Symptomatic Participants Research Articles

Incremental declines in independence associated with disease progression in early symptomatic Alzheimer’s disease (AD)

AbstractBackgroundAssociations between disease progression (DP) and health outcomes are poorly characterized in mild cognitive impairment (MCI) and mild AD (MILD). To address this, we examined the impact of DP on incremental changes in independent functioning over 18 months; baseline factors associated with DP were also explored.MethodsParticipants included amyloid‐positive participants assigned to placebo in EXPEDITION‐1/2/3 (solanezumab) and AMARANTH (lanabecestat) studies. DP defined as worsening ³5 (MCI1) or ³9 (MILD2) points on the Integrated Alzheimer’s Disease Rating Scale (iADRS). Endpoints included proportions of participants requiring home supervision (³1 hour) or unable to leave home independently (score <3) and change in total care partner time. Machine learning methods using penalized logistic regression and random forest identified factors associated with DP. Least squares mean change (LSMC) was estimated from mixed‐model repeated measures.ResultsOf 1884 participants (274 MCI, 1610 MILD), 56% of MCI and 63% of MILD participants met DP criteria over 18 months.Baseline AD medication use, greater care partner time, worse functional activities questionnaire (FAQ) score and CDR‐SB, higher iADRS, and lower BMI and MMSE increased odds of DP for MILD (Figure 1) but not for MCI.Proportion of participants with DP requiring home supervision (p<0.001; MILD only) and not leaving home independently (p<0.05; MCI&MILD) increased significantly at each post‐baseline visit over 18 months (Figure 2). DP in MILD only had significantly higher proportions of participants who could not be left home alone or travel outside of home independently vs no DP (p<0.05).In those with DP, total care partner time increased significantly from baseline to 18 months (LSMC: 46.0±12.5 hours/month for MCI and 73.2±5.5 for MILD) (Figure 3). For DP vs no DP, increased care partner time at 18 months was significantly higher for MILD (LSMC difference, 66.0±9.3 hours/month; p<0.001) but not for MCI.ConclusionsEarly symptomatic AD participants who progressed over 18 months had reduced independence and required more care partner time. Treatments that slow DP may preserve independence and reduce overall health care burden.

Remote assessment of functional impairment in Alzheimer’s disease: results of the RADAR‐AD study

AbstractBackgroundRemote monitoring technologies (RMTs), such as smartphone apps and smartwatches, are changing the way functional and cognitive performance are measured in Alzheimer’s disease (AD). Due to their sensitivity, objectivity, and the option of long‐term and continuous measurement, RMTs have the potential to detect a subtle decline in the earliest stages of AD. Here, we present the results of the European RADAR‐AD project (Remote Assessment of Disease and Relapse – Alzheimer’s disease), which aims to test feasibility, acceptability and validity of RMT measures across all stages of AD, from cognitively normal to mild dementia.MethodFour study groups (amyloid negative healthy controls, and amyloid positive preclinical AD, prodromal AD, mild‐to‐moderate AD) were included in this cross‐sectional study (N = 175). During 8 weeks, participants wore two activity trackers (Fitbit and Axivity) measuring physical activity, heart rate and sleep continuously, and used two interactive smartphone apps (Mezurio and Altoida’s research algorithm: DNS‐MCI) measuring cognition daily/weekly. At baseline, participants underwent extensive neuropsychological, physical examinations, and did two sensor‐based tests (banking app and walk test). Features were extracted for all RMTs (Figure 1) and compared across groups using ANCOVA, with adjustment for relevant confounders. This study is part of an ongoing investigation into high‐end multimodal analyses for real‐world functional performance of continuous RMT data streams.ResultCompliance was high, but decreased with cognitive impairment (feasibility). User experience did not differ between groups but was lower for smartwatches compared to interactive smartphone apps (Table 1) (acceptability). Various individual sensors discriminated symptomatic AD participants from asymptomatic participants (p<0.05), for example the two active apps, but did not discriminate preclinical AD from healthy controls (Table 1) (validity).ConclusionThe RADAR‐AD study provides unique insights in the feasibility, acceptability, and validity of remote monitoring of functional abilities in AD and their potential to differentiate between syndromic stages. This work has received support from the EU/EFPIA Innovative Medicines Initiative Joint Undertaking (grant No 806999) and their associated partners. www.imi.europa.eu. This communication reflects the views of the RADAR‐AD consortium and neither IMI nor the European Union and EFPIA are liable for any use that may be made of the information contained herein.

Relationship between loss of awareness of cognitive decline and tau pathology in the Alzheimer’s disease spectrum: modulatory role of resting‐state functional connectivity

