Neuropsychiatric symptoms are intrinsic to Progressive Supranuclear Palsy (PSP) and a spoonful of studies investigated their imaging correlates. Describe (I) the frequency and severity of neuropsychiatric symptoms in PSP and (II) their structural imaging correlates. Twenty-six PSP patients underwent Neuropsychiatric Inventory (NPI) and brain 3D T1-weighted MRI. Spearman’s rho with Bonferroni correction was used to investigate correlations between NPI scores and volumes of gray matter regions. More than 80% of patients presented at least one behavioral symptom of any severity. The most frequent and severe were depression/dysphoria, apathy, and irritability/lability. Significant relationships were found between the severity of irritability and right pars opercularis volume (p < 0.001) as well as between the frequency of agitation/aggression and left lateral occipital volume (p < 0.001). Depression, apathy, and irritability are the most common neuropsychiatric symptoms in PSP. Moreover, we found a relationship between specific positive symptoms as irritability and agitation/aggression and greater volume of the right pars opercularis cortex and lower volume of the left occipital cortex, respectively, which deserve further investigations. Progressive Supranuclear Palsy (PSP) is a rare neurodegenerative disease characterized by postural instability, ocular motor dysfunction, akinesia, and cognitive as well as neuropsychiatric disturbances  the frequency and severity of neuropsychiatric symptoms screened with the NPI in non-demented PSP patients and (II) their structural imaging correlates.; Litvan et al. Consecutive patients with a diagnosis of PSP according to the Movement Disorders Society clinical criteria were enrolled at the Center for Neurodegenerative Diseases of the University of Salerno, Italy, at the movement disorder section, between November 2015 and April 2019 . Only patients qualifying for a degree of diagnostic certainty of probability were included in the present study. Caregivers completed the NPI with reference to the patients, assessing frequency and severity of 12 behavioral areas, including delusions, hallucinations, agitation/aggression, depression/dysphoria, anxiety, euphoria, apathy, disinhibition, irritability/lability, aberrant motor behavior, and sleep and eating disorders. Specifically, frequency was measured with a 5-point Likert scale  and severity was measured with a 3-point Likert scale . The emotional or psychological stress of the caregiver section was measured with a 6-point Likert scale . The NPI section regarding caregiver’s stress was filled in but was not used in the correlation analysis with imaging data as it primarily concerns the caregiver and not the patient. According to the NPI instructions, caregivers were asked to refer to situation of the patient in the 6 weeks preceding the interview . We chose the NPI as it is a solid instrument to evaluate behavioral disturbances in a wide range of neurodegenerative diseases and has been administered to PSP patients in several previous studies . Raw T1w images of all subjects were imported in FreeSurfer and submitted to the standard structural image preprocessing and reconstruction pipeline via the “recon-all" command   data were acquired on a 3 T MRI scanner  operated with a 20-channel head and neck coil. A 3D anatomical T1-weighted (T1w) Magnetization Prepared RApid Gradient Echo (MPRAGE) sequence was acquired with repetition time (TR) = 2400 ms and echo time (TE) = 2.25 ms, spatial resolution = 1 × 1 × 1 mm3, matrix size = 256 × 256, anterior–posterior phase encoding direction, and generalized autocalibrating partially parallel acquisitions (GRAPPA) factor of 2 in phase encoding. MPRAGE images were processed using FreeSurfer version 6.0 . Particularly, correlation was calculated between frequency of symptoms and regional volumes in all patients and between severity of symptoms and regionals volumes only in the subgroup of patients presenting symptoms (frequency > 0). Correlations were considered strong with coefficients > 0.70 and moderate with coefficients between 0.30 and 0.70.Comparison of presence of behavioral symptoms between groups was assessed using the Chi-squared test. Spearman’s correlation with Bonferroni correction was used to explore correlations among neuropsychiatric symptoms frequency. The relationship between MRI cortical and subcortical volumes and neuropsychiatric symptoms was evaluated by Spearman’s correlations with Bonferroni correction for multiple comparisons on the number of regions ] with a mean (± standard deviation) age equal to 68.92 ± 5.93, a mean education equal to 9.12 ± 5.86, and a mean disease duration equal to 3.15 ± 1.74 were included The mean MOCA and PSP-rs scores were 17.54 ± 4.07 and 37 ± 14.98, respectively.In the whole sample, 80.8% of PSP patients presented at least one behavioral symptom of any severity. No differences were detected in the distribution of behavioral symptoms between sexes (p = 0.619) or PSP phenotypes (p = 0.192).The frequency and severity of neuropsychiatric symptoms as reported by the NPI are shown in Table As for the correlation of frequency of neuropsychiatric symptoms between each other, depression was significantly related to apathy , disinhibition was significantly related to euphoria  and apathy was significantly related to sleep disorders . No other associations between neuropsychiatric symptoms were detected.As for the correlation between neuropsychiatric symptoms and imaging data, Spearman’s correlation showed a significant relationship between the severity of irritability and right pars opercularis volume  as well as between the frequency of agitation/aggression and left lateral occipital volume . No other significant correlations were found.Figure Herein, we confirmed that the majority of PSP patients report neuropsychiatric disturbances  and dementia does not refer to PSP population (Ilardi et al. In conclusion, we demonstrated that depression/dysphoria, apathy, and irritability/lability are the most common neuropsychiatric symptoms in non-demented PSP patients. Our data also suggest a relationship between specific positive symptoms as irritability and agitation/aggression and greater volume of the right pars opercularis cortex and lower volume of the left occipital cortex, respectively, which deserve further investigations.


