Proportion of Patients in the United States Who Fill Their Nirmatrelvir/Ritonavir Prescriptions.

INTRODUCTION: Although real-world studies demonstrate that those prescribed nirmatrelvir/ritonavir (and particularly within 5 days of symptom onset) are less likely to experience severe COVID-19 outcomes, prior studies show that only a small fraction of patients with COVID-19 who are eligible for nirmatrelvir/ritonavir receive a prescription. Studies calculating the proportion of nirmatrelvir/ritonavir prescriptions filled and identifying individual- and pharmacy-level correlates of filling nirmatrelvir/ritonavir are lacking. METHODS: This retrospective cohort study included individuals aged ≥ 12 years with a nirmatrelvir/ritonavir prescription ordered at a large national retail pharmacy (December 22, 2021-August 12, 2023). Those taking contraindicated medications were excluded. For those with only one nirmatrelvir/ritonavir prescription ordered, the outcome was whether the prescription was filled (yes/no). In a subanalysis of these individuals, the outcome was whether the prescription was filled within 5 days of symptom onset (yes/no). For those with multiple prescriptions ordered, the outcome was whether > 1 (vs. 0 or 1) prescriptions were filled. A log-binomial regression with generalized estimating equations was used to identify individual (clinical and demographic) and pharmacy-level (percentage of trade area that is non-Hispanic white, urbanicity, US Census region, and tract-level area deprivation index) correlates. RESULTS: A total of 2,103,570 unique nirmatrelvir/ritonavir prescriptions were ordered for 1,985,990 individuals. Among the 95% of individuals prescribed only one nirmatrelvir/ritonavir course, 88% filled their prescription. Among those with > 1 prescription ordered, 77% (82,993/108,411) filled one and 13% (13,662/108,411) filled > 1. Patients ≥ 50 years of age and those with documented high-risk conditions were slightly more likely to fill prescriptions, regardless of whether one or multiple courses were ordered. Individuals with cancer, asthma, or taking corticosteroids or immunosuppressive medications were more likely to fill multiple prescriptions. CONCLUSIONS: Most patients filled their nirmatrelvir/ritonavir prescriptions. Interventions to improve uptake should focus on increasing patient and provider awareness, reducing nirmatrelvir/ritonavir prescribing disparities, and ensuring treatment initiation within 5 days.

Relationship Between Quantitative Tracheal Geometry and Clinical Course in Various Types of Vascular Ring.

To investigate the relationship between quantitative tracheal geometry and clinical course among various types of vascular ring and to identify factors correlating with symptom presentation. Patients with vascular ring diagnosed between April 2010 and December 2022 were included. All the patients were classified as type 1 (complete double aortic arch); type 2 (incomplete double aortic arch); type 3 (circumflex aorta); type 4 (right aortic arch and aberrant left subclavian artery with a left retroesophageal diverticulum of Kommerell); or type 5 (mirror-imaged right aortic arch with retroesophageal aortic diverticulum). Their clinical characteristics and quantitative variables on computed tomography (CT) were compared. Of the 50 patients enrolled, those with type 1 tended to have a smaller luminal tracheal diameter at the level of the ring. The median symptom-free survival time was shortest in this group (16.0 days [95% confidence interval (CI): 9.4-51.0]), followed by type 3 (138.0 days [95% CI: 0.0-851.4]). Type 1 (hazard ratio [HR]: 9.0; 95% CI: 2.3-35.0; P = 0.001), type 3 (HR: 4.2; 95% CI: 1.4-13.2; P = 0.013), and the percentage of tracheal narrowing in the anteroposterior projection (HR: 0.87; 95% CI: 0.78-0.96; P = 0.008) were significantly associated with symptom presentation in the time-dependent course. The aortic arch encircling the entire circumference in type 1 and high-pressure vasculature in front of the vertebral body in types 1 and 3 may contribute to raising the risk of symptom presentation.

Factors impacting D-dimer levels in patients with acute ischemic cerebrovascular events.