AbstractBackgroundPatients with Alzheimer’s disease (AD) often demonstrate anosognosia, which is reduced awareness of cognitive decline. Anosognosia has been associated with tau accumulation (d'Oleire Uquillas et al., 2020) and impaired resting‐state functional connectivity (FC) in self‐referential networks (Vannini et al., 2017, Valera‐Bermejo et al., 2022). The explicit links between AD pathological deposits and large‐scale functional networks associated with anosognosia have yet to be elucidated. Here, we sought to examine whether FC plays a modulatory role in the effect of tau on awareness in participants across the AD spectrum.MethodWe included 58 participants from two observational cohorts—44 asymptomatic (Clinical Dementia Rating (CDR) global score = 0) and 14 symptomatic (CDR≥0.5) individuals (Table1). Awareness was measured as the participant‐study partner discrepancy on the Cognitive Function Index. Flortaucipir‐PET was used to quantify tau accumulation, and segregation analysis was applied to resting‐state fMRI data to asses within‐network connectivity. For both modalities, the mean value in each of the Yeo 7 networks was used. First, a linear regression model was performed to assess the association between awareness and group (i.e., symptomatic/asymptomatic). Linear regression models were also used to assess the relationship between awareness and tau in the 7 networks, separately. Finally, we examined the effect of the FC×tau interaction on awareness. All models were adjusted for age, sex, and education.ResultHolding age, sex, and education constant, mean awareness was 0.18 lower in symptomatic (vs. asymptomatic) participants (p<0.01). Lower awareness was associated with a higher tau burden in all 7 networks (Table2). Interaction effects between tau and FC were observed. Specifically, reduced awareness was associated with high tau burden when the salience network was less functionally connected (Figure1A; β = ‐0.23, p = 0.02) and when the dorsal attention network was more functionally connected (Figure1B; β = 0.70, p = 0.03). For all other networks, the relationship between awareness and tau was not modified by the FC of the same network (Table2).ConclusionThese findings provide new insights into the neuropathological correlates of anosognosia in AD. It suggests that anosognosia is not only due to local pathology in single brain areas but also to altered connectivity between them, especially within self‐referential networks.

Association of low frequency variants with regional cortical grey matter volumes in genetic frontotemporal dementia: Results from GENFI

AbstractBackgroundFrontotemporal dementia (FTD) is a neurodegenerative condition characterized by heterogeneous clinical, pathological, and genetic features. Mutations in three genes account for the majority of autosomal dominant FTD: GRN, MAPT, and C9orf72. We tested whether gene‐based aggregate burden of genome‐wide low‐frequency variants contribute to variation in regional cortical and subcortical grey matter volumes in the GENetic Frontotemporal dementia Initiative (GENFI), after controlling for effects of autosomal dominant mutations.MethodGENFI recruits symptomatic and presymptomatic participants from families segregating genetic FTD. We included 517 participants with genotype (Neurochip; imputed against TOPMed), and T1w‐MRI brain volumetric data. Gene‐based burden tests that aggregate the number of uncommon/rare variants by gene were used to examine the association of low‐frequency variants (minor allele frequency: 0.000001 to <0.05) with regional cortical and subcortical grey matter volumes, controlling for age, sex, total intracranial volume, mutation status, population stratification, and family membership (kinship matrix). In two separate analyses, we used the following set of annotations to account for (i) loss of function mutations (LOF): start gain, stop loss, start loss, essential splice site, stop gain, normal splice site, and non‐synonymous, (ii) insertions, deletions, and frameshift mutations (indel‐fs).ResultOf the 517 participants (300 women), 307 were mutation carriers (symptomatic = 82). For LOF mutations (731 genes tested; significance threshold: p = 0.05/731 = 6.8×10−5), aggregate burden of variants in BSND were associated with lower volumes in: temporal (p = 6.6×10−6), left insula (p = 5.0×10−5), and ventromedial prefrontal cortical (p = 2.8×10−5) regions. For indel‐fs mutations (826 genes tested; significance threshold: p = 0.05/826 = 6.05×10−5), aggregate burden of variants in: (i) E2F2 was associated with lower volumes in occipital (p = 8.7×10−6) regions; (ii) TMEM61 was associated with lower volumes in left temporal (p = 7.8×10−7), and left cingulate regions (p = 5.5×10−5); (iii) KDM4A‐AS1 was associated with lower volumes in the right temporal (p = 3.2×10‐7) region. All genes are variably expressed in the brain.ConclusionIdentification of deleterious or protective low‐frequency variants contributing to FTD imaging phenotypes may help identify genetic modifiers of familial FTD. Replication of results followed by functional studies are needed.

2653. Duration of Respiratory Virus Detection by Multipathogen PCR Testing after Acute Respiratory Illness

Abstract Background Persons with respiratory viral infections (RVI) may shed detectable virus after symptom recovery. Duration of detection by molecular methods is not well described for non-SARS-CoV-2 respiratory viruses. Methods School KIDS is a prospective respiratory viral surveillance program in a Missouri school district. Participating students and staff with RVI symptoms can receive respiratory viral testing using self-collected nasal swabs. Symptomatic participants with detectable virus(es) on primary swabs were scheduled to receive 2 convalescent swabs weekly after initial test during weekly school surveillance testing. All convalescent tests performed within 21 days of the primary specimen were included. Only participants providing ≥ 1 convalescent swab were included. Specimens were tested using Hologic® Panther Fusion® or QIAstat-Dx PCR assays that included adenovirus (AdV); seasonal coronaviruses (sCoV) 229E, HKU1, NL63, OC43; human metapneumovirus, influenza A and B (Flu), parainfluenza viruses 1-4, respiratory syncytial virus, rhinovirus/ enterovirus (RV/EV), and SARS-CoV-2. We used survival analysis to quantify median number of days until individuals tested negative for each virus. Results From November 3, 2022 – April 14, 2023, 344 symptomatic participants (141 preK/elem, 49 middle, 22 high, 132 staff) submitted 586 primary specimens; 292 (50%) were positive for a virus. For positive primary specimens, median [IQR] time of symptom onset to specimen collection was 2 [1,3] days. A total of 320 viruses were detected; most common were RV/EV (37%) and sCoVs (25%) (Table). An additional 370 convalescent specimens were collected (87 specimens on days 1-7 following primary positive; 166 specimens on days 8-14; and 117 specimens on days 15-21). Median number of days [95% confidence interval] when repeat convalescent tests became negative varied by virus (AdV 15 [11,undefined] days, Flu A 14 [9,19] days, RV/EV 12 [11,14] days, SARS-CoV-2 14 [14,17] days, sCoV 10 [9,12] days) (Figure).Table.Characteristics of primary positive and convalescent testing (i.e. ongoing positivity) of nasal swabs from preK—12 grade students and staff with respiratory symptoms—Missouri, November 2022 -April 2023Figure.Cumulative probability of testing negative for a respiratory virus on subsequent respiratory viral testing Conclusion Students and staff continued to have detectable virus by nasal swabs 10-15 days after symptomatic positive specimen. Further data are needed to determine when participants are no longer infectious. Disclosures Rangaraj Selvarangan, BVSc, PhD, D(ABMM), FIDSA, FAAM, Abbott: Honoraria|Altona Diagnostics: Grant/Research Support|Baebies Inc: Advisor/Consultant|BioMerieux: Advisor/Consultant|BioMerieux: Grant/Research Support|Bio-Rad: Grant/Research Support|Cepheid: Grant/Research Support|GSK: Advisor/Consultant|Hologic: Grant/Research Support|Lab Simply: Advisor/Consultant|Luminex: Grant/Research Support