Paroxysmal nocturnal hemoglobinuria (PNH) is characterized by hemolytic anemia, bone marrow failure, thrombophilia. COVID‐19, caused by a novel severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) with many variants including Omicron.This study collected demographic and clinical data of 20 PNH patients with SARS‐CoV‐2 Omicron infection.They all were with high disease activity, and LDH level exceeded any documented since the diagnosis of PNH, and those reported in the literature for previously stable treatment with complement inhibitors. D‐dimer level elevated in 10 patients. 2 patients developed mild pulmonary artery hypertension. Glomerular filtration rate declined in 5 patients. 1 patient developed acute renal failure and underwent hemodialysis. Anemia and hemolysis were improved in 5 patients treated with eculizumab.Hemolytic exacerbation of PNH with COVID‐19 is severe and eculizumab may be an effective treatment. Severe acute respiratory syndrome coronavirus 2 infection could induce a hemolytic exacerbation in patients with paroxysmal nocturnal hemoglobinuria but eculizumab can effectively control acute hemolysis. The blockade of glycosylphosphatidylinositol (GPI) synthesis caused by mutation results in the absence of GPI‐anchored protein (such as CD55 and CD59), and CD55‐deficient and CD59‐deficient blood cells are more susceptible to complement attack and lysis.Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired and clonal disease characterized by hemolytic anemia, bone marrow failure, thrombophilia, and multiorgan damage, which results from the mutation of the 22.1The study reviewed clinical data of all outpatients in the four centers: the First Affiliated Hospital with Nanjing Medical University , the second people's hospital of Lianyungang , Wuxi People's Hospital , and Funing People's Hospital  from December 2022 to February 2023. Twenty patients with PNH infected SARS‐CoV‐2 Omicron were enrolled and registered in this study. Patients signed informed consent. The study was conducted according the Declaration of Helsinki and approved by the hospital ethics committee.2.2PNH patients were confirmed by flow cytometry using a reagent called fluorescent aerolysin (FLAER), which is the principal virulence factor of the bacterium Aeromonas hydrophilia, binds selectively and with high affinity to the GPI anchor.Patients infected with COVID‐19 were considered to have fever, cough, nasal congestion, sore throat, or other uncomfortable symptom and their reverse transcription polymerase chain reaction or antigen testing  for SARS‐CoV‐2 was positive.High disease activity (HDA) was defined as evidence of hemolysis  and a history of at least one of the following signs or symptoms—fatigue, hemoglobinuria, abdominal pain, dyspnea, anemia (hemoglobin <100 g/L), MAVEs (including TEs), dysphagia, or erectile dysfunction.2.3d‐dimer, IL‐6, and pulmonary artery systolic pressure), treatment, and outcomes in the cohort. Data on 20 patients with PNH registered in four centers is to evaluate the occurrence and clinical characteristics of SARS‐CoV‐2 infection, and the efficacy of eculizumab.We collected the patient demographics, clinical manifestations, laboratory data2.4All laboratory tests were done by the medical centers where the individual patients visited.CBC used EDTA as anticoagulants by blood cell analyzer following the two principles of electricity  and optical (laser scattering method and spectrophotometry).LDH, TBIL, IBIL, creatinine, GFR, and BUN used heparin as anticoagulants by a biochemical analyzer following the principle of photoelectric colorimetry.d‐dimer used sodium citrate as anticoagulants detected by the technique of immunofluorescence.IL‐6 used EDTA as anticoagulants detected by the technique of chemiluminescence.2.5U test. Paired samples conformed to a normal distribution use paired sample T‐test, otherwise Wilcoxon test is used for examination. Data management and analysis were performed using IBM SPSS Statistics, Version 26.0.: IBM Corp. p Values .05 was considered statistically significant.Categorical variables were described using frequencies and percentages, and continuous variables were described using median, minimum, and maximum. Shapiro–Wilk test is used to test whether the data conform to a normal distribution. The degree of SARS‐CoV‐2‐induced hemolysis compared with the literature was examined by Mann–Whitney 33.1A total of 20 PNH patients diagnosed with SARS‐CoV‐2 Omicron infection were enrolled in this study. Six  were male, 14  were female and the median age was 37 years (range: 15−75 years). Eleven patients  presented classical PNH and 9 patients  were diagnosed with PNH/AA. They accepted glucocorticoid maintenance and transfusion in the past. None of them were treated with complement inhibitors. The median time to episode occurred is 3 days after SARS‐CoV‐2 Omicron infection (1−5 days).d‐dimer  was elevated in 10 patients, and all of them received prophylactic low molecular weight heparin.Ten patients  complained of hemoglobinuria. Other 10 patients  presented with worsen fatigue and cytopenia. Although no thrombotic event happened, 2 One patient underwent hemodialysis due to acute renal failure.Mild pulmonary hypertension was found in 2 patients . The GFR in 5 patients  was lower than 60 mL/min/1.73 m.p = .011), TBIL , and IBIL  were higher than the most severe hemolysis previously recorded. Anemia became worsened compared to the previous period—RBC , Hb  (Table 2p = .055).We compared the current Omicron‐induced hemolysis and previous most drastic hemolysis. Five 29.41%, 5/17) were male, 12  were female and the median age was 38 years (range: 17−73 years). Ten patients  presented classical PNH and 7 patients  were diagnosed with PNH/AA. The level of LDH , and RBC count , and level of hemoglobin  were also improved significantly (Table p = .057). The elevated d‐dimers in 2 patients also decreased significantly after treatment—4.04 versus 1.47 mg/L, 2.15 versus 1.37 mg/L, respectively. During hemolysis, 1 patient had a high IL‐6 serum concentration, 31.29 times higher than the upper limit of the normal—165.83 pg/mL while after eculizumab treatment IL‐6 drops to 4.98 pg/mL. Because of emergency use, the patients treated by eculizumab could not be vaccinated against Neisseria meningitidis and Streptococcus pneumoniae in advance, but infection did not occur with the whole course of penicillin prophylaxis.Five patients were administrated with eculizumab. One 20%, 1/5) were male, 4  were female and the median age was 59 years (range: 26−67 years). Three patients  presented classical PNH and 2 patients  were diagnosed with PNH/AA. After eculizumab treatment, hemolysis was controlled  were hospitalized. Two  patients developed severe COVID‐19—one with severe viral pneumonia but recovered after two doses of eculizumab with oxygen support and the other with acute renal failure but recovered after hemodialysis.Of the 5 patients using eculizumab, 2 were not in HDA status. But 13 of the other 15 patients remained in HDA status during the second week after infection with SARS‐CoV‐2 Omicron.4PNH is a complement‐mediated hemolytic anemiaCurrent study found that Omicron‐induced hemolysis was more intense than ever happened since diagnosis. On the one hand, SARS‐CoV‐2 triggered complement activation through three pathwaysd‐dimer values of a half of patients were beyond the ULN. Zlatko et al.2), even 1 accepted hemodialysis.In this study, there was no thromboembolism, but p = .04) and improved tissue oxygenation compared with 45 patients who received supportive care alone. Another case reported that after Diurnop < .001). In our study, 5 patients receiving eculizumab achieved improvement in hemolysis and anemia, and COVID‐19 was also relieved. Eculizumab maybe a good choice for patients with PNH after SARS‐CoV‐2 infection.C5 inhibitors have been recommended as the first line treatment for PNH,In conclusion, our study preliminarily demonstrate SARS‐CoV‐2 infection could induce a hemolytic exacerbation in patients with PNH but eculizumab can effectively control acute hemolysis. It is the unavoidable association between PNH hemolytic exacerbation and visiting hospital. A large amount of long‐term follow‐up data are still needed to assess the impact of SARS‐CoV‐2 on patients with PNH, evaluate the dose and duration of eculizumab, and develop better prevention and control plans.Research idea and study design: Hui Yang and Xingxing Chai. Data collection: Hui Yang, Yuemin Gong, Xinyu Zhang, Lingling Wang, Jinge Xu, and Dan Xu. Data analysis: Hui Yang, Xingxing Chai, and Xiaoyu Chen. Wrote the manuscript: Hui Yang and Xingxing Chai. Supervision or mentorship: Xin Zhou, Jianyong Li, and Guangsheng He.The authors declare no conflict of interest.This study was approved by the First Affiliated Hospital of Nanjing Medical University ethics committee  conducted following the principle of the Helsinki Declaration. Informed consent was obtained from all individual participants included in the study. The authors confirms that the work has not been published before and the publication has been approved by all coauthors.