BACKGROUND AND OBJECTIVES: A better understanding of the factors influencing D-dimer levels in code stroke patients is needed to guide further investigations of concomitant thrombotic conditions. This study aimed to investigate the impact of time from symptom onset and other factors on D-dimer levels in patients with acute ischemic stroke (AIS) or transient ischemic attack (TIA). METHODS: Data on consecutive AIS and TIA patients treated at our tertiary-care stroke center between January 2015 and December 2020 were retrospectively assessed. Patients with available D-dimer levels were evaluated for eligibility. Multivariable non-linear regression analyses were performed. RESULTS: In total, 2467 AIS patients and 708 TIA patients were included. The median D-dimer levels differed between the AIS and TIA groups (746 µg/L [interquartile range 381-1468] versus 442 µg/L [interquartile range 244-800], p<0.001). In AIS patients, an early increase in D-dimer levels was demonstrated within the first 6 h (standardized beta coefficient [ß] 0.728; 95% confidence interval [CI] 0.324-1.121). This was followed by an immediate decrease (ß -13.022; 95% CI -20.401 to -5.643) and then by a second, late increase after 35 h (ß 11.750; 95% CI 4.71-18.791). No time-dependent fluctuation in D-dimer levels was observed in TIA patients. CONCLUSION: The time from symptom onset may affect D-dimer levels in patients with AIS but not those with TIA. Further studies confirming these findings and validating time-specific variations are needed to enable D-dimer levels to be used efficiently as an acute stroke and thrombotic risk biomarker.

A dual-energy computed tomography-based radiomics nomogram for predicting time since stroke onset: a multicenter study.

OBJECTIVES: We aimed to develop and validate a radiomics nomogram based on dual-energy computed tomography (DECT) images and clinical features to classify the time since stroke (TSS), which could facilitate stroke decision-making. MATERIALS AND METHODS: This retrospective three-center study consecutively included 488 stroke patients who underwent DECT between August 2016 and August 2022. The eligible patients were divided into training, test, and validation cohorts according to the center. The patients were classified into two groups based on an estimated TSS threshold of ≤ 4.5 h. Virtual images optimized the visibility of early ischemic lesions with more CT attenuation. A total of 535 radiomics features were extracted from polyenergetic, iodine concentration, virtual monoenergetic, and non-contrast images reconstructed using DECT. Demographic factors were assessed to build a clinical model. A radiomics nomogram was a tool that the Rad score and clinical factors to classify the TSS using multivariate logistic regression analysis. Predictive performance was evaluated using receiver operating characteristic (ROC) analysis, and decision curve analysis (DCA) was used to compare the clinical utility and benefits of different models. RESULTS: Twelve features were used to build the radiomics model. The nomogram incorporating both clinical and radiomics features showed favorable predictive value for TSS. In the validation cohort, the nomogram showed a higher AUC than the radiomics-only and clinical-only models (AUC: 0.936 vs 0.905 vs 0.824). DCA demonstrated the clinical utility of the radiomics nomogram model. CONCLUSIONS: The DECT-based radiomics nomogram provides a promising approach to predicting the TSS of patients. CLINICAL RELEVANCE STATEMENT: The findings support the potential clinical use of DECT-based radiomics nomograms for predicting the TSS. KEY POINTS: Accurately determining the TSS onset is crucial in deciding a treatment approach. The radiomics-clinical nomogram showed the best performance for predicting the TSS. Using the developed model to identify patients at different times since stroke can facilitate individualized management.

Early Surgery Versus Exercise Therapy and Patient Education for Traumatic and Nontraumatic Meniscal Tears in Young Adults-An Exploratory Analysis From the DREAM Trial.

OBJECTIVE: To compare the effect of early meniscal surgery versus exercise and education with the option of later surgery on pain, function, and quality of life in young patients with a meniscal tear, taking symptom onset into account. DESIGN: Randomized controlled trial. METHODS: In a randomized controlled trial (the "Danish RCT on Exercise versus Arthroscopic Meniscal surgery for young adults" [DREAM] trial), 121 patients aged 18-40 years with a magnetic resonance imaging-verified meniscal tear were randomized to surgery or 12 weeks of supervised exercise and patient education. For this exploratory study, the analyses were stratified by symptom onset (traumatic/nontraumatic). The main outcome was the difference in change after 12 months in the mean score of 4 Knee injury and Osteoarthritis Outcome Score subscales (KOOS4) covering pain, symptoms, function in sport and recreation, and quality of life. RESULTS: Forty-two patients (69%) in the exercise therapy group and 47 (78%) in the surgery group were categorized as having a traumatic tear. We observed no difference in change in the KOOS4 after 12 months between the 2 treatment groups for either traumatic tears (18.8 versus 16.0 in the surgery versus exercise therapy groups; adjusted mean difference, 4.8 [95% confidence interval, -1.7 to 11.2]) or nontraumatic tears (20.6 versus 17.3 in the surgery versus exercise therapy groups; adjusted mean difference, 7.0 [95% confidence interval, -3.7 to 17.7]). CONCLUSION: In patients with traumatic and nontraumatic meniscus tears, early meniscal surgery did not appear superior to exercise and education in improving pain, function, and quality of life after 12 months. Further research is needed to confirm the clinical applicability of these findings. J Orthop Sports Phys Ther 2024;54(5):1-10. Epub 22 February 2024. doi:10.2519/jospt.2024.12245.