930. COVID-19 symptom and viral load rebound among individuals reporting nirmatrelvir/ritonavir use compared to propensity score matched individuals not taking COVID-19 treatment

930. COVID-19 symptom and viral load rebound among individuals reporting nirmatrelvir/ritonavir use compared to propensity score matched individuals not taking COVID-19 treatment

Symptoms, Viral Loads, and Rebound Among COVID-19 Outpatients Treated With Nirmatrelvir/Ritonavir Compared With Propensity Score-Matched Untreated Individuals.

Nirmatrelvir/ritonavir (N/R) reduces severe outcomes from coronavirus disease 2019 (COVID-19); however, rebound after treatment has been reported. We compared symptom and viral dynamics in individuals with COVID-19 who completed N/R treatment and similar untreated individuals. We identified symptomatic participants who tested severe acute respiratory syndrome coronavirus 2-positive and were N/R eligible from a COVID-19 household transmission study. Index cases from ambulatory settings and their households contacts were enrolled. We collected daily symptoms, medication use, and respiratory specimens for quantitative polymerase chain reaction for 10 days during March 2022-May 2023. Participants who completed N/R treatment (treated) were propensity score matched to untreated participants. We compared symptom rebound, viral load (VL) rebound, average daily symptoms, and average daily VL by treatment status measured after N/R treatment completion or 7 days after symptom onset if untreated. Treated (n = 130) and untreated participants (n = 241) had similar baseline characteristics. After treatment completion, treated participants had greater occurrence of symptom rebound (32% vs 20%; P = .009) and VL rebound (27% vs 7%; P < .001). Average daily symptoms were lower among treated participants without symptom rebound (1.0 vs 1.6; P < .01) but not statistically lower with symptom rebound (3.0 vs 3.4; P = .5). Treated participants had lower average daily VLs without VL rebound (0.9 vs 2.6; P < .01) but not statistically lower with VL rebound (4.8 vs 5.1; P = .7). Individuals who completed N/R treatment experienced fewer symptoms and lower VL but rebound occured more often compared with untreated individuals. Providers should prescribe N/R, when indicated, and communicate rebound risk to patients.

Dietary and lifestyle factors associated with troublesome gastroesophageal reflux symptoms in Vietnamese adults.

Dietary and lifestyle habits related to troublesome gastroesophageal reflux symptoms (tGERS) differ significantly across populations. There have yet to be studies on the Vietnamese population. To identify dietary and lifestyle habits associated with tGERS in Vietnamese adults. A cross-sectional survey was conducted among Vietnamese adults aged 18 years and older from March 2023 to May 2023. Participants were recruited online through a widely read national newspaper and Facebook, one of Vietnam's most popular social media platforms. The survey questionnaire comprised 27 questions covering participants' basic demographic information, dietary and lifestyle habits, the presence and characteristics of tGERS, and inquiries about specific dietary and lifestyle patterns, foods, and beverages associated with tGERS. A total of 4,400 valid responses were collected, including 2050 participants without tGERS and 2,350 participants with tGERS. Multivariate analysis showed several factors associated with tGERS, including eating beyond fullness (OR 1.383, CI95% 1.127-1.698), tight clothing (OR 1.627, CI95% 1.256-2.107), stress (OR 1.566, CI95% 1.363-1.800), and insomnia (OR 1.321, CI95% 1.129-1.546). Among habits associated with tGERS, eating beyond fullness was the most frequently reported (64.6%). Interestingly, although a short meal-to-bed time and staying up late after midnight were not risk factors for tGERS, they were two common factors associated with tGERS in symptomatic participants, particularly those with nocturnal reflux symptoms. For food triggers, the three most common ones were greasy foods (71.9%), sour/spicy soups (64.7%), and citrus fruits (36.0%). In terms of beverages, carbonated soft drinks were at the top of triggering tGERS (40.3%), and beer and orange juice were the second and third most common triggers, accounting for 35.7 and 30.6%, respectively. We reported the dietary and lifestyle habits associated with tGERS in Vietnamese adults for the first time. These findings will serve as a basis for future studies on the primary prevention and nondrug management of tGERS in Vietnam.

