODS: We reviewed the medical records of 280 ET syndrome patients in an ongoing cross-sectional study in a Chinese population and reclassified them according to the new criteria. Clinico-demographic characteristics were compared between ET and ET-plus patients. Risk factors of diagnosis of ET-plus were explored using logistic regression. RESULTS: A total of 121 patients (50.8%) were reclassified as having ET and 117 as having ET-plus. ET-plus group was significantly older at tremor onset, less educated, and more likely to have cranial tremor, depression symptom, anxiety symptom, and probable REM sleep behavior disorder. ET-plus group also showed more severe upper limb tremor and cognition impairment. Regression analysis identified four independent risk factors associated with ET-plus: late tremor onset (OR 3.04, 95%CI 1.60-5.79), less educated (OR 0.91, 95%CI 0.85-0.97), severe upper limb tremor (OR 2.46, 95%CI 1.30-4.62), and presence of cranial tremor (OR 2.30, 95%CI 1.20-4.41). CONCLUSIONS: The new classification scheme emphasized that ET syndrome is heterogeneous. ET-plus cannot be seen as a subtype or a diagnosis of ET syndrome, but rather as a placeholder, representing an area of current scientific uncertainty.

Non-motor symptoms are associated with midline tremor in essential tremor.

OBJECTIVES: Essential tremor (ET) patients presenting tremor in the midline structures may be a distinct subtype of the syndrome. Therefore, we sought to explore the clinical manifestations, especially non-motor symptoms (NMS) of Chinese ET patients with midline tremor (MT). METHODS: In the cross-sectional study, we grouped 290 definite or probable ET patients based on their MT conditions. The NMS in ET patients were evaluated using the NMS scale (NMSS). NMS and other clinical correlates were then compared among subgroups with, and without MT. RESULTS: We revealed that 39.0%, 27.6%, and 6.9% of the patients respectively had neck, voice, and facial tremors. With the accumulation of tremor in midline structures, NMS became more severe and prevalent. Logistic regression analyses revealed that factors such as: female gender (OR = 2.164, 95% CI: 1.307-3.583), having least or highest action arm tremor (OR = 2.512, 95% CI: 1.520-4.151), having higher score of sleep/fatigue domain (OR = 1.692, 95% CI: 1.004-2.850) and mood/apathy (OR = 1.926, 95% CI: 1.143-3.246) domain, to be independently associated with MT manifestation. CONCLUSIONS: Our study demonstrates the heterogeneity of symptoms in ET patients with MT, especially in prominent NMS. In addition, the discrepancy of NMS between patients with, and without MT provides novel insight into the underlying pathophysiology and therapeutic of ET.

Clinical features of multiple system atrophy with or without rapid eye movement behavior disorder: a cross-sectional study in southwest China.

OBJECTIVE: The aim of this study was to investigate the prevalence of rapid eye movement behavior disorder (RBD) in Chinese patients with multiple system atrophy (MSA) and to compare motor and non-motor symptoms and sleep disturbance of MSA patients with and without RBD. METHODS: A total of 55 patients who were consecutively admitted to West China Hospital of Sichuan University from 2016 to 2019 and subsequently diagnosed with probable MSA were enrolled in this cross-sectional study. The diagnosis of RBD was based on the results of video polysomnography (PSG) and a history of abnormal sleep-related behaviors. The patients were divided into two groups: those with RBD and those without. These two groups were then compared in terms of severity of motor symptoms (Unified Multiple System Arophy Rating Scale) and non-motor symptoms (Non-Motor Symptoms Scale, Mini-Mental State Examination score, Epworth Sleepiness Scale, Fatigue Severity Scale, Pittsburgh Sleep Quality Index, REM Sleep Behavior Disorder Screening Questionnaire, Hamilton Depression Rating Scale, Hamilton Anxiety Rating Scale) and sleep parameters as recorded on PSG. RESULTS: Of the 55 patients (35 males), 18 (33%, 13 males) were diagnosed with RBD. Patients with or without RBD did not differ in demographic characteristics, clinical features, or sleep parameters based on PSG. CONCLUSION: There was no difference in motor and non-motor symptoms between MSA patients with or without RBD, indicating that the presence of RBD may not be significantly associated with the severity of motor or non-motor dysfunction in MSA.

Technical note: developmental validation of a novel 6-dye typing system with 36 Y-STR loci.

Y-chromosomal short tandem repeats (Y-STRs) have proven to be very useful in investigating sexual assault cases and in paternity lineage differentiation. However, currently available commercial Y-STR multiplex amplification systems bear the limitations in the identification of related males from the same paternal lineage due to there being an insufficient number of loci in any single amplification kit. The aim of this study was to establish and validate a novel 6-dye, 36-plex Y-STR multiplex amplification system that incorporated all of the loci present in the Yfiler™ Plus kit (DYS19, DYS385a/b, DYF387S1, DYS389I/II, DYS390, DYS391, DYS392, DYS393, DYS437, DYS438, DYS439, DYS448, DYS449, DYS456, DYS458, DYS460, DYS481, DYS518, DYS533, DYS570, DYS576, DYS627, DYS635, Y_GATA_H4) as well as a further nine highly polymorphic Y-STR loci (DYS388, DYS444, DYS447, DYS522, DYS527a/b, DYS549, DYS596, DYS643). The novel system was optimized and validated by a series of studies that tested the effect of different PCR-based conditions as well as the species specificity, sensitivity, stability, stutter precision, suitability for use on DNA mixtures, reproducibility, and parallel testing of the system, as well as its performance on casework samples and population analysis, according to the SWGDAM developmental validation guidelines. A total of 246 haplotypes were found for the 36 Y-STRs among 247 Guangdong Han unrelated males. Collectively, the results demonstrate that the developed 36-plex Y-STR system is sensitive, robust, reliable, and highly informative for use in forensic genetics.