Supplementation of NAD+ through NR in water improved longevity and partially enhanced olfaction in aged mice. Our studies provide mechanistic and biological insights into the olfaction decline during aging and highlight the role of NAD+ for preserving smelling function and general health.Olfactory dysfunction is a prevalent symptom and an early marker of age‐related neurodegenerative diseases in humans, including Alzheimer's and Parkinson's Diseases. However, as olfactory dysfunction is also a common symptom of normal aging, it is important to identify associated behavioral and mechanistic changes that underlie olfactory dysfunction in nonpathological aging. In the present study, we systematically investigated age‐related behavioral changes in four specific domains of olfaction and the molecular basis in C57BL/6J mice. Our results showed that selective loss of odor discrimination was the earliest smelling behavioral change with aging, followed by a decline in odor sensitivity and detection while odor habituation remained in old mice. Compared to behavioral changes related with cognitive and motor functions, smelling loss was among the earliest biomarkers of aging. During aging, metabolites related with oxidative stress, osmolytes, and infection became dysregulated in the olfactory bulb, and G protein coupled receptor‐related signaling was significantly down regulated in olfactory bulbs of aged mice. Poly ADP‐ribosylation levels, protein expression of DNA damage markers, and inflammation increased significantly in the olfactory bulb of older mice. Lower NAD + improved longevity and partially enhanced olfaction in aged mice.In the present study, the smelling loss of C57BL/6J mice during non‐pathological aging was systematically characterized. Our data showed that smelling changes were among the earliest changed behaviors during aging. Metabolites related with oxidative stress, osmolytes, and infection were dysregulated in brain regions related with olfaction. DNA damage markers, inflammation, and glial activation increased significantly in OBs of older mice, which together contributed to olfaction decline. Supplementation of NAD DGdentategyrusGCLgranule cell layerGLglomerular layerGOgene ontologyHPChippocampus+NADnicotinamideadenine dinucleotideNRnicotinamide ribosideOBolfactory bulbPARylationADP‐ribosylationPFCprefrontal cortex1The prevalence of olfactory dysfunction increases significantly in older individuals, as more than 50% of people at 65–80 years old experience decreased ability to smell  is a coenzyme for redox reactions and an essential cofactor for non‐redox NAD+‐dependent enzymes which plays vital roles in DNA repair, cell metabolism, and cell survival  on olfactory function in aged mice.Here, we used wild‐type C57BL/6J mice, a commonly used mouse strain for aging research, to systematically investigate olfaction decline during aging. We tracked the changes of olfactory function in different domains across the lifespan , comparing their time courses with other cognitive and motor changes in aging. We explored molecular mechanisms that drive olfactory dysfunction, and we tested the effects of NAD22.1C57BL/6J mice at mature age (5M), middle age (13M), old age (21M) and advanced age (31M) were used in the present study. Significant weight gain was observed from 5 to 21 months of age, while animal weight decreased from 21 to 31 months of age Figure , similarTo evaluate olfactory function, we performed several well‐characterized behavioral assays to assess the four major domains of olfaction which include odor detection, sensitivity, discrimination, and habituation for different odors. In the buried food test, the time required for a food‐deprived mouse to find and grasp a hidden/buried piece of food was recorded to measure odor detection. Our results showed that aged mice spent a significantly longer time before digging in the correct location Figure  and to r5‐fold, while the sensitivity threshold was worse for mice older than 13M. Specifically, the threshold for 21M mice was 104‐fold dilution, while 31M mice could not detect the odorant at the highest tested concentration (103‐fold dilution). These results show that there is an age‐dependent decline of odor sensitivity. In addition, 5M females showed higher odor sensitivity (lower concentration threshold for odor detection) than age‐matched males, while no sex‐specific differences were observed in mice in other age cohorts  3 times in a row before a new odorant (odor B) was presented. Mice normally spend less time sniffing a repeatedly presented odor due to habituation. When a new odor is presented, mice spend more time investigating it if they are able to distinguish it from the previously presented odor , we measured whether they spent more time investigating the new odor B versus the third presentation of odor A. Mice in all age groups had preserved discrimination for food odors; however, for urine odors, which are associated with social activity, only 5M mice were able to distinguish urines collected from different pairs of mice Figure . These rWe also compared the performance of female and male mice at different ages for different pairs of odors. Major sex differences were observed in differentiating hexyl acetate from octyl acetate. Female mice in all age groups except 5M were able to distinguish these two odors while male mice at 5, 21 and 31M all failed to do so Figure . With reTo compare these results to the time course of changes related with other behaviors, we performed additional assays related with motor functions and memory. In the open field test, mice showed a significant decline in vertical rearing activity with aging Figure ; and thiA summary of the behavioral changes with age is shown in Table 2.2To identify metabolic changes associated with smelling dysfunction during aging, metabolites from the olfactory bulb (OB), hippocampus (HPC), and prefrontal cortex (PFC) were analyzed. In total, we identified 127 known and 226 unknown metabolites, using metabolite abundance in 3M old mice as a reference. The data in the heatmap Figure  summarieAmong metabolites commonly altered in all regions Figure , glyceroSeven metabolites were exclusively changed in the OB during aging, including sorbitol, arabitol, 3‐phosphoglycerate, methionine sulfoxide, erythronic acid lactone, N‐acetylneuraminic acid, and threonine Figure . Among tFinally, among the 20 changed metabolites in the OB, four of them  function as osmolytes, which is important in cell volume adaptation Figure . As regu2.3SLAMF9, CD52, C4A, IRF7, IFI27L2A, C4B, EGR2, and GM1987), five of them  were reported to be changed in mouse microglia during aging in Diseases/Drugs analysis through Enrichr  and olfactory bulb  by cell type analysis through Enrichr , AP‐1 transcription factor network , and IL‐17 signaling  etc. Interestingly, more genes are differentially expressed with aging in the HPC than in the OB or PFC  term analysis showed that the most altered terms in the oldest (31M) versus youngest (5M) groups were related to immune response, sensory perception of smell, and G protein coupled receptor protein signal Figure . GO term2.4Further analysis of the effects of aging on different cellular organelles in OB, HPC, and PFC indicates that most of these compartments were downregulated during aging, with the nucleus being the top hit across regions Figure . BecauseInterestingly, despite the significant increase of PARylation in the OB, the protein levels of ATM, 53BP1 and XRCC1, which play important roles in DNA repair, were down regulated in OB tissue from the 31M group compared to the younger groups Figure . InsuffiWe examined protein levels of cGAS and STING, which have been shown to induce senescence and inflammation after activation by DNA damage, processes that we found evidence for in aged mice. cGAS protein was significantly increased in OB tissue from 31M mice; nonsignificant trends were seen in HPC and PFC. STING protein was not significantly altered during aging Figure .Together our results suggest increased protein PARylation and altered expression of DNA repair proteins in the OB of the oldest cohort of mice. We postulate that these changes might lead to increased DNA damage and inflammation, and eventually lead to olfactory dysfunction.2.5Since the microarray and WB analyses revealed increased inflammation in OB and HPC of old mice, we further investigated whether there was activation of microglia and astrocytes, two important types of glial cells in the brain. Astrocytes comprise the most abundant population of glia in the mammalian brain. They not only provide structural support for the brain but also play a variety of essential functions in synapse development, neurotransmitter homeostasis, and neurogenesis etc. An active inflammatory state of astrocytes is associated with increased expression of GFAP and is routinely observed in brain diseases and neuropathology  were measured and compared between samples from different ages. With increasing age there was a significant decline in NAD+ (Figure NAD+ Figure  and a si+ Figure .+ with NR preserves smelling function in aging, 24M old mice were provided with water containing 12 mM NR for 8 months before smelling‐related behavior tests were performed. Mice dosed with NR had a longer lifespan than the water‐only control group (Figure + also altered expression of γ‐H2AX, cGAS, STING and IFNγ in older mice. Expression of these three proteins was lower in NR‐treated mice than in control mice (Figure + reduces neuroinflammation and stimulates DNA repair.To investigate whether supplementation of NADp Figure . In the p Figure . Howeverp Figure . These se Figure . This ise Figure  showing 3+ through NR preserves olfaction and improved longevity in aged mice.Here, we systematically performed a multi‐domain behavioral test battery to characterize olfactory, cognitive, and locomotor changes in wild type healthy C57BL6/J mice of four ages. We demonstrate that smelling loss potentially is an early biomarker of aging compared to memory and motor behaviors. In addition, we show that inflammation and DNA damage confer risks to olfaction decline by using metabolomics, transcriptomics, and signal protein profiling approaches. Finally, we found that supplementation of NADHuman olfactory function typically begins to decline in the sixth decade of life (Mullol et al., Besides the effects of age on olfactory function, we also evaluated sex differences in all the olfactory tests among mice at different ages. Table We investigated whether smelling loss comes earlier than other behavioral changes by comparing the timeline of the changes. Motor function and cognition, which are two important functions significantly affected by aging, are monitored by a battery of behavioral tests. Among these, the earliest change was observed in the rotarod test as 13M and older mice displayed a significantly shorter latency to fall off when compared to 5M mice on the last of five trials, indicating a decline in motor coordination and balance. Some of the gait features started to show differences at 21M, like hind paw angle and hind stance width, notably few prior studies have linked these parameters with aging. Among the gait features which start to change at 31M, the ataxia coefficient is relevant to human aging as an index of step‐to‐step variability that predicts risk of falling (Callisaya et al., Pathologic conditions mostly disorganize metabolic processes, resulting in changes that can be observed as metabolic signatures (Botas et al., Inflammation and glial activation induce loss of smelling and atrophy of the OB (Hasegawa‐Ishii et al., + level significantly declined with age in OB tissue (Figure + levels are associated with Xeroderma Pigmentosum complementation (Fang et al., + through NR reduced expression of markers for DNA damage and inflammatory signaling in OB, and improved smelling behavioral test performance in aged mice. Additionally, it significantly increased the lifespan of wild‐type C57BL/6J mice, indicating that NAD+ supplementation not only provides benefits to smelling but also for general health.The nucleus and nucleosomes were the most significantly affected cellular compartments in OB tissues from 31M versus 5M. Accordingly, aged OB tissue had reduced DNA repair capacity and higher protein levels of Ƴ‐H2AX and p21. In our study, we found that the NADe Figure . As an e+ began to decline as early as 13M in brain regions related with smelling; proteins important for DNA repair, including ATM and PARP1 decreased from 13M; significant changes in olfaction related GO terms were found in HPC as early as 13M, while changes in OB and PFC regions occurred later at 21M. These results also indicate that HPC may be a brain region related to olfaction changes in early aging. This idea is consistent with our GFAP staining, showing that the earliest ages showing increases were 13M and 31M for HPC and OB, respectively. Significant aging‐related molecular changes were detected in OB, including increases in DNA damage markers, inflammation related pathways, IBA1 and GFAP staining, cGAS protein level, and plasma cytokine levels.Collectively, our findings show that the earliest smelling decline in mice can be observed at 13M via odor discrimination for urine samples, while impairment in odor sensitivity and investigation are evident by 21M. Consistently, we observed molecular and protein‐level changes as early as 13M. Specifically, the levels of glycerol, tocopherol alpha, 5‐methoxytryptamine, N‐acetylneuraminnic