Dual-energy computed tomography angiography-based quantification of lesion net water uptake to identify stroke onset time.

Objectives: To explore whether dual-energy computed tomography (DECT) angiography can provide reliable quantitative information on net water uptake (NWU) of ischemic brain to identify stroke patients within 4.5 h. Methods: We retrospectively reviewed 142 patients with stroke occurrence and who underwent DECT angiography between August 2016 and May 2022. DECT angiography manual drawn the ischemic area by referring to the normal area of the contralateral hemisphere and follow-up images. The NWU in the ischemic area was determined using virtual non-contrast and monoenergetic (VNC &VM) images acquired from DECT angiography. The NWU values in the ischemic area were compared between stroke patients within and beyond 4.5 h. The diagnostic performance of the NWU values derived from the VNC and VM images was assessed through receiver operating characteristic curve analysis. Additionally, Furthermore, we examined the correlation between the NWU values and the stroke onset time. Results: Seventy-eight (54.93 %) stroke patients underwent DECT angiography and within 4.5 h. These patients with lower median National Institute of Health stroke scale (NIHSS) scores on admission than those beyond 4.5 h (p < 0.05). Furthermore, the group within 4.5 h had lower NWU values than did the group beyond 4.5 h on all VNC and VM images (p < 0.001). The analysis revealed that the NWU values determined using the VM (60 keV) images had the highest predictive efficiency (AUC, 0.95; sensitivity, 100 %; and specificity, 89.06 %) and showed the strongest positive correlation with stroke onset time (r-value = 0.58, p < 0.001). Conclusions: Our findings showed that DECT angiography-based quantification of NWU helps identify the stroke patients within 4.5 h with high predictive efficiency. Thus, NWU values determined using VM (60 keV) images could serve as a significant biomarker for stroke onset time.

Cardiac, possible cardiac, and likely non-cardiac origin of chest pain : A hitherto underestimated parameter in German chest pain units.

BACKGROUND: Current guidelines emphasize the diagnostic value of non-cardiac or possibly cardiac chest pain. The goal of this analysis was to determine whether German chest pain units (CPUs) adequately address conditions with "atypical" chest pain in existing diagnostic structures. METHOD: A total of 11,734 patients from the German CPU registry were included. The analyses included mode of admission, critical time intervals, diagnostic steps, and differential diagnoses. RESULTS: Patients with unspecified chest pain were younger, more often female, were less likely to have classic cardiovascular risk factors and tended to present more often as self-referrals. Patients with acute coronary syndrome (ACS) mostly had prehospital medical contact. Overall, there was no difference between these two groups regarding the time from the onset of first symptoms to arrival at the CPU. In the CPU, the usual basic diagnostic measures were performed irrespective of ACS as the primary working diagnosis. In the non-ACS group, further ischemia-specific diagnostics were rarely performed. Extra-cardiac differential diagnoses were not specified. CONCLUSION: The establishment of broader awareness programs and opening CPUs for low-threshold evaluation of self-referring patients should be discussed. Regarding the rigid focus on the clarification of cardiac causes of chest pain, a stronger interdisciplinary approach should be promoted.

Celiac Disease in Moroccan Children: Diagnostic Characteristics and Determinants of Diagnosis Delay.

