Low Hemoglobin Level and Elevated Inflammatory Hematological Ratios Associated With Depression and Sleep Disturbance.

BACKGROUND: The relationship between blood cell profiles, including hemoglobin (Hb) levels and inflammatory hematological ratios, and mental health problems currently remains unclear. AIM: This study aimed to investigate the relationship between blood cell profiles and mental health issues, including depressive state and sleep disturbance, while adjusting for potential demographic confounders. METHODOLOGY: This retrospective, cross-sectional, observational study used a population-based medical database from the Tohoku Medical Megabank Project with more than 60,000 volunteers. Data on age, sex, daily tobacco use, body mass index, and self-reported scores on the Kessler Psychological Distress Scale (K6), Athens Insomnia Scale (AIS), and the Center for Epidemiologic Studies Depression Scale (CES-D) were collected. RESULTS: A total of 62,796 volunteers (23,663 males and 39,133 females), aged ≥20 years at the time of the blood test, agreed to participate in this study. Among the evaluated blood cell profiles, Hb, hematocrit, neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) were significantly correlated with the K6, AIS, and CES-D scores, with strong statistical significance (p<0.0001 for all) in bivariate correlation analyses. A significant adjusted odds ratio (aOR) of the Hb level for elevated CES-D scores (aOR=0.965 [95% CI: 0.949-0.981], p<0.0001) was confirmed after adjusting for demographic data and daily tobacco use using a logistic regression model. Sensitivity analyses revealed that these associations existed in both males and females but were more prominent in the former. In male participants, a low Hb level was significantly associated with an elevated AIS score. The evaluated inflammatory hematological ratios, including NLR, PLR, and monocyte-to-lymphocyte ratio (MLR), also showed significant aORs with the K6, AIS, and CES-D scores after adjusting for demographic background. CONCLUSION: Low Hb levels and elevated inflammatory hematological ratios (NLR, MLR, and PLR) were associated with depressive state and sleep disturbances in the general population.

Improved Activities of Daily Living With Adjunctive Intravenous Steroids in Bacterial Meningitis: A Nationwide, Population-Based Medical Database Study.

The benefit of using adjunctive intravenous steroids (IVS) to reduce the neurological sequelae in bacterial meningitis remains inconclusive. This study evaluated the effect of IVS on improving the subsequent Activities of Daily Living (ADL) in bacterial meningitis by analyzing data from a large nationwide administrative medical database in Japan. Data from 1,132 hospitals, covered by the administrative Diagnosis Procedure Combination (DPC) payment system from 2016 to 2022, were evaluated. The ADL levels at admission and discharge were measured using the Barthel Index (BI). Out of the cumulative 47,366,222 patients hospitalized, 8,736 were diagnosed with acute bacterial meningitis and had BI data available. The BI at discharge, adjusted for sex, age, and BI at admission, was significantly better among those treated with IVS (p<0.0001). Exploratory subgroup analyses suggested that this benefit is expected across a broad spectrum of bacterial species. In summary, the use of IVS for improving the subsequent ADL level in bacterial meningitis was suggested.

Stochastic models for the onset and disease course of multiple sclerosis.

OBJECTIVE: Exact causes and mechanisms regulating the onset and progression in many chronic diseases, including multiple sclerosis (MS), remain uncertain. Until now, the potential role of random process based on stochastic models in the temporal course of chronic diseases remains largely unevaluated. Therefore, the present study investigated the applicability of stochastic models for the onset and disease course of MS. METHODS: Stochastic models with random temporal process in disease activity, underlying clinical relapse and/or subclinical brain atrophy, were developed. The models incorporated parameters regarding the distribution of temporal changes in disease activity and the drift constant. RESULTS: By adjusting the parameters (temporal change dispersion and drift constant) and the threshold for the onset of disease, the stochastic disease progression models could reproduce various types of subsequent disease course, such as clinically isolated syndrome (monophasic), relapsing-remitting MS, primary-progressive MS, and secondary-progressive MS. Furthermore, the disease prevalence and distribution of onset age could be also reproduced with stochastic models by adjusting the parameters. The models could further explain why approximately half of the patients with relapsing-remitting MS will eventually experience a transition to secondary-progressive MS. CONCLUSION: Stochastic models with random temporal changes in disease activity could reproduce the characteristic onset age distribution and disease course forms in MS. Further studies by using real-world data to underscore the significance of random process in the occurrence and progression of MS are warranted.