acid, and NAD+ supplementation. Thus, our data support the concept that olfactory dysfunction has the potential to be an early biomarker of aging, and NR treatment can preserve olfaction in aged individuals.In the present study, we have performed a systematic characterization of smelling loss in non‐ pathological aging. This includes a multi‐age timeline of changes within different odor domains, sex differences, and a comparison with other age‐related behavioral and molecular changes. While it is not our main goal to distinguish between olfactory dysfunction linked to non‐pathological aging and disease‐associated pathology in the present study, our results are helpful in addressing this question by showing the baseline of smelling loss in normal aging and serves as reference when a disease mouse model, on a similar background, are evaluated. Additionally, our findings indicate that both DNA damage repair and inflammation contribute to olfaction decline, which is partially preserved by NAD+ measurement. Y.Z. and D.L.C. performed microarray analysis. X.D. and S.G. wrote and B.Y., D.L.C., M.P.M., and V.A.B. revised the manuscript. All authors contributed to writing the final manuscript.X.D., B.Y., D.L.C., and V.A.B. designed experiments. B.Y., Q.C., S.G. and R.M. performed animal treatment and behavior tests. B.Y. and D.F. collected the mice samples. X.D. and X.C. performed Western blot and histology. X.D, D.L.C. and Chris Morrell performed metabolism analysis. X.D. performed NADV.A.B. had CRADA arrangements with ChromaDex but receives no personal benefit. All others declare no competing interests.Appendix S1: Supporting InformationClick here for additional data file.Appendix S2: Supporting InformationClick here for additional data file.


Suspected immune‐mediated polyneuropathy has been increasingly reported in cats, especially in the last decade, but the condition remains poorly understood.Refine the clinical description and review the classification of this condition based on electrodiagnostic investigation and evaluate the benefit of corticosteroid treatment and L‐carnitine supplementation.Fifty‐five cats presented with signs of muscular weakness and electrodiagnostic findings consistent with polyneuropathy of unknown origin.Retrospective, multicenter study. Data from the medical records were reviewed. The owners were contacted by phone for follow‐up at the time of the study.The male‐to‐female ratio was 2.2. The median age of onset was 10 months, with 91% of affected cats being <3 years of age. Fourteen breeds were represented in the study. The electrodiagnostic findings supported purely motor axonal polyneuropathy. Histological findings from nerve biopsies were consistent with immune‐mediated neuropathy in 87% of the tested cats. The overall prognosis for recovery was good to excellent, as all but 1 cat achieved clinical recovery, with 12% having mild sequelae and 28% having multiple episodes during their lifetime. The outcome was similar in cats with no treatment when compared with cats receiving corticosteroids or L‐carnitine supplementation.Immune‐mediated motor axonal polyneuropathy should be considered in young cats with muscle weakness. This condition may be similar to acute motor axonal neuropathy in Guillain‐Barré syndrome patients. Based on our results, diagnostic criteria have been proposed. ACPacute canine polyradiculoneuritisAIDPacute inflammatory demyelinating polyneuropathyAMANacute motor axonal neuropathyCHVACentre hospitalier vétérinaire AdvetiaCHVPCentre hospitalier vétérinaire PommeryCIDPchronic inflammatory demyelinating polyneuropathyCMAPcompound muscle action potentialCSFcerebrospinal fluidENVAEcole nationale vétérinaire d'AlfortGBSGuillain‐Barré syndromeIMPNimmune‐mediated polyneuropathyIQRinterquartile rangesMNCVmotor nerve conduction velocitySNAPsensory nerve action potentialSNCVsensory nerve conduction velocity1Polyneuropathies have been described infrequently in young cats. Several authors have reported non‐hereditary, polyneuropathies, especially in the last decade.Our primary objective was to refine the classification of this condition based on a large case series with comprehensive electrodiagnostic investigation. In particular, similarities among Guillain‐Barré syndrome (GBS), chronic inflammatory demyelinating polyneuropathy (CIDP), and acute canine polyradiculoneuritis (ACP) are discussed. Our secondary objective was to investigate the potential benefits of corticosteroid treatment and L‐carnitine supplementation in our cohort.22.1Medical records at the Ecole nationale vétérinaire d'Alfort (ENVA), Centre hospitalier vétérinaire Advetia (CHVA), and Centre hospitalier vétérinaire Pommery (CHVP) were retrospectively reviewed for cats with muscular weakness and electrodiagnostic findings consistent with polyneuropathy from January 2010 to January 2022. Cats with causes of neuromuscular disease other than idiopathic or IMPN , incomplete data, notable comorbidities , or concurrent central neurological signs were excluded. Data from the medical records included signalment, history, clinical signs, results of electrodiagnostic studies, and follow‐up information. Results of additional diagnostic evaluations, such as CBC, serum biochemistry profile, urinalysis, cerebrospinal fluid (CSF) analysis, infectious disease testing, diagnostic imaging, and muscle and nerve histology were reviewed when available. Of the ENVA cases, 1 has been published previously by 2 of the authors (AJ and SB) and 2 were included in a previous study.2.2Electrodiagnostic studies were performed under general inhalation anesthetic protocol by a board‐certified neurologist or a neurology resident in training supervised by a board‐certified neurologist using similar devices  on the left side of the cats.Electrodiagnostic data were interpreted and compared with retrospectively reviewed results obtained in the intact limb of cats with traumatic plexus injury or non‐neurologic lameness of the contralateral limb from 2010 to 2022.2.2.12 sampling area) and a SC ground electrode were used for electromyography. Abnormal spontaneous electromyographic activity  was graded from 1+ to 3+ (mild to severe) in all cats, according to a published grading scale.A disposable bipolar concentric needle electrode  were obtained with supramaximal stimuli of 0.1 ms duration, delivered at a frequency of 1 Hz. The sciatic‐tibial CMAP was recorded from the plantar interosseous muscle after stimulation of the sciatic notch and hock. The sciatic‐fibular CMAP was recorded from the 2.2.3Monopolar electrodes were positioned similar to distal CMAP recording to record the H‐reflex and F wave. The H‐reflex was obtained for the sciatic‐tibial and ulnar nerves with a submaximal stimulus of 0.1 ms duration. The