Advances in the field of celiac disease have led to a better understanding of the disease, but it remains underdiagnosed and poses a daily challenge to clinicians to make a timely diagnosis. This study aims to analyze and describe diagnosis characteristics, diagnosis delay, and the factors influencing this delay in Moroccan children. Our study included 324 children diagnosed during the study period from January 01, 2010, to December 30, 2019, at the Department of Pediatrics, Hassan II University Hospital in Fez, Morocco. Data were collected using a collection grid and then analyzed using SPSS 26 software (IBM Corp., Armonk, NY). The results showed a female predominance (n=197, 60.8%), with a diagnosis age of 73.8±46.8 months. The mean age onset of symptoms was 51.3±41.2 months, and the diagnosis delay was 22.2±22.6 months, with only 32.7% (n=106) diagnosed less than 12 months after symptom onset. The most common consultation reason was diarrhea (n=149, 46%) and growth delay (n=105, 32.4%) and 50.5% (n=98) of parents consulted a pediatrician first. The three clinical, serologic, and histologic criteria made it possible to agree on the diagnosis, with the clinical profile dominated by the digestive form at 84.9% (n=279), serologic with the presence of IgA transglutaminase antibodies (95.7%; n=310), and histologic with villous atrophy at 91.7% (n=297). Unfortunately, 14.8% (n=48) of the children were diagnosed with a celiac crisis. The multivariate logistic regression analysis showed that as symptoms onset age increased, so did the risk of late diagnosis (OR=0.96, 95% CI: 0.94 to 0.97, p<0.001). Age of diagnosis was also associated with delayed diagnosis (OR=19.68, 95% CI: 8.77 to 44.15, p<0.001). The combination of these variables and the diagnosis delay argues in favor of adopting a diagnosis strategy that includes raising awareness among healthcare professionals of the need to identify typical and atypical cases early in order to reduce the adverse effects of late diagnosis and the complications that can result. This methodology for improving diagnoses may also unearth previously unknown aspects of celiac disease in Moroccan children.

Individualized estimated years from onset of Alzheimer's disease- related decline for adults with Down syndrome.

Introduction: Adults with Down syndrome (DS) are at increased risk for Alzheimer's disease (AD) and vary in their age of transition from AD preclinical to prodromal or more advanced clinical stages. An empirically based method is needed to determine individual "estimated years from symptom onset (EYO)," the same construct used in studies of autosomal dominant AD . Methods: Archived data from a previous study of > 600 adults with DS were examined using survival analysis methods. Age-specific prevalence of prodromal AD or dementia, cumulative risk, and EYOs were determined. Results: Individualized EYOs for adults with DS ranging in age from 30 to 70+ were determined, dependent upon chronological age and clinical status. Discussion: EYOs can be a useful tool for studies focused on biomarker changes during AD progression in this and other populations at risk, studies that should contribute to improved methods for diagnosis, prediction of risk, and identification of promising treatment targets. HIGHLIGHTS: Years from Alzheimer's disease (AD) onset (EYO) was estimated for adults with Down syndrome (DS).EYOs were informed by AD clinical status and age, ranging from 30 to > 70 years.Influences of biological sex and apolipoprotein E genotype on EYOs were examined.EYOs have advantages for predicting risk of AD-related dementia compared to age.EYOs can be extremely informative in studies of preclinical AD progression.

Rapid review and meta-analysis of serial intervals for SARS-CoV-2 Delta and Omicron variants.

BACKGROUND: The serial interval is the period of time between symptom onset in the primary case and symptom onset in the secondary case. Understanding the serial interval is important for determining transmission dynamics of infectious diseases like COVID-19, including the reproduction number and secondary attack rates, which could influence control measures. Early meta-analyses of COVID-19 reported serial intervals of 5.2 days (95% CI: 4.9-5.5) for the original wild-type variant and 5.2 days (95% CI: 4.87-5.47) for Alpha variant. The serial interval has been shown to decrease over the course of an epidemic for other respiratory diseases, which may be due to accumulating viral mutations and implementation of more effective nonpharmaceutical interventions. We therefore aggregated the literature to estimate serial intervals for Delta and Omicron variants. METHODS: This study followed Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. A systematic literature search was conducted of PubMed, Scopus, Cochrane Library, ScienceDirect, and preprint server medRxiv for articles published from April 4, 2021, through May 23, 2023. Search terms were: ("serial interval" or "generation time"), ("Omicron" or "Delta"), and ("SARS-CoV-2" or "COVID-19"). Meta-analyses were done for Delta and Omicron variants using a restricted maximum-likelihood estimator model with a random effect for each study. Pooled average estimates and 95% confidence intervals (95% CI) are reported. RESULTS: There were 46,648 primary/secondary case pairs included for the meta-analysis of Delta and 18,324 for Omicron. Mean serial interval for included studies ranged from 2.3-5.8 days for Delta and 2.1-4.8 days for Omicron. The pooled mean serial interval for Delta was 3.9 days (95% CI: 3.4-4.3) (20 studies) and Omicron was 3.2 days (95% CI: 2.9-3.5) (20 studies). Mean estimated serial interval for BA.1 was 3.3 days (95% CI: 2.8-3.7) (11 studies), BA.2 was 2.9 days (95% CI: 2.7-3.1) (six studies), and BA.5 was 2.3 days (95% CI: 1.6-3.1) (three studies). CONCLUSIONS: Serial interval estimates for Delta and Omicron were shorter than ancestral SARS-CoV-2 variants. More recent Omicron subvariants had even shorter serial intervals suggesting serial intervals may be shortening over time. This suggests more rapid transmission from one generation of cases to the next, consistent with the observed faster growth dynamic of these variants compared to their ancestors. Additional changes to the serial interval may occur as SARS-CoV-2 continues to circulate and evolve. Changes to population immunity (due to infection and/or vaccination) may further modify it.