Erythrocyte Disorders Mimicking Congenital Dyserythropoietic Anemia Based on Bone Marrow Pathology Exposed By Genetic Evaluation

Congenital dyserythropoietic anemias (CDAs) are a rare group of heterogeneous genetic diseases characterized by hemolysis, ineffective erythropoiesis predisposing to iron overload, and the pathologic finding of bi- and multinucleated erythroblasts in the bone marrow (BM). With the identification of causative genetic mutations over the last two decades, the current classification includes the following types with the causative gene in parenthesis: Ia ( CDAN1), Ib ( CDIN1); II ( SEC23B); IIIa ( KIF23), IIIb ( RACGAP1); IV ( KLF1) ; and XLTD ( GATA1). Clinical presentation can vary widely even within the same type, ranging from mild cases of anemia to severe cases in which patients are subject to lifelong transfusion dependency. The CDA registry (CDAR) in North America (NCT02964494) was established to allow natural history studies on patients with CDA. Participants without a genetic diagnosis are offered whole genome sequencing (WGS) for patients and parents and may elect to provide samples to the CDAR biorepository to support collaborative mechanistic studies. Currently 169 subjects from 73 different families are enrolled in CDAR (85 patients, 84 unaffected family members). After genetic evaluation, 13 patients were found to be affected not by CDA, but rather by other causes of hereditary hemolytic anemia with secondary dyserythropoiesis. Three patients were diagnosed with pyruvate kinase deficiency (PKD). Patient (pt) 1 had a history of chronic anemia requiring sporadic transfusions since birth and was diagnosed with CDA-II based on BM studies. WGS revealed that the patient was heterozygous for a known PKLR pathogenic variant c.1022G&amp;gt;C p.(Gly341Ala)and for a novel variant of uncertain significance (c.695-3C&amp;gt;G).PK activity assay confirmed the diagnosis of PKD and the patient is now treated with the PK activator mitapivat. Pt 2 had severe transfusion dependent anemia since birth and iron overload. The patient underwent splenectomy at the age of 4 with mild improvement of symptoms. He was diagnosed with CDA II based on BM pathology. Genetic testing was performed and he was found to be compound heterozygous for 2 pathogenic variants in PKLR: c.644dup p.(Arg216fs) and c.994_1003dup p.(Val335fs). Pt 3 had a history of anemia and jaundice since birth; she has not had frequent transfusions but was splenectomized at age 17. The patient was found to be homozygous for c.1436G&amp;gt;A p.(Arg510Gln), a known pathogenic variant in PKLR. Four patients were diagnosed with HBB pathogenic variants causing frameshift and transcription of an elongated β-globin chain, i.e. unstable hemoglobinopathy. Pt 4 was first diagnosed with CDA II at 12 years of age based on BM studies performed due to chronic hemolytic anemia. After enrolling in CDAR, WES revealed heterozygous HBB p.(Lys96Asnfs*63). Pts 5, 6, and 7 are all symptomatic participants from the same family (mother and children). The mother (Pt 5) had frequent transfusion requirement, misdiagnosed in childhood as CDA IV due to BM dyserythropoiesis and the finding of high fetal hemoglobin. Her children had a similar phenotype requiring episodic transfusions initially, transitioning to scheduled transfusions by 8 y.o. WES in pt 5 revealed heterozygous HBB c.348_349delinsG (Hb Grand Junction) with follow-up HBB sequencing confirming that the children also carry the same variant . Three more patients were diagnosed with SPTA1 variants causing RBC membrane disorders. Pt 8 was found to have homozygous c.4339-99C&amp;gt;T (alpha-LEPRA) and heterozygous c.4347G&amp;gt;T p.(Lys1449Asn) with a phenotype of hereditary spherocytosis. Pts 9 and 10 are sisters, who presented with chronic, transfusion-dependent anemia since birth. They were diagnosed with CDA-II based on binucleated erythroblasts in BM studies performed in early childhood. They had splenectomy at 5 years of age and became transfusion-independent but continued to have mild anemia and reticulocytosis. WGS performed for them and their parents revealed a novel homozygous intronic variant in SPTA1 c.5834-18A&amp;gt;G. Phenotypic analysis was compatible with hereditary spherocytic pyropoikilocytosis. Hemolytic anemias with stress erythropoiesis may mimic the clinical presentation and pathologic findings of CDAs, making the phenotypic diagnosis challenging. Including genetic evaluation in the diagnostic workup of these patients can improve accuracy, timing of diagnosis, and management by specific therapy, if available.

Evidence of Ongoing Cerebral Microstructural Reorganization in Children With Persisting Symptoms Following Mild Traumatic Brain Injury: A NODDI DTI Analysis.