A Reduction in the Number of Hospitalized Cases of Acute Meningitis during the COVID-19 Pandemic in Japan.

Objective The changes in the prevalence of acute meningitis during the coronavirus disease 2019 (COVID-19) pandemic remain unclear. This study aimed to compare the prevalence of acute meningitis before and during the COVID-19 pandemic in Japan. Methods We retrospectively reviewed the Japanese nationwide administrative medical payment system database, Diagnosis Procedure Combination (DPC), from 2016 to 2022. A total of 547 hospitals consistently and seamlessly offered DPC data during this period. The study period was divided into the following three periods: April 2016 to March 2018 (fiscal years 2016-2017), April 2018-March 2020 (2018-2019), and April 2020-March 2022 (2020-2021). Results Among the 28,161,806 patients hospitalized during the study period, 28,399 were hospitalized for acute meningitis: 16,678 for viral/aseptic type, 6,189 for bacterial type, 655 for fungal type, 429 for tuberculous, 2,310 for carcinomatous type, and 2,138 for other or unknown types of meningitis. A significant decrease during the pandemic was confirmed in viral (n=7,032, n=5,775, and n=3,871 in each period; p<0.0001) and bacterial meningitis (n=2,291, n=2,239, and n=1,659; p<0.0001) cases. Meanwhile, no decrease was observed in fungal meningitis (n=212, n=246, and n=197; p=0.056) or carcinomatous meningitis (n=781, n=795, and n=734; p=0.27). The decrease in the number of tuberculous meningitis cases was equivocal (n=166, n=146, and n=117; p=0.014). The decrease during the pandemic was more remarkable in younger populations aged <50 years than in older populations, both for viral and bacterial meningitis. Conclusion The number of hospitalized cases of acute meningitis clearly decreased during the COVID-19 pandemic, especially for viral and bacterial meningitis in younger populations aged <50 years.

Basal Ganglia Atrophy and Impaired Cognitive Processing Speed in Multiple Sclerosis.

Impaired cognitive processing speed is among the important higher brain dysfunctions in multiple sclerosis (MS). However, the exact structural mechanisms of the dysfunction remain uncertain. This study aimed to identify the brain regions associated with the impaired cognitive processing speed in MS by comparing the cognitive processing speed, measured using the Cognitive Processing Speed Test (CogEval) z-score, and brain regional volumetric data. Altogether, 80 patients with MS (64 with relapsing-remitting MS [RRMS] and 16 with secondary progressive MS [SPMS]) were enrolled. Consequently, CogEval z-scores were worse in patients with SPMS than in those with RRMS (p=0.001). In the univariate correlation analyses, significant correlations with CogEval z-score were suggested in the MS lesion volume (p<0.001; Spearman's rank correlation test) and atrophies in the cerebral cortex (p=0.031), cerebral white matter (p=0.013), corpus callosum (p=0.001), thalamus (p=0.001), and putamen (p<0.001). Multiple linear regression analysis revealed that putamen atrophy was significantly associated with CogEval z-score (p=0.038) independent of volume in other brain regions, while thalamic atrophy was not (p=0.79). Univariate correlation analyses were further performed in each of RRMS and SPMS. None of the evaluated volumetric data indicated a significant correlation with the CogEval z-score in RRMS. Meanwhile, atrophies in the cerebral white matter (p=0.008), corpus callosum (p=0.002), putamen (p=0.011), and pallidum (p=0.017) demonstrated significant correlations with CogEval z-score in SPMS. In summary, the putamen could be an important region of atrophy contributing to the impaired cognitive speed in MS, especially in the later disease stages after a transition to SPMS.

Demographic profiles and risk factors for mortality in acute meningitis: A nationwide population-based observational study.