Demographic and geographic variations in the access time of pediatric patients presenting with staring spells.

OBJECTIVE: To assess the demographic and geographic variations in access time - defined as years between the date of symptom onset and initial date of neurological care - in pediatric patients presenting with staring spells. MATERIALS AND METHODS: We conducted a secondary analysis of a retrospective chart review study from 2011 to 2021. A total of 1,353 staring spell patients, aged 0 to 17.9 years, were analyzed for age, sex, race/ethnicity, insurance, county, average county annual per capita personal income, and access time. RESULTS: Patients aged 0-2.9 years had the shortest median access time of 0.3 years, compared to 1.2 years in patients aged 3-12.9 years and 1.0 year in patients aged 13-17.9 years. Statistically significant differences were seen based on race/ethnicity and insurance with White patients having shorter access time of 0.5 years compared to Black patients with 1.0 year and self-pay patients having the shortest access time of 0.4 years compared to patients with private insurance (0.7 years). Warren County had the largest annual per capita personal income of $65,855 and access time of 0.5 years compared to Preble county with the least annual per capita personal income of $45,016 and access time of 1.1 years. CONCLUSION: Demographic parameters of age, race/ethnicity, insurance, and annual county per capita personal income appeared to be associated with access time to initial neurological care in patients with staring spells. These associations need to be investigated further to ensure timely access to neurological care and to ensure equity in health care.

Pre-hospital delay, clinical characteristics, angiographic findings, and in-hospital mortality in young and middle-aged adults with acute coronary syndrome: a single-centre registry analysis.

There are several differences between younger and older adults with acute coronary syndrome (ACS). However, few studies have evaluated these differences. We analysed the pre-hospital time interval [symptom onset to first medical contact (FMC)], clinical characteristics, angiographic findings, and in-hospital mortality in patients aged ≤50 (group A) and 51-65 (group B) years hospitalised for ACS. We retrospectively collected data from 2010 consecutive patients hospitalised with ACS between 1 October 2018 and 31 October 2021 from a single-centre ACS registry. Groups A and B included 182 and 498 patients, respectively. ST-segment elevation myocardial infarction (STEMI) was more common in group A than group B (62.6 and 45.6%, respectively; P < 0.001). The median time from symptom onset to FMC in STEMI patients did not significantly differ between groups A and B [74 (40-198) and 96 (40-249) min, respectively; P = 0.369]. There was no difference in the rate of sub-acute STEMI (symptom onset to FMC > 24 h) between groups A and B (10.4% and 9.0%, respectively; P = 0.579). Among patients with non-ST elevation acute coronary syndrome (NSTE-ACS), 41.8 and 50.2% of those in groups A and B, respectively, presented to the hospital within 24 h of symptom onset (P = 0.219). The prevalence of previous myocardial infarction was 19.2% in group A and 19.5% in group B (P = 1.00). Hypertension, diabetes, and peripheral arterial disease were more common in group B than group A. Active smoking was more common in group A than group B (67 and 54.2%, respectively; P = 0.021). Single-vessel disease was present in 52.2 and 37.1% of participants in groups A and B, respectively (P = 0.002). Proximal left anterior descending artery was more commonly the culprit lesion in group A compared with group B, irrespective of the ACS type (STEMI, 37.7 and 24.2%, respectively; P = 0.009; NSTE-ACS, 29.4 and 21%, respectively; P = 0.140). The hospital mortality rate for STEMI patients was 1.8 and 4.4% in groups A and B, respectively (P = 0.210), while for NSTE-ACS patients it was 2.9 and 2.6% in groups A and B, respectively (P = 0.873). No significant differences in pre-hospital delay were found between young (≤50 years) and middle-aged (51-65 years) patients with ACS. Although clinical characteristics and angiographic findings differ between young and middle-aged patients with ACS, the in-hospital mortality rate did not differ between the groups and was low for both of them.