Approximately 300-550 children per 100,000 sustain a mild traumatic brain injury (mTBI) each year, of whom ∼25-30% have long-term cognitive problems. Following mTBI, free water (FW) accumulation occurs in white matter (WM) tracts. Diffusion tensor imaging (DTI) can be used to investigate structural integrity following mTBI. Compared with conventional DTI, neurite orientation dispersion and density imaging (NODDI) orientation dispersion index (ODI) and fraction of isolated free water (FISO) metrics may allow a more advanced insight into microstructural damage following pediatric mTBI. In this longitudinal study, we used NODDI to explore whole-brain and tract-specific differences in ODI and FISO in children with persistent symptoms after mTBI (n = 80) and in children displaying clinical recovery (n = 32) at 1 and 2-3 months post-mTBI compared with healthy controls (HCs) (n = 21). Two-way repeated measures analysis of variance (ANOVA) and voxelwise two-sample t tests were conducted to compare whole-brain and tract-specific diffusion across groups. All results were corrected at positive false discovery rate (pFDR) <0.05. We also examined the association between NODDI metrics and clinical outcomes, using logistical regression to investigate the value of NODDI metrics in predicting future recovery from mTBI. Whole-brain ODI was significantly increased in symptomatic participants compared with HCs at both 1 and 2 months post-injury, where the uncinate fasciculus (UF) and inferior fronto-occipital fasciculus (IFOF) were particularly implicated. Using region of interest (ROI) analysis in significant WM, bilateral IFOF and UF voxels, symptomatic participants had the highest ODI in all ROIs. ODI was lower in asymptomatic participants, and HCs had the lowest ODI in all ROIs. No changes in FISO were found across groups or over time. WM ODI was moderately correlated with a higher youth-reported post-concussion symptom inventory (PCSI) score. With 87% predictive power, ODI (1 month post-injury) and clinical predictors (age, sex, PCSI score, attention scores) were a more sensitive predictor of recovery at 2-3 months post-injury than fractional anisotropy (FA) and clinical predictors, or clinical predictors alone. FISO could not predict recovery at 2-3 months post-injury. Therefore, we found that ODI was significantly increased in symptomatic children following mTBI compared with HCs at 1 month post-injury, and progressively decreased over time alongside clinical recovery. We found no significant differences in FISO between groups or over time. WM ODI at 1 month was a more sensitive predictor of clinical recovery at 2-3 months post-injury than FA, FISO, or clinical measures alone. Our results show evidence of ongoing microstructural reorganization or neuroinflammation between 1 and 2-3 months post-injury, further supporting delayed return to play in children who remain symptomatic. We recommend future research examining the clinical utility of NODDI following mTBI to predict recovery or persistence of post-concussion symptoms and thereby inform management of mTBI.

Increased number of symptoms during the acute phase of SARS-CoV-2 infection in athletes is associated with prolonged time to return to full sports performance—AWARE VIII

PurposeThe aim of the study was to identify factors associated with prolonged time to return to full performance (RTFP) in athletes with recent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. MethodsProspective cohort study with cross sectional analysis. A total of 84 athletes with confirmed SARS-CoV-2 infection assessed at a coronavirus disease 2019 recovery clinic gave a history of age, sex, type/level of sport, co-morbidities, pre-infection training hours, and 26 acute SARS-CoV-2 symptoms from 3 categories (“nose and throat”, “chest and neck”, and “whole body”/systemic). Data on days to RTFP were obtained by structured interviews. Factors associated with RTFP were demographics, sport participation, history of co-morbidities, pre-infection training history, and acute symptoms (type, number). Outcomes were: (a) days to RTFP (median, interquartile range (IQR)) in asymptomatic (n = 7) and symptomatic athletes (n = 77), and (b) hazard ratios (HRs; 95% confidence interval) for symptomatic athletes with vs. without a factor (univariate, multiple models). HR < 1 was predictive of higher percentage chance of prolonged RTFP. Significance was p < 0.05. ResultsDays to RTFP were 30 days (IQR: 23–40) for asymptomatic and 64 days (IQR: 42–91) for symptomatic participants (p > 0.05). Factors associated with prolonged RTFP (univariate models) were: females (HR = 0.57; p = 0.014), endurance athletes (HR = 0.41; p < 0.0001), co-morbidity number (HR = 0.75; p = 0.001), and respiratory disease history (HR = 0.54; p = 0.026). In symptomatic athletes, prolonged RTFP (multiple models) was significantly associated with increased “chest and neck” (HR = 0.85; p = 0.017) and “nose and throat” (HR = 0.84; p = 0.013) symptoms, but the association was more profound between prolonged RFTP and increased total number of “all symptoms” (HR = 0.91; p = 0.001) and “whole body”/systemic (HR = 0.82; p = 0.007) symptoms. ConclusionA larger number of total symptoms and specifically “whole body”/systemic symptoms during the acute phase of SARS-CoV-2 infection in athletes is associated with prolonged RTFP.

Determination of Optimal Eosinophil Thresholds for Diagnosis of Eosinophilic Gastritis and Duodenitis: A Pooled Analysis of 4 Prospective Studies.

Consensus is lacking regarding the number of eosinophils (eos) required for the diagnosis of eosinophilic gastritis (EoG) and eosinophilic duodenitis (EoD). In addition, thresholds that require multiple high-power fields (HPFs) may not be practical for clinical use, resulting in delayed or missed diagnoses. This pooled analysis of 4 prospective studies assessed thresholds for multiple and single HPFs used to diagnose EoG and EoD. Studies included the phase 2 ENIGMA1, the phase 3 ENIGMA2, an EoG/EoD prevalence study and a healthy volunteer study. Eos were quantified in the epithelium and lamina propria for controls and symptomatic participants. Symptomatic participants were further divided by histologic diagnosis of EoG/EoD. Peak eos counts were assessed, and the area under the receiver operating characteristic curve was analyzed to identify eos cutoffs for detection of EoG/EoD using the Youden index and sensitivity and specificity equality approaches. Based on the highest specificity analysis in 740 patients, the optimal eos threshold was determined to be 20 eos/HPF in 5 gastric HPFs for EoG (71% sensitivity and 94% specificity) and 33 eos/HPF in 3 duodenal HPFs for EoD (49% sensitivity and 100% specificity). For single-field analysis, the optimal eos thresholds were 33 eos/HPF (EoG) and 37 eos/HPF (EoD), both corresponding to 93% sensitivity and 93% specificity. Highly specific single gastric and duodenal HPF thresholds may have more clinical applicability than thresholds requiring multiple HPFs and could better facilitate development of practical histopathologic guidelines to aid pathologists and clinicians in the detection and diagnosis of EoG and/or EoD.