Aim: Acute meningitis encompasses bacterial, viral (aseptic), fungal, tuberculous, and carcinomatous meningitis. The rate and risks of mortality in each type remain uncertain. This study aimed to elucidate these aspects in each type of meningitis. Methods: This study utilized Japan's nationwide administrative Diagnosis Procedure Combination (DPC) database. Patients with acute meningitis, treated at 1132 DPC-covered hospitals from 2016 to 2022, were enrolled. Results: Among 47,366,222 cumulative hospitalized patients, 48,758 (0.10%) were hospitalized with acute meningitis. The types of meningitis were as follows: 10,338 with bacterial, 29,486 with viral/aseptic, 965 with fungal, 678 with tuberculous, and 3790 with carcinomatous meningitis. Bacterial and viral meningitis exhibited bimodal age distributions, with the first peak occurring at 0-9 years. The median onset age was below 50 years only in viral meningitis. The mortality rate was the highest in carcinomatous meningitis (39%), followed by fungal meningitis (21%), and the lowest in viral meningitis (0.61%). Mortality rates increased with age across all meningitis types, but this trend was less prominent in carcinomatous meningitis. The duration from admission to mortality was longer in fungal and tuberculous meningitis compared with other types. Staphylococcus aureus in bacterial meningitis (adjusted odds ratio 1.71; p = 0.0016) and herpes simplex virus in viral meningitis (adjusted odds ratio 1.53; p = 0.0467) exhibited elevated mortality rates. Conclusion: Distinct demographic profiles and mortality rates were observed among different meningitis types. The high mortality rates in less common types of meningitis emphasize the necessity to further optimize the required diagnostic and treatment strategies.

Enlarged choroid plexus in multiple sclerosis is associated with increased lesion load and atrophy in white matter but not gray matter atrophy.

BACKGROUND: Enlargement of the choroid plexus (CP) is reported to associate with inflammatory activity and contribute to brain atrophy in patients with multiple sclerosis (pwMS). However, a recent study in healthy volunteers (HVTs) has suggested that CP enlargement can be attributed to ventriculomegaly. OBJECTIVES: To clarify the pathological significance of the enlargement of CP in multiple sclerosis (MS). METHODS: A total of 102 pwMS (89 with relapsing-remitting MS and 13 with secondary progressive MS) and 41 HVTs were cross-sectionally evaluated using brain volumetry. The CP volume was compared between disease groups and investigated for the relationships with other brain regional volumes. RESULTS: CP volume was significantly larger in pwMS than in HVTs in the univariate analysis, but not in multivariable analysis. Meanwhile, the CP and lateral ventricle (LV) volumes were significantly correlated. CP enlargement was significantly associated with increased lesion load and cerebral white matter (WM) atrophy, even after adjusting for LV volume. In contrast, multivariable analyses revealed that LV enlargement, but not CP enlargement, was associated with total gray matter (GM) atrophy. CONCLUSION: CP enlargement was closely associated with LV enlargement. After adjusting for LV volume, CP enlargement in pwMS was associated with increased lesion load and WM atrophy but not GM atrophy.

Evaluation of Statistical Approaches in Developing a Predictive Model of Severe COVID-19 during Early Phase of Pandemic with Limited Data Resources.

As evidence of risk factors for severe cases of coronavirus disease 2019 (COVID-19) was uncertain in early phases of the pandemic, the development of an efficient predictive model for severe cases to triage high-risk individuals represented an urgent yet challenging issue. It is crucial to select appropriate statistical models when available data and evidence are limited. This study was conducted to assess the accuracy of different statistical models in predicting severe cases using demographic data from patients with COVID-19 prior to the emergence of consequential variants. We analyzed data from 929 consecutive patients diagnosed with COVID-19 prior to March 2021, including their age, sex, body mass index, and past medical histories, and compared areas under the receiver operating characteristic curve (ROC AUC) between different statistical models. The random forest (RF) model, deep learning (DL) models with not too many neurons, and naïve Bayes model exhibited AUC measures of > 0.70 with the validation datasets. The naïve Bayes model performed the best with the AUC measures of > 0.80. The accuracies in RF were more robust with narrower distribution of AUC measures compared to those in DL. The benefit of performing feature selection with a training dataset before building models was seen in some models, but not in all models. In summary, the naïve Bayes and RF models exhibited ideal predictive performance even with limited available data. The benefit of performing feature selection before building models with limited data resources depended on machine learning methods and parameters.

Prenatal hypertension as the risk of eclampsia, HELLP syndrome, and critical obstetric hemorrhage.