Early Invasive Strategy Based on the Time of Symptom Onset of Non-ST-Segment Elevation Myocardial Infarction.

BACKGROUND: A limitation of the current guidelines regarding the timing of invasive coronary angiography for patients with non-ST-segment elevation acute coronary syndrome is the randomization time. To date, no study has reported the clinical outcomes of invasive strategy timing on the basis of the time of symptom onset. OBJECTIVES: The aim of this study was to investigate the effect of invasive strategy timing from the time of symptom onset on the 3-year clinical outcomes of patients with non-ST-segment elevation myocardial infarction (NSTEMI). METHODS: Among 13,104 patients from the Korea Acute Myocardial Infarction Registry-National Institutes of Health, 5,856 patients with NSTE myocardial infarction were evaluated. The patients were categorized according to symptom-to-catheter (StC) time (<48 or ≥48 hours). The primary outcome was 3-year all-cause mortality. RESULTS: Overall, 3,919 patients (66.9%) were classified into the StC time <48 hours group. This group had lower all-cause mortality than the group with StC time ≥48 hours (7.3% vs 13.4%; P < 0.001). The lower risk for all-cause mortality in the group with StC time <48 hours group was consistent in all subgroups. Notably, emergency medical service use (HR: 0.31; 95% CI: 0.19-0.52) showed a lower risk for all-cause mortality than no emergency medical service use (HR: 0.54; 95% CI: 0.46-0.65; P value for interaction = 0.008). CONCLUSIONS: An early invasive strategy on the basis of StC time was associated with a decreased risk for all-cause mortality in patients with NSTEMI. Because the study was based on a prospective registry, the results should be considered hypothesis generating, highlighting the need for further research. (iCReaT Study No. C110016).

The APOE4 effect: structural brain differences in Alzheimer's disease according to the age at symptom onset.

BACKGROUND AND PURPOSE: How the APOE genotype can differentially affect cortical and subcortical memory structures in biomarker-confirmed early-onset (EOAD) and late-onset (LOAD) Alzheimer's disease (AD) was assessed. METHOD: Eighty-seven cerebrospinal fluid (CSF) biomarker-confirmed AD patients were classified according to their APOE genotype and age at onset. 28 were EOAD APOE4 carriers (+EOAD), 21 EOAD APOE4 non-carriers (-EOAD), 23 LOAD APOE4 carriers (+LOAD) and 15 LOAD APOE4 non-carriers (-LOAD). Grey matter (GM) volume differences were analyzed using voxel-based morphometry in Papez circuit regions. Multiple regression analyses were performed to determine the relation between GM volume loss and cognition. RESULTS: Significantly more mammillary body atrophy in +EOAD compared to -EOAD is reported. The medial temporal and posterior cingulate cortex showed less GM in +LOAD compared to -LOAD. Medial temporal GM volume loss was also found in +EOAD compared to -LOAD. With an exception for +EOAD, medial temporal GM was strongly associated with episodic memory in the three groups, whilst posterior cingulate cortex GM volume was more related with visuospatial abilities. Visuospatial abilities and episodic memory were also associated with the anterior thalamic nucleus in -LOAD. CONCLUSIONS: Our results show that the APOE genotype has a significant effect on GM integrity as a function of age of disease onset. Specifically, whilst LOAD APOE4 genotype is mostly associated with increased medial temporal and parietal atrophy compared to -LOAD, for EOAD APOE4 might have a more specific effect on subcortical (mammillary body) structures. The findings suggest that APOE genotype needs to be taken into account when classifying patients by age at onset.

A Spatiotemporal Solution to Control COVID-19 Transmission at the Community Scale for Returning to Normalcy: COVID-19 Symptom Onset Risk Spatiotemporal Analysis.