Breast Cancer Survivors and COVID-19: Prevalence and Risk of Severe Disease in a Screening Study.

Determining the risk of severe course coronavirus disease 2019 (COVID-19) and its related factors in survivors of common cancers such as breast cancer is important. This study has been designed to evaluate the prevalence of COVID-19 infection in breast cancer survivors and also estimate the risk of severe disease in this population. Out of 6134 patients in the Shiraz Breast Cancer Registry (SBCR), A total of 292 patients who elapsed less than a year from their breast cancer diagnosis were excluded. We called 5842 patients. Finally, 4135 breast cancer survivors who agreed to cooperate were screened for COVID-19 symptoms by a symptom-based questionnaire in November 2020. COVID-19 in symptomatic participants was confirmed by a polymerase chain reaction (PCR) test. The clinical and paraclinical data of the COVID-19 course were collected for patients with a positive PCR test. A total of 247 (5.9%) participants had at least reported one of the COVID-19 symptoms. Also, 17% of symptomatic participants had a positive PCR test; 83.7% had mild disease, 9.5% moderate, and 16.7% had severe conditions. Chronic cardiovascular disease, hypertension, and diabetes were related to an increased risk of severe illness ( P = 0.018, P = 0.018, P = 0.002). This study suggests that breast cancer intermediate and longtime survivors without other underlying diseases are considered at low risk for developing severe/critical COVID-19.

Results of Eustachian tube balloon dilation measured using the nine-step test

Suggested several decades ago, the nine-step test is an intuitive test of Eustachian tube function. However, studies employing the nine-step test to assess the results of Eustachian tube balloon dilation (EBD) are limited. We aimed to objectively evaluate the efficacy of EBD in opening failure patients with decreased maximal peak pressure difference (MPD) using the nine-step test. Patients who had MPD values ≤ 13 daPa in the nine-step test were enrolled. The patients were categorized into two groups according to treatment decisions after discussion with a clinician: an EBD group (N = 26) and a medication group (N = 30). One month after treatment, the seven-item Eustachian Tube Dysfunction Questionnaire (ETDQ7) and the nine-step test were administered to all participants and subgroups of symptomatic participants (ETDQ7 > 15). MPD improved (increased) in both the EBD group and the medication group. ETDQ7 values improved (decreased) in the EBD group, but not in the medication group. In subgroup analysis, MPD and ETDQ7 values improved only in the symptomatic EBD group. According to the nine-step test, EBD can normalize 53.8% of decreased MPD. Posttreatment MPD and ETDQ7 scores were significantly better in the EBD group than in the medication group. However, EBD in patients with abnormal nine-step test results seemed less efficacious when the treatment results of the medication group were considered.

Quality of Life in Patients With Confirmed and Suspected Spinal CSF Leaks.

Spontaneous intracranial hypotension (SIH) is a debilitating condition typically producing orthostatic headache limiting upright time. SIH is often difficult to diagnose and treat, negatively affecting quality of life (QoL) in patients with the disorder. We studied QoL in patients with confirmed and suspected SIH using standardized instruments, including suicidality. We performed a cross-sectional survey of adult patients with confirmed and clinically suspected SIH evaluated in our Headache and Facial Pain Program from 2016 to 2022. Using an online data collection tool (REDCap V 11.2.2), participants completed validated questionnaires assessing general well-being (SF-36), depression (PHQ-9), generalized anxiety disorder-7 (GAD-7), spiritual well-being during chronic illness therapy (FACIT-Sp-12), and headache impact (HIT-6). Subsequently, we interviewed willing participants to administer the Columbia-Suicide Severity Rating Scale (C-SSRS) assessing suicidal behavior and ideation. A total of 234 patients met inclusion criteria and were invited to participate in the study, and 95 patients (59 confirmed and 36 clinically suspected) completed the questionnaires. The average age of the cohort was 51.1 years (SD: 15.5), predominantly female (69.5%), White (91.6%), and married (69.5%). Three-quarters (74.5%) scored within the most severe headache category (HIT-6). SF-36 scores were significantly inferior (p < 0.0001) to the general population and lower than reported values for patients with multiple sclerosis and idiopathic intracranial hypertension. Almost half (49.1%) of respondents scored in the moderate depression range or worse (>10), and 25.4% scored with moderate anxiety or worse (>10). FACIT-Sp-12 scores were significantly worse (p < 0.0001) in symptomatic participants than in the validation cohorts of patients with AIDS and cancer. Of the 67 respondents who completed the C-SSRS, more than half (64.2%) endorsed a wish to be dead, and 22.4% had demonstrated suicidal behavior. Patients with symptom-free SIH (n = 22) scored significantly better than symptomatic patients, comparable with the general population. Based on our single-center cohort, SIH is associated with severe headache pain and high rates of depression, anxiety, and disability, affecting basic activities of daily living. Individuals with confirmed and suspected spinal CSF leaks scored similarly on these measures including suicidality. Outcomes were comparable with the general population after successful treatment or spontaneous remission. Improved identification and treatment of SIH are imperative to improve patients' QoL.