Critical bleeding is a common cause of maternal mortality in obstetric patients. However, the non-obstetric factors underlying critical obstetric bleeding remain uncertain. Therefore, this study aimed to clarify the impact of chronic hypertension on obstetric hemorrhage by evaluating a nationwide administrative database in Japan. Women who gave birth between 2018 and 2022 were enrolled. The primary outcome was critical hemorrhage requiring massive red blood cell (RBC) transfusion during childbirth. In total, 354, 299 eligible women were selected from the database. The maternal mortality rate was >1.0% among those who received a massive RBC transfusion (≥4000 cc), and this amount was used as the cutoff of the outcome. Critical hemorrhage was less frequent with elective Caesarean section (CS) compared with vaginal childbirth or emergent CS (odds ratio [OR], 0.38; 95% confidence interval, 0.30-0.47). Multiple logistic regression analysis adjusting for these obstetric risks revealed that a higher maternal age (adjusted OR [aOR] per 1 year, 1.07 [1.05-1.09]); oral medications with prednisolone (aOR, 2.5 [1.4-4.4]), anti-coagulants (aOR, 10 [5.4-19]), and anti-platelets (aOR, 2.9 [1.3-6.4]); and a prenatal history of hypertension (aOR, 2.5 [1.5-4.4]) and hypoproteinemia (aOR, 5.8 [1.7-20]) are the risks underlying critical obstetric hemorrhage. Prenatal history of hypertension was significantly associated with obstetric disseminated intravascular coagulation (OR, 1.9 [1.5-2.4]); Hemolysis, Elevated Liver enzymes, and Low platelet count (HELLP) syndrome (OR, 3.3 [2.7-4.2]); and eclampsia (OR, 6.1 [4.6-8.1]). In conclusion, a maternal prenatal history of hypertension is associated with the development of HELLP syndrome, eclampsia, and resultant critical hemorrhage. The incidence of HELLP syndrome and eclampsia increased more than fivefold in the presence of prenatal hypertension. However, the likelihood of subsequently developing DIC or experiencing critical bleeding did not change by the presence of prenatal hypertension.

Progression independent of relapses in aquaporin4-IgG-seropositive neuromyelitis optica spectrum disorder, myelin oligodendrocyte glycoprotein antibody-associated disease, and multiple sclerosis.

OBJECTIVES: To determine whether progression independent of relapse activity (PIRA) is present in Aquaporin4-IgG-seropositive neuromyelitis optica spectrum disorder (AQP4+NMOSD), Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) and relapsing remitting Multiple sclerosis (RRMS). METHODS: We retrospectively studied the change in EDSS, confirmed disability worsening (CDW) (i.e., PIRA), and new MRI lesions in AQP4+NMOSD, and MOGAD and MS patients. Linear mixed-effect regression model was used to compare the longitudinal changes in EDSS, and Cox regression was used to compare changes in MRI. RESULTS: The estimated mean ΔEDSS in the AQP4+NMOSD and matched MS group were +0.06 (95%CI: -0.40, +0.52, p = 0.76), and +0.02 (95%CI: -0.05, +0.08, p = 0.6) respectively. The same estimate was -0.08 (95%CI: -0.18, +0.02, p = 0.12) in MOGAD and +0.05 (95%CI: -0.05, +0.15, p = 0.35) in matched MS group. Comparing groups for the presence of CDW (i.e., PIRA) showed that PIRA is more associated with MS compared to AQP4+NMOSD (p = 0.02) and MOGAD (p<0.001). Compared to their matched MS groups, the annualized rate of PIRA was significantly lower in AQP4 (0.08 vs 0.44; p<0.0001), and MOG groups (0.04 vs 0.13; p<0.0001). New T2 or enhancing lesions on brain MRI were higher in MS compared to AQP4+NMOSD and MOGAD patients. CONCLUSION: Relapse-independent changes in the EDSS, CDW, and MRI activity are not common in AQP4+NMOSD and MOGAD, especially when compared with MS. Since our patients were on relapse prevention therapies at the time of EDSS measurements, our study supports the importance of preventing relapses in AQP4+NMOSD and MOGAD and suggests different pathologic mechanisms of relapse-free neurological damage between MS and AQP4+NMOSD/MOGAD.

Recently Added Frameshift Mutation in Human Monkeypox Virus (hMPXV) OPG191 Gene.