H‐reflex was identified as the most prominent wave with a submaximal stimulus for the M‐wave or in the absence of an M‐wave. The latency rate was calculated using a previously described equation: limb length/(H latency − M latency).2.2.4Repetitive supramaximal stimulation of the sciatic‐fibular nerve was performed with trains of 10 supramaximal stimuli of 0.1 ms duration for each stimulus rate, delivered at different frequencies from 0.1 to 3 Hz. A minimum of 1 minute of recovery time elapsed between trains of stimuli. Compound muscle action potential amplitude and area under the curve were compared among the first, fourth, fifth, and tenth potentials to assess decremental responses.2.3triceps brachii, biceps femoris, cranial tibialis muscles, and right superficial sciatic‐fibular nerve at the level of the stifle joint as previously described.Under general inhalation anesthesia, biopsy specimens were collected from the right Muscle biopsy specimens were flash frozen in isopentane precooled in liquid nitrogen (−130°C) and stored at −80°C until further processing. Muscle cryosections (10 μm thick) were stained using standard protocols, including hematoxylin‐eosin, modified Gomori trichrome, ATPase preincubation at different pH , periodic acid‐Schiff‐hematoxylin, oil red O, and 2,4‐dinitrophenylhydrazine. All muscle biopsy specimens were analyzed at the time of the study. For each biopsy sample, the degree of myofiber atrophy was evaluated and graded as mild (+), moderate (++), or marked (+++), defined as follows: mild (rare angular myofibers), moderate , and marked (myofibers reduced to pyknotic nuclear clumps or fascicular atrophy). Fiber type groupings and IM nerve branches also were evaluated.Nerve biopsy specimens were placed on a tongue depressor and immersion fixed in Karnovsky's solution for 2 hours before being transferred to 2.5% glutaraldehyde solution in 0.1 M sodium phosphate buffer (pH 7.4). The specimens then were sent to the Section of Clinical & Comparative Neuropathology, Center for Clinical Veterinary Medicine, Ludwig‐Maximilians‐Universität München, Munich, Germany.2.4All owners were contacted by phone at the time of the study. Recovery status, time from examination to recovery, treatments prescribed, and residual neurological deficits (referred to as sequelae) were reviewed. If multiple episodes were mentioned, only data from the episode for which the electrodiagnostic study was performed (referred to as the studied episode) were used. Time from examination to recovery was defined as the time between the electrodiagnostic study and stabilization of clinical signs (complete recovery or recovery with sequelae). The duration of the studied episode was defined as the sum of the duration of clinical signs at presentation and the time from examination to recovery. If corticosteroid treatment was started later in the absence of improvement with or without another treatment, the cat was considered to be treated with corticosteroids, the time from examination to recovery started from corticosteroid treatment initiation, and the duration of the studied episode included the time from presentation to initiation of corticosteroids.A cat was considered lost to follow‐up if no data were available regarding clinical examination at least 1 month after the electrodiagnostic study and the owners could not be reached after that time, unless the cat returned to normal during that period.2.5Because all variables were non‐normally distributed, data are presented as medians and interquartile ranges (IQR). Statistical analysis was performed using R software  and Excel software .33.1The final cohort included 55 cats: 18 from ENVA, 32 from CHVA, and 5 from CHVP. Of the cohort, 38 (69%) were male and 17 (31%) were female. The male‐to‐female ratio was 2.2. Thirty (55%) cats were neutered. The overall median age at presentation was 10 months , with 50 cats (91%) < 3 years of age . Four cats (7%) had ≥1 similar episodes that resolved without sequelae, with or without treatment. No seasonality was observed; cats were presented in similar proportions in winter , spring , summer , and fall . All cats had pelvic limb weakness associated with difficulty in jumping. Thoracic limbs also were involved in 37 cats (67%), and the owners reported that pelvic limb involvement was either concomitant or occurred before thoracic limb involvement.Except for neurological dysfunction, physical examination results were unremarkable in all cats. Neurological examination identified postural and gait abnormalities involving all limbs or only the pelvic limbs in all cats, including tetraparesis , paraparesis , plantigrade stance , ataxia , palmigrade stance , and passive cervical ventroflexion . Forty‐seven cats (87%) were ambulatory and 8 cats (13%) were non‐ambulatory. Ambulatory cats generally walked a few steps and then frequently would sit or lie down. Clinical signs were symmetrical. Postural tremors were reported in 2 cats. Postural reactions were decreased in 48 cats (87%), with pelvic limb involvement in 48 cats (87%) and thoracic limb involvement in 39 cats (71%). Decreased or absent spinal reflexes were found in 41 cats (75%), including the pelvic limb withdrawal reflex , patellar reflex , and thoracic limb withdrawal reflex . Bilateral facial paresis was noted in 6 cats (11%). None of the cats had urinary or fecal incontinence.3.2Toxoplasma gondii testing was performed in 13 cats, and was negative in all cats. Cerebrospinal fluid was collected from the cerebellomedullary cistern in 13 cats with a median duration of 4 weeks of clinical signs before collection : 11 cats (85%) had total nucleated cell counts and protein concentration within the reference interval, and 2 cats (15%) had increased total protein concentration (0.45 and 1.22 g/L) with total nucleated cell counts within the reference interval .Serum biochemical analysis, serum electrolyte concentrations, CBC, urinalysis, and thoracic radiography were performed in 34, 26, 12, 5, and 25 cats, respectively, and were unremarkable in all cats. Serum creatine phosphokinase activity was within the reference range or slightly increased in all tested cats . Serology for acetylcholine receptor antibody, FeLV, FIV, coronavirus, and 3.33.3.1Abnormal spontaneous electromyographic activity, including either positive sharp waves and fibrillation potentials  or complex repetitive discharges , was reported with variable intensity from 1+ to 3+ (mild to severe). Pelvic limbs were involved in all cats and thoracic limbs were involved in 52 cats  and for the ulnar nerve in 30/47 cats (64%). Because limb size was not available for all cats, latency rate could only be calculated for 8 cats for the sciatic‐tibial nerve and 3 cats for the ulnar nerve. The median latency rate was decreased for both nerves: 23.5 m/s  and 15.4 m/s , respectively. The F‐wave was obtained for the sciatic‐fibular nerve in 37/50 cats (74%) and for the radial nerve in 12/20 cats (60%). The median F‐ratio was moderately decreased for both nerves: 2.38  and 2.02 , respectively , including 42 e Figure . Other as Figure . For casNerve biopsies were performed in 33 (60%) cats. Two biopsies were nondiagnostic for technical reasons. Among the 31 remaining samples, 27 (87%) were consistent with IMPN with histological evidence of nerve fiber adhesive or invasive inflammatory infiltrates or both directed at the axons, nodes of Ranvier, and Schwann cells,3.5After the electrodiagnostic study, 12 cats (22%) received no treatment, 27 (49%) received L‐carnitine supplementation at 50 mg/kg q12h for a median duration of 17 weeks , and 16 (29%) received corticosteroids for a median duration of 17 weeks . In 3 cats, corticosteroids were initiated in the absence of substantial improvement after 1 month of L‐carnitine supplementation, and complete recovery was achieved in 5 days for 1 cat and in 3 weeks for 2 cats.Follow‐up data were available for 43 cats  and follow‐up Table  were sim3.6.2Of the 43 cats with follow‐up, complete recovery was reported in 10/11 (91%) cats receiving no treatment , 9/12 cats (75%) that received corticosteroids , and 18/20 cats (90%) that received L‐carnitine supplementation . The only cat that did not recover was treated with prednisolone (2 mg/kg/day) after presentation. Treatment was gradually discontinued after no signs of improvement. To calculate the time from examination to recovery and the duration of the studied episode, 7 cats were not included: time from examination to recovery could not be estimated for 3 cats because of sequelae or absence of recovery, 3 cats received corticosteroids in the absence of substantial improvement after 1 month of L‐carnitine supplementation, and the duration of signs at presentation was missing for 1 cat. The time from examination to recovery was similar in cats receiving no treatment , corticosteroids , or L‐carnitine . By extrapolation, the duration of the studied episode was similar in cats receiving no treatment , corticosteroids , or L‐carnitine  compared to cats without previous episode  or acute inflammatory demyelinating polyneuropathy (AIDP) subtypes.In contrast to a recent studyOur study had some limitations based on its retrospective nature. There was no standardization of clinical data reported by different clinicians. Therefore, some clinical signs may not have been recorded at the time of the clinical examination, and the recorded duration of the episodes may be imprecise. Moreover, because follow‐up by phone does not allow for direct neurological examination, sequelae may be underestimated. Finally, not all of the cats were histologically diagnosed. Nevertheless, the subgroup with nerve histology consistent with IMPN showed similar results to those of the remainder of the cohort for electrodiagnostic and outcome data, except for the relapse rate. Thus, sampling effect cannot be excluded from this feature.To date, no diagnostic criteria are available for definitive diagnosis. Nerve histology alone is insufficient and may be unremarkable. It should be included in a broader diagnostic approach, based on several criteria. We propose diagnostic criteria in Table Authors declare no conflict of interest.Authors declare no off‐label use of antimicrobials.Authors declare no IACUC or other approval was needed.Authors declare human ethics approval was not needed for this study.Table S1: Abnormal spontaneous electromyographic activity in pelvic and thoracic limbs.Click here for additional data file.


To evaluate the impact of radiosensitivity on outcomes of spinal metastases treated with stereotactic body radiotherapy (SBRT) and identify the correlated prognostic factors.The authors retrospectively reviewed the records of all patients who underwent SBRT with no prior radiation for spinal metastases between October 2015 and October 2020 at Sun Yat‐sen University Cancer Center. On the basis of radiosensitivity, patients were divided into two groups—radiosensitive and radioresistant. The endpoints included local control (LC), overall survival (OS), pain relief, and time to pain relief.p = 0.02 and p < 0.001, respectively). The presence of other metastases (p = 0.04) and pain at enrollment assessed by the Brief Pain Inventory predicted for worse OS (p = 0.01). The 6‐, 12‐, and 24‐month LC rates were 88%, 86%, and 82%, respectively. Younger age was identified for better LC and pain relief . There was no variable independently associated with time to pain relief. As for toxicity, no Grade ≥3 toxicity was observed.A total of 259 (82.5%) patients with 451 lesions were assessable with a median follow‐up time of 10.53 months. The 1‐, 2‐, and 3‐year OS rates were 59%, 52%, and 44%, respectively. The median survival was 33.17 months. Higher Karnofsky Performance Scale score and shorter time to diagnosis of spinal metastases from primary cancer at consult predicted for better OS (Regardless of radiosensitivity, SBRT is feasible and appears to be an effective treatment paradigm for patients with spinal metastases, with limited accepted toxicities. The definition of pain flare was temporary worsening of pain in the treated site, which maybe a potential side effect of palliative radiotherapy for symptomatic bone metastases.Therefore, this study aimed to assess the influence of tumor radiosensitivity on the effect of SBRT to patients with spinal metastases, and attempt to elucidate indications for patient selection. Further categorizing tumors with different radiosensitivity ,22.1We retrospectively reviewed a consecutive series of 547 lesions in 314 patients who were treated with SBRT for spinal metastases at Sun Yat‐sen University Cancer Center between October 2015 and October 2020, and gathered outcomes until December 2020. All patients had histologically proven primary cancer diagnosis. Spinal metastases were diagnosed by CT and/or MRI and/or PET‐CT. Institutional review board (IRB) approval was obtained at the Sun Yat‐sen University Cancer Center, Guangzhou, China.Eligibility criteria included: age >18 years; a pathological diagnosis of primary cancer; oligometastasis ; KPS score of ≥70; lesions treated with radiographic or clinical follow‐up; a maximum of three separate sites of treatment, up to two contiguous levels within one radiation field. Patients were ineligible if they had acute spinal cord compression or the presence of overt spinal instability.2.2SBRT was performed using intensity‐modulated radiation therapy planning or other dose painting techniques. Unless contraindicated, all patients underwent 3 mm slice thickness contrast‐enhanced CT and/or MRI simulation scanning. Patients received radiation in one to six fractions with a 6–8 MV X‐ray beam applied using the Elekta Precise Treatment System (Elekta AB) or the Elekta Versa HD System (Elekta AB). The contouring guidelines for the targets and organs‐at‐risk, dose delivering and dose restriction of spinal metastases treated with SBRT in accordance with previous studies2.3LC was defined as no progression within the treated vertebral body level on following CT or MRI. Vertebral compression fracture (VCF) was defined as de novo and progressive preexisting fractures. Toxicity was graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.2.4A retrospective review of the hospital records and radiographic studies of these patients was performed. Data on each patient including age, sex, date of initial diagnosis of primary cancer, histology of primary cancer, date of diagnosis of first spinal metastasis, location of the spinal metastasis , radiation sites, other metastases , further radiotherapy to other sites, the presence of paraspinal extension, further systemic treatment, number of the spinal metastasis, previous treatments  and KPS score, pre‐SBRT pain as assessed by the BPI (when available), ESCC grade pre‐SBRT, and SBRT information  were gathered.2.5p‐values were two‐sided. Here, a p < 0.05 was considered statically significant. Statistical analysis was performed using SPSS software .Both continuous and categorical variables were summarized. The Kaplan–Meier product‐limit method was used to estimate OS, and survival curves were compared using the log‐rank test. Factors associated with OS after SBRT were assessed using univariate and multivariate Cox proportional hazards analyses, as well as LC. Hazard ratios (HRs) and their corresponding 95% confidence intervals (CIs) were computed. Factors associated with pain palliation and the incidence of SBRT complications were assessed using univariate and multivariate logistic regression analyses. Factors associated with the time of pain palliation were assessed using linear regression. All mean values are presented as mean ± standard error. All 33.1During the study period, 314 patients treated with SBRT were included between October 2015 and October 2020, and 55 patients have been lost to follow‐up. The demographic, tumor, and treatment characteristics of 259 patients with 451 lesions are summarized in Table n = 66), followed by prostate cancer (n = 66) and others. The ESCC grades were 0 in 186 (71.8%), 1a in 8 (3.1%), 1b in 31 (12.0%), 1c in 9 (3.5%), and 2 in 25 (9.6%). Of the 24 patients with epidural disease compressing the spinal cord (Bilsky Grade 2), 12 underwent surgery. Because of the medical comorbidities and intolerance for surgery, the other 12 patients were treated with SBRT alone. The spinal metastases with paraspinal extension were 82 (40.59%). One hundred sixty‐two (62.5%) patients experienced prior chemotherapy, and 156 (60.2%) prior bisphosphonate therapy. Patients treated with radiation therapy on other sites were 73 (28.2%). In this consecutive series, 137 (30.4%) lesions were from radiosensitive tumors, 341 (69.6%) from radioresistant malignancies.Among all treated lesions, 27 (10.4%) were cervical, 129 (49.8%) thoracic, 86 (33.2%) lumbar, and 17 (6.6%) sacral. There were 258 patients defined as oligometastases. The most common lesions treated were metastatic tumors of the lung . Of the 451 lesions, 40 (15.4%) were treated with SBRT postoperatively. The median total dose delivered was 30 Gy , with a median fraction number of 5 . The median biologically effective dose delivered was 48.0 Gy .3.2p < 0.001). There was no statistical significance in radiosensitivity (p = 0.12)   , the presence of other metastases (p = 0.04), treating site (p = 0.02), and the presence of pain at enrollment (p < 0.001). On multivariate analysis, KPS score (p = 0.04), treating site (p = 0.04), the presence of pain (p = 0.02), and other metastases (p = 0.02) were significant factors of worse OS  to be prognostic for better pain relief. On multivariate analysis, age retained its significance in terms of pain relief (p = 0.04). The others were not significant factors, including treating site, paraspinal extension, KPS score at consult, the number of metastases, dose, fractions, time to spinal metastases, Bilsky grade, and use of surgery. The median time to pain relief was 0.8 months . On univariate and multivariate analyses, there were no significant factors with time to pain relief.Of the 143 patients with baseline pain, 8 patients were lost to follow‐up and 135 patients were assessable. Because of the retrospective characteristic of our study, it was hard to avoid several patients not to keep up with the follow‐up. The range “0” of time to pain relief means that the patients attained pain relief on the day of radiation. Almost at the time of receiving radiation, pain palliation was achieved. We reported a 76.3% (103/135 patients) of pain relief. Univariate analysis identified age  patients, immunotherapy in 43 (13.69%) patients, and targeted therapy in 105 (33.44%) patients. Obviously, almost these treatments were for primary cancer. In addition, other local treatments were applied, including surgery in 8 (2.55%) patients and radiation for other sites in 66 (21.0%) patients. Meanwhile, 156 patients (49.68%) were receiving bisphosphonate. Bisphosphonates were mainly used in reducing the incidence of bone disease, bone pain, and fracture.3.6p = 0.045). There was no statistically significant difference for radiosensitivity (p = 0.39). On multivariate analysis, the use of bisphosphonate was a predictor for the occurrence of VCF (p = 0.02). Two patients experienced pain flare after SBRT that required hospitalization. Grade 1/2 toxicity consisted of fatigue during treatment for nine patients, and one patient had decreasing smelling after SBRT not requiring treatment. No patient had persistent or worsening neurological symptoms.All patients tolerated SBRT well with minimal complications or toxicity, with no Grade ≥3 toxicities observed in any patient. And there were no cases of myelopathy or radiculopathy. Overall, 26 (8.28%) patients experienced VCFs. Of these patients, two were surgically stabilized before SBRT, with 24 VCFs occurring after SBRT in the nonsurgical sites. Twenty‐one of 26 were de novo VCFs and others were the progression of an existing VCF. On univariate analysis, the factor that significantly affected the rate of VCF was use of bisphosphonate . According to above studies, we can think that SBRT could provide durable local tumor control regardless of radiosensitivity. Of the 28 patients regarded as local failure, liver cancer and renal cell cancer take up 21.4%, respectively. As for LC