BACKGROUND: Following the recent COVID-19 pandemic, returning to normalcy has become the primary goal of global cities. The key for returning to normalcy is to avoid affecting social and economic activities while supporting precise epidemic control. Estimation models for the spatiotemporal spread of the epidemic at the refined scale of cities that support precise epidemic control are limited. For most of 2021, Hong Kong has remained at the top of the "global normalcy index" because of its effective responses. The urban-community-scale spatiotemporal onset risk prediction model of COVID-19 symptom has been used to assist in the precise epidemic control of Hong Kong. OBJECTIVE: Based on the spatiotemporal prediction models of COVID-19 symptom onset risk, the aim of this study was to develop a spatiotemporal solution to assist in precise prevention and control for returning to normalcy. METHODS: Over the years 2020 and 2021, a spatiotemporal solution was proposed and applied to support the epidemic control in Hong Kong. An enhanced urban-community-scale geographic model was proposed to predict the risk of COVID-19 symptom onset by quantifying the impact of the transmission of SARS-CoV-2 variants, vaccination, and the imported case risk. The generated prediction results could be then applied to establish the onset risk predictions over the following days, the identification of high-onset-risk communities, the effectiveness analysis of response measures implemented, and the effectiveness simulation of upcoming response measures. The applications could be integrated into a web-based platform to assist the antiepidemic work. RESULTS: Daily predicted onset risk in 291 tertiary planning units (TPUs) of Hong Kong from January 18, 2020, to April 22, 2021, was obtained from the enhanced prediction model. The prediction accuracy in the following 7 days was over 80%. The prediction results were used to effectively assist the epidemic control of Hong Kong in the following application examples: identified communities within high-onset-risk always only accounted for 2%-25% in multiple epidemiological scenarios; effective COVID-19 response measures, such as prohibiting public gatherings of more than 4 people were found to reduce the onset risk by 16%-46%; through the effect simulation of the new compulsory testing measure, the onset risk was found to be reduced by more than 80% in 42 (14.43%) TPUs and by more than 60% in 96 (32.99%) TPUs. CONCLUSIONS: In summary, this solution can support sustainable and targeted pandemic responses for returning to normalcy. Faced with the situation that may coexist with SARS-CoV-2, this study can not only assist global cities in responding to the future epidemics effectively but also help to restore social and economic activities and people's normal lives.

Transient expression of antinuclear RNP-A antibodies in patients with acute COVID-19 infection.

Introduction: Viral infections have been implicated in the initiation of the autoimmune diseases. Recent reports suggest that a proportion of patients with COVID-19 develop severe disease with multiple organ injuries. We evaluated the relationship between COVID-19 severity, prevalence and persistence of antinuclear and other systemic and organ specific autoantibodies as well as SARS-CoV-2 infection specific anti-nucleocapsid (N) IgG antibodies and protective neutralizing antibody (Nab) levels. Methods: Samples from 119 COVID-19 patients categorized based on their level of care and 284 healthy subjects were tested for the presence and persistence of antinuclear and other systemic and organ specific autoantibodies as well as SARS-CoV-2 and neutralizing antibody levels. Results: The data shows significantly increased levels of anti RNP-A, anti-nucleocapsid and neutralizing antibody among patients receiving ICU care compared to non-ICU care. Furthermore, subjects receiving ICU care demonstrated significantly higher nucleocapsid IgG levels among the RNP-A positive cohort compared to RNP-A negative cohort. Notably, the expression of anti RNP-A antibodies is transient that reverts to non-reactive status between 20 and 60 days post symptom onset. Conclusions: COVID-19 patients in ICU care exhibit significantly higher levels of transient RNP-A autoantibodies, anti-nucleocapsid, and SARS-CoV-2 neutralizing antibodies compared to patients in non-ICU care.

Understanding spatiotemporal symptom onset risk of Omicron BA.1, BA.2 and hamster-related Delta AY.127.

Purpose: Investigation of the community-level symptomatic onset risk regarding severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern, is crucial to the pandemic control in the new normal. Methods: Investigated in this study is the spatiotemporal symptom onset risk with Omicron BA.1, BA.2, and hamster-related Delta AY.127 by a joint analysis of community-based human mobility, virus genomes, and vaccinations in Hong Kong. Results: The spatial spread of Omicron BA.2 was found to be 2.91 times and 2.56 times faster than that of Omicron BA.1 and Delta AY.127. Identified has been an early spatial invasion process in which spatiotemporal symptom onset risk was associated with intercommunity and cross-community human mobility of a dominant source location, especially regarding enhancement of the effects of the increased intrinsic transmissibility of Omicron BA.2. Further explored is the spread of Omicron BA.1, BA.2, and Delta AY.127 under different full and booster vaccination rate levels. An increase in full vaccination rates has primarily contributed to the reduction in areas within lower onset risk. An increase in the booster vaccination rate can promote a reduction in those areas within higher onset risk. Conclusions: This study has provided a comprehensive investigation concerning the spatiotemporal symptom onset risk of Omicron BA.1, BA.2, and hamster-related Delta AY.127, and as such can contribute some help to countries and regions regarding the prevention of the emergence of such as these variants, on a strategic basis. Moreover, this study provides scientifically derived findings on the impact of full and booster vaccination campaigns working in the area of the reduction of symptomatic infections.