Human monkeypox virus (hMPXV) has caused sporadic outbreaks intermittently across countries in recent years, with the largest outbreak in 2022. However, the underlying mechanisms remain unclear. This study searched for recently developed structural variants of the viral genome. A total of 22 hMPXV whole genome sequences were randomly selected from the National Center for Biotechnology Information GenBank sequence database for initial screening. As a result, a recent frameshift mutation based on a 2-base insertion in a coding region was identified at the 3' terminal of the OPG191 gene, which encodes MPXVgp168 (B7R) protein. With this insertion, the protein was prematurely truncated, and the last 11 amino acids were missing, with 3 alternative amino acids added. Among the hMPXV genome sequences registered in the GenBank database as of January 2023, 61 sequences lacked the 2-base insertion and 3,362 sequences were inserted. All 61 sequences without mutations were collected before 2020, whereas 3,358 (99.9%) of the 3,362 sequences with the insertion were collected during or after 2022. These findings imply that a 2-base insertion has recently emerged and has been fixed among the virus population that prevailed in 2022. In summary, a recently emerged frameshift mutation with a 2-base insertion was identified in hMPXV OPG191 gene. Although the structural and functional consequences of this mutation on virulence and infectivity are unknown, research on the possible associations between this mutation and recent hMPXV outbreaks is warranted.

Blood Culture Result Profile in Patients With Central Line-Associated Bloodstream Infection (CLABSI): A Single-Center Experience.

Background Central line-associated bloodstream infection (CLABSI) is among the most common bloodstream infections in the university hospital and intensive care unit settings. This study evaluated the routine blood test findings and microbe profiles of bloodstream infection (BSI) by the presence and types of central vein (CV) access devices (CVADs). Methods A total of 878 inpatients at a university hospital who were clinically suspected for BSI and underwent blood culture (BC) testing between April 2020 and September 2020 were enrolled. Data regarding age at BC testing, sex, WBC count, serum C-reactive protein (CRP) level, BC test results, yielded microbes, and usage and types of CVADs were evaluated. Results The BC yields were detected in 173 patients (20%), suspected contaminating pathogens in 57 (6.5%), and 648 (74%) with a negative yield. The WBC count (p=0.0882) and CRP level (p=0.2753) did not significantly differ between the 173 patients with BSI and the 648 patients with negative BC yields. Among the 173 patients with BSI, 74 used CVADs and met the diagnosis of CLABSI; 48 had a CV catheter, 16 had CV access ports, and 10 had a peripherally inserted central catheter (PICC). Patients with CLABSI showed lower WBC counts (p=0.0082) and serum CRP levels (p=0.0024) compared to those with BSI who did not use CVADs. The most commonly yielded microbes in those with CV catheters, CV-ports, and PICC were Staphylococcus epidermidis (n=9; 19%), Staphylococcus aureus (n=6; 38%), and S. epidermidis (n=8; 80%), respectively. Among those with BSI who did not use CVADs, Escherichia coli (n=31; 31%) was the most common pathogen, followed by S. aureus (n=13; 13%). Conclusion Patients with CLABSI showed lower WBC counts and CRP levels than those with BSI who did not use CVADs. Staphylococcus epidermidis was among the most common microbes in CLABSI and accounted for the majority of yielded microbes in patients who used PICC.

Associations between neuromyelitis optica spectrum disorder, Sjögren's syndrome, and conditions with electrolyte disturbances.

OBJECTIVE: Electrolyte disorders are among the important conditions negatively affecting the disease course of neuromyelitis optica spectrum disorder (NMOSD). Possible mechanisms may include renal tubular acidosis (RTA) accompanying Sjögren's syndrome (SS), syndrome of inappropriate antidiuretic hormone secretion (SIADH), and central diabetes insipidus (DI). Currently, the overlap profiles between these conditions remain uncertain. METHODS: This cross-sectional study collected data from the nationwide administrative Diagnosis Procedure Combination (DPC) database and evaluated the overlap profiles. RESULTS: Among the 28,285,908 individuals from 1203 DPC-covered hospitals, 8477 had NMOSD, 174108 had SS, 4977 had RTA, 7640 had SIADH, and 24,789 had central DI. Of those with NMOSD, 986 (12%) had SS. The odds ratio (OR) for a diagnosis of NMOSD in those with SS compared with those without was 21 [95% confidence interval (CI), 20-23]. Overlap between NMOSD and SS was seen both in males (OR, 28 [95% CI, 23-33]) and females (OR, 16 [15-17]) and was more prominent in the younger population. Among patients with SS, the prevalence of RTA was lower in patients with NMOSD compared with those without NMOSD. Patients with NMOSD showed a higher prevalence of SIADH (OR, 11 [7.5-17]; p < 0.0001) and DI (OR, 3.7 [2.4-5.3]; p < 0.0001). Comorbid SS in NMOSD was associated with a higher prevalence of DI. CONCLUSIONS: Patients with NMOSD are likely to have SS, SIADH, and central DI. RTA in SS does not facilitate the overlap between NMOSD and SS. SS in NMOSD may predispose patients to DI.