A Flexible Regression Modeling Approach Applied to Observational Laboratory Virological Data Suggests That SARS-CoV-2 Load in Upper Respiratory Tract Samples Changes with COVID-19 Epidemiology.

(1) Background. Exploring the evolution of SARS-CoV-2 load and clearance from the upper respiratory tract samples is important to improving COVID-19 control. Data were collected retrospectively from a laboratory dataset on SARS-CoV-2 load quantified in leftover nasal pharyngeal swabs (NPSs) collected from symptomatic/asymptomatic individuals who tested positive to SARS-CoV-2 RNA detection in the framework of testing activities for diagnostic/screening purpose during the 2020 and 2021 winter epidemic waves. (2) Methods. A Statistical approach (quantile regression and survival models for interval-censored data), novel for this kind of data, was applied. We included in the analysis SARS-CoV-2-positive adults >18 years old for whom at least two serial NPSs were collected. A total of 262 SARS-CoV-2-positive individuals and 784 NPSs were included: 193 (593 NPSs) during the 2020 winter wave (before COVID-19 vaccine introduction) and 69 (191 NPSs) during the 2021 winter wave (all COVID-19 vaccinated). We estimated the trend of the median value, as well as the 25th and 75th centiles of the viral load, from the index episode (i.e., first SARS-CoV-2-positive test) until the sixth week (2020 wave) and the third week (2021 wave). Interval censoring methods were used to evaluate the time to SARS-CoV-2 clearance (defined as Ct < 35). (3) Results. At the index episode, the median value of viral load in the 2021 winter wave was 6.25 log copies/mL (95% CI: 5.50-6.70), and the median value in the 2020 winter wave was 5.42 log copies/mL (95% CI: 4.95-5.90). In contrast, 14 days after the index episode, the median value of viral load was 3.40 log copies/mL (95% CI: 3.26-3.54) for individuals during the 2020 winter wave and 2.93 Log copies/mL (95% CI: 2.80-3.19) for those of the 2021 winter wave. A significant difference in viral load shapes was observed among age classes (p = 0.0302) and between symptomatic and asymptomatic participants (p = 0.0187) for the first wave only; the median viral load value is higher at the day of episode index for the youngest (18-39 years) as compared to the older (40-64 years and >64 years) individuals. In the 2021 epidemic, the estimated proportion of individuals who can be considered infectious (Ct < 35) was approximately half that of the 2020 wave. (4) Conclusions. In case of the emergence of new SARS-CoV-2 variants, the application of these statistical methods to the analysis of virological laboratory data may provide evidence with which to inform and promptly support public health decision-makers in the modification of COVID-19 control measures.

Differences in Strength and Fatigue Resistance of Scapular Protractors and Retractors Between Symptomatic and Asymptomatic Dyskinesis.

Scapular dyskinesis is a shoulder dysfunction that can be asymptomatic or associated with pain or weakness. Reduced strength and fatigue resistance of the scapular protractor and retractor muscles that stabilize the scapula might contribute to dyskinesis. To determine the strength and fatigue resistance profiles of participants with symptomatic or asymptomatic scapular dyskinesis and compare them with healthy control (HC) individuals using isokinetic assessment. Cross-sectional study. University hospital. Twenty HC individuals and 21 overhead athletes with symptomatic (n = 10) or asymptomatic (n = 11) scapular dyskinesis. Strength (peak torque, maximum work), fatigue resistance (total work), and protraction:retraction ratios measured during a closed chain isokinetic protocol (40 repetitions in concentric mode at 24.4 cm/s). The scapular protractors' strength and fatigue resistance were higher (P < .01) in HC individuals (peak torque = 5.0 ± 0.9 N/kg, maximum work = 2.4 ± 0.5 J/kg, total work = 72.4 ± 0.6 J/kg) than in asymptomatic (peak torque = 3.4 ± 0.7 N/kg, maximum work = 1.7 ± 0.4 J/kg, total work = 50.0 ± 13.7 J/kg) or symptomatic (peak torque = 3.8 ± 0.6 N/kg, maximum work = 1.8 ± 0.3 J/kg, total work = 58.1 ± 12.9 J/kg) dyskinetic participants. The symptomatic dyskinetic group presented the highest retractor strength and fatigue resistance (P < .01) values (peak torque = 5.2 ± 0.6 N/kg, maximum work = 2.9 ± 0.8 J/kg, total work = 87.7 ± 22.7 J/kg), followed by the HC individuals (peak torque = 4.7 ± 1.0 N/kg, maximum work = 2.1 ± 0.5 J/kg, total work = 65.3 ± 17.9 J/kg) and the asymptomatic dyskinetic participants (peak torque = 3.9 ± 1.0 N/kg, maximum work = 1.9 ± 0.6 J/kg, total work = 58.6 ± 18.5 J/kg). The protraction:retraction ratios showed a gradual decrease (P < .001) from the HC individuals (1.1) to the asymptomatic (0.9) and symptomatic (0.7) dyskinetic participants. Scapular dyskinesis is characterized by weaker scapular protractors and reduced agonist:antagonist ratios, especially when patients are symptomatic. Targeting the scapular protractors to achieve a better balance of scapular musculature in rehabilitation and strengthening programs may improve shoulder symptoms and function, but more interventional studies are required.