Two-Dose Vaccination Significantly Prolongs the Duration from Symptom Onset to Death: A Retrospective Study Based on 173,894 SARS-CoV-2 Cases in Khyber Pakhtunkhwa, Pakistan.

This research was carried out to quantify the duration from symptom onset to recovery/death (SOR/SOD) during the first four waves and the Alpha/Delta period of the epidemic in Khyber Pakhtunkhwa, Pakistan, and identify the associated factors. A total of 173,894 COVID-19 cases were admitted between 16 March 2020 and 30 November 2021, including 458 intensive care unit (ICU) cases. The results showed that the case fatality rate (CFR) increased with age, and females had a higher CFR. The median SOR of ICU cases was longer than that of non-ICU cases (27.6 vs. 17.0 days), while the median SOD was much shorter (6.9 vs. 8.4 days). The SOR and SOD in the Delta period were slightly shortened than the Alpha period. Age, cardiovascular diseases, chronic lung disease, diabetes, fever, breathing issues, and ICU admission were risk factors that were significantly associated with SOD (p < 0.001). A control measure, in-home quarantine, was found to be significantly associated with longer SOD (odds ratio = 9.49, p < 0.001). Infected vaccinated individuals had longer SOD than unvaccinated individuals, especially for cases that had received two vaccine doses (p < 0.001). Finally, an advice on getting full-dose vaccination is given specifically to individuals aged 20-59 years.

Idling for Decades: A European Study on Risk Factors Associated with the Delay Before a Narcolepsy Diagnosis.

Purpose: Narcolepsy type-1 (NT1) is a rare chronic neurological sleep disorder with excessive daytime sleepiness (EDS) as usual first and cataplexy as pathognomonic symptom. Shortening the NT1 diagnostic delay is the key to reduce disease burden and related low quality of life. Here we investigated the changes of diagnostic delay over the diagnostic years (1990-2018) and the factors associated with the delay in Europe. Patients and Methods: We analyzed 580 NT1 patients (male: 325, female: 255) from 12 European countries using the European Narcolepsy Network database. We combined machine learning and linear mixed-effect regression to identify factors associated with the delay. Results: The mean age at EDS onset and diagnosis of our patients was 20.9±11.8 (mean ± standard deviation) and 30.5±14.9 years old, respectively. Their mean and median diagnostic delay was 9.7±11.5 and 5.3 (interquartile range: 1.7-13.2 years) years, respectively. We did not find significant differences in the diagnostic delay over years in either the whole dataset or in individual countries, although the delay showed significant differences in various countries. The number of patients with short (≤2-year) and long (≥13-year) diagnostic delay equally increased over decades, suggesting that subgroups of NT1 patients with variable disease progression may co-exist. Younger age at cataplexy onset, longer interval between EDS and cataplexy onsets, lower cataplexy frequency, shorter duration of irresistible daytime sleep, lower daytime REM sleep propensity, and being female are associated with longer diagnostic delay. Conclusion: Our findings contrast the results of previous studies reporting shorter delay over time which is confounded by calendar year, because they characterized the changes in diagnostic delay over the symptom onset year. Our study indicates that new strategies such as increasing media attention/awareness and developing new biomarkers are needed to better detect EDS, cataplexy, and changes of nocturnal sleep in narcolepsy, in order to shorten the diagnostic interval.

Estimated incubation period for monkeypox cases confirmed in the Netherlands, May 2022.

In May 2022, monkeypox outbreaks have been reported in countries not endemic for monkeypox. We estimated the monkeypox incubation period, using reported exposure and symptom-onset times for 18 cases detected and confirmed in the Netherlands up to 31 May 2022. Mean incubation period was 9.0 [corrected] days (5th-95th percentiles: 4.2-17.3), underpinning the current recommendation to monitor or isolate/quarantine case contacts for 21 days. However, as the incubation period may differ between different transmission routes, further epidemiological investigations are needed.