Predictors for the Development of Hypoxia or Prolonged Acute Symptoms among Non-Hospitalized Mild-to-Moderate Patients with Coronavirus Disease 2019.

The coronavirus disease 2019 (COVID-19) pandemic remains a global public health concern. The clinical course and risk of developing severe illness among patients with COVID-19 who are at low-risk of severe COVID-19 remain uncertain. This retrospective cohort study from an isolation facility for low-risk COVID-19 patients in Japan evaluated the potential risks for severe disease with hypoxia (SpO2 ≤ 93%) or experiencing prolonged isolation period longer than 14 days with persistent acute symptoms. The study was performed before the spread of the alpha variant in the country and before the start of a nationwide mass vaccination campaign against COVID-19. Among the 929 participants with reliable outcome data regarding the development of hypoxia, 63 (6.8%) developed severe disease with hypoxia during their stays at the facility. Higher age [adjusted odds ratio (aOR), 1.08; 95% confidence interval (CI), 1.06-1.10] and male sex (aOR, 4.70; 95% CI, 2.39-9.22) were associated with this outcome. As for the experience of prolonged isolation period, higher age (aOR, 1.02; 95% CI, 1.01-1.04), atopic diseases (aOR, 1.69, 95% CI, 1.09-2.64), presence of cough at onset (aOR, 1.64; 95% CI, 1.09-2.48), and prescription of oral antibiotics before positive test results for COVID-19 (aOR, 2.37; 95% CI, 1.33-4.22) were associated with this outcome. In summary, 5-10% of low-risk COVID-19 patients later develop hypoxia. Older age and male sex were associated with both the development of hypoxia and prolonged acute symptoms. The unnecessary prescription of antibiotics before COVID-19 diagnosis may prolong COVID-19 symptoms.

White blood cell count profiles in anti-aquaporin-4 antibody seropositive neuromyelitis optica spectrum disorder and anti-myelin oligodendrocyte glycoprotein antibody-associated disease.

White blood cell (WBC) count profiles in anti-aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder (AQP4-NMOSD) and anti-myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) are still unknown. This study evaluated the total WBC count, differential WBC counts, monocyte-to-lymphocyte ratio (MLR), and neutrophil-to-lymphocyte ratio (NLR) in patients with these diseases within three months from an attack before acute treatment or relapse prevention and compared the profiles with those in matched volunteers or in multiple sclerosis (MS) patients. AQP4-NMOSD patients (n = 13) had a higher neutrophil count (p = 0.0247), monocyte count (p = 0.0359), MLR (p = 0.0004), and NLR (p = 0.0037) and lower eosinophil (p = 0.0111) and basophil (p = 0.0283) counts than those of AQP4-NMOSD-matched volunteers (n = 65). Moreover, patients with MOGAD (n = 26) had a higher overall WBC count (p = 0.0001), neutrophil count (p < 0.0001), monocyte count (p = 0.0191), MLR (p = 0.0320), and NLR (p = 0.0002) than those of MOGAD-matched volunteers (n = 130). The three demyelinating diseases showed similar levels of the total and differential WBC counts; however, MOGAD and MS showed different structures in the hierarchical clustering and distributions on a two-dimensional canonical plot using differential WBC counts from the other three groups. WBC count profiles were similar in patients with MOGAD and MS but differed from profiles in matched volunteers or patients with AQP4-NMOSD.

Time-Dependent Analysis of Sicca Symptoms and Anti-Ro/SSA and Anti-La/SSB Antibodies in Patients with AQP4-IgG-Positive Neuromyelitis Optica Spectrum Disorder.

Anti-aquaporin-4 antibody (AQP4-IgG)-positive neuromyelitis optica spectrum disorder (NMOSD) and Sjögren syndrome (SS) are likely comorbidities. However, the exact effects of age and disease duration on the positivity rates of serum anti-Ro/SSA and anti-La/SSB (anti-SSA/SSB) antibodies and the presence of sicca symptoms in patients with AQP4-IgG remain unknown. In the present study, we evaluated the data from patients with suspected NMOSD who had neurological episodes and tested for serum AQP4-IgG. Associations between the presence of serum AQP4-IgG and SS-related findings were evaluated. The presence of anti-SSA/SSB antibodies [odds ratio (OR), 7.34; 95% confidence interval (CI), 5.71-9.43; p < 0.0001] and that of sicca symptoms (OR, 2.08; 95% CI, 1.67-2.58; p < 0.0001) were both higher in patients with AQP4-IgG (n = 1,651) than in those without AQP4-IgG (n = 2,796). Meanwhile, neither age nor the elapsed time from neurological onset was linked to the prevalence of anti-SSA/SSB antibodies or sicca symptoms, and the prevalence rates of the SS-related factors were elevated since the onset of neurological episodes in those with AQP4-IgG. The frequency of sicca symptoms among those with anti-SSA/SSB antibodies was irrespective of AQP4-IgG (OR, 1.11; 95% CI, 0.67-1.85; p = 0.6892). The measured AQP4-IgG titers did not differ significantly according to the presence of anti-SSA/SSB antibodies (p = 0.2386; Mann-Whitney U test). In summary, age and duration of NMOSD were not the factors producing an elevated prevalence of anti-SSA/SSB antibodies and sicca symptoms in patients with AQP4-IgG, implying that the occurrence of comorbid SS is likely to temporarily precede or synchronize with the onset of AQP4-IgG-positive NMOSD.

Insertion and deletion mutations preserved in SARS-CoV-2 variants.

The insertion/deletion (indel) mutation profiles of SARS-CoV-2 variants, including Omicron, remain unclear. We compared whole-genome sequences from various lineages and used preserved indels to infer the ancestral relationships between different lineages. Thirteen indel patterns from twelve sites were seen in ≥ 2 sequences; six of these sites were located in the N-terminal domain of the viral spike gene. Preserved indels in the coding regions were also identified in the non-structural protein 3 (Nsp3), Nsp6, and nucleocapsid genes. Seven of the thirteen indel patterns were specific to the Omicron variants, four of which were observed in BA.1, making it the most mutated variant. Other preserved indels observed in the Omicron variants were also seen in Alpha and/or Gamma, but not Delta, suggesting that Omicron is phylogenetically more proximal to Alpha. We demonstrated distinct profiles of preserved indels among SARS-CoV-2 variants and sublineages, suggesting the importance of indels in viral evolution.

Trinucleotide Substitutions at Two Locations in the SARS-CoV-2 Nucleocapsid (N) Gene.

The genomes of sarbecoviruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), incorporate mutations with short sequence exchanges based on unknown processes. Currently, the presence of such short-sequence exchanges among the genomes of different SARS-CoV-2 lineages remains uncertain. In the present study, multiple SARS-CoV-2 genome sequences from different clades or sublineages were collected from an international mass sequence database and compared to identify the presence of short sequence exchanges. Initial screening with multiple sequence alignments identified two locations with trinucleotide substitutions, both in the nucleocapsid (N) gene. The first exchange from 5'-GAT-3' to 5'-CTA-3' at nucleotide positions 28,280-28,282 resulted in a change in the amino acid from aspartic acid (D) to leucine (L), which was predominant in clade GRY (Alpha). The second exchange from 5'-GGG-3' to 5'-AAC-3' at nucleotide positions 28,881-28,883 resulted in an amino acid change from arginine and glycine (RG) to lysine and arginine (KR), which was predominant in GR (Gamma), GRY (Alpha), and GRA (Omicron). Both trinucleotide substitutions occurred before June 2020. The sequence identity rate between these lineages suggests that coincidental succession of single-nucleotide substitutions is unlikely. Basic local alignment search tool sequence search revealed the absence of intermediating mutations based on single-base substitutions or overlapping indels before the emergence of these trinucleotide substitutions. These findings suggest that trinucleotide substitutions could have developed via an en bloc exchange. In summary, trinucleotide substitutions at two locations in the SARS-CoV-2 N gene were identified. This mutation may provide insights into the evolution of SARS-CoV-2.