Assessment of the detection accuracy of SARS-CoV-2 rapid antigen test in children and adolescents: An updated meta-analysis.

Real-time and appropriate antigen tests play a pivotal role in preventing severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. However, a previous meta-analysis reported that the antigen test had lower sensitivity for the detection of SARS-CoV-2 in children. To provide a comprehensive evaluation of diagnostic efficiency, we performed an updated meta-analysis to assess the detection accuracy of SARS-CoV-2 antigen tests stratified by days after symptom onset and specimen type in children and adolescents. We comprehensively searched for appropriate studies in the PubMed, Embase, and Cochrane Library databases. Studies on the diagnostic accuracy of antigen tests for SARS-CoV-2 in children and adolescents were included. The relevant data of the included studies were extracted to construct a 2 × 2 table on a per-patient basis. The overall sensitivity and specificity of the SARS-CoV-2 antigen tests were estimated using a bivariate random-effects model. Seventeen studies enrolling 10,912 patients were included in the present meta-analysis. For the detection accuracy of SARS-CoV-2 antigen tests, the meta-analysis generated a pooled sensitivity of 77.9% (95% confidence interval (CI): 67.3-85.8%) and a pooled specificity of 99.6% (95% CI: 98.9-99.8%). The subgroup analysis of studies that examined antigen tests in symptomatic participants ≦7 days after symptom onset generated a pooled sensitivity of 79.4% (95% CI: 47.6-94.2%) and a pooled specificity of 99.4% (95% CI: 98.2-99.8%). Another subgroup analysis of studies that evaluated nasal swab specimens demonstrated a pooled sensitivity of 80.1% (95% CI: 65.0-89.7%) and a pooled specificity of 98.5% (95% CI: 97.3-99.2%). Our findings demonstrated that the antigen test performed using nasal swab specimens exhibited high sensitivity for the detection of SARS-CoV-2 within 7 days after symptom onset. Therefore, antigen testing using nasal swabs may be effective in blocking SARS-CoV-2 transmission in children.

Vision Quality of Life with Time Survey: Normative Data and Repeatability.

To develop a novel Vision Quality of Life (QoL) survey that emphasizes the amount of time a visual activity can be performed before symptoms occur. The Vision Quality of Life with Time (VisQuaL-T) survey was developed with 10 daily activities and a list of common visual symptoms. Participants were recruited from a university campus. Participants were not excluded based on binocular impairments to obtain a normative dataset. Participants were instructed to denote when they first experience symptoms within certain time ranges. If participants did not engage in one of the 10 activities, they were instructed to denote "N/A". A composite score (range 0-3) was determined by only accounting for the questions that were answered. The normative data cohort had a sample size of 376 participants and the repeatability cohort had 54 participants. The normative, test, and retest datasets had a mean composite score of 2.47±0.54, 2.69±0.42, and 2.67±0.49 and 95% confidence interval of 2.38-2.71, 2.58-2.81, 2.54-2.80, respectively. There was good reliability and high correlation between the test and retest timepoints with an ICC of 0.825 and a Pearson correlation coefficient of 0.839 in the repeatability cohort. The normative data cohort showed good internal consistency with a Cronbach's alpha value of 0.803. Test and retest timepoints showed no statistical significance among the individual questions (p > 0.1). A lower bound score of 2.4 can potentially be used to differentiate visually normal and symptomatic participants. Statistical analysis showed the survey is repeatable and reliable. Using time as a metric for assessing symptomology could be a useful method for identifying patients with QoL issues and for assessing effectiveness of binocular vision, accommodative, and eye movement treatments.

Evaluation of lumbar lordosis in symptomatic individuals and comparative analysis of six different techniques: a retrospective radiologic study.

The aim of this study; evaluate lumbar lordosis (LL) in symptomatic individuals with six different techniques and to examine the techniques comparatively. Thus, to provide an overview of lumbal lordosis and techniques. Cobb L1-L5, Cobb L1-S1, Posterior Tangent, tangential radiologic assessment of lumbar lordosis (TRALL), vertebral centroid measurement of lumbar lordosis (CLL) and Risser Ferguson measurement techniques were used to assess LL from radiographs of 175 symptomatic adults. Correlations between techniques and relationship between the measurements obtained, gender and age were analyzed. Also ınterclass correlation (ICC) analyzed. Bland-Altman plots were performed to compare the techniques with Cobb. ICC for all methods were greater than 0.96. For each method, no difference in LL was observed with respect to gender or age (p > 0.05). High positive correlation was observed between the Risser Ferguson, Posterior Tangent, Cobb L1-L5, Cobb L1-S1 and CLL techniques (p < 0.001), and moderate positive correlation between TRALL and all other techniques (p < 0.001). In this study, it was found that the mean lumbar lordosis values of symptomatic participants were lower than most of the other asymptomatic studies in the literature and there was no significant difference in lumbar lordosis values in terms of gender and age in symptomatic individuals. Based on statistical findings, Risser Ferguson can be used to assess LL. These results and the data obtained as a result of the comparative examination of techniques according to age groups and gender will benefit clinicians and those working in the field by providing a better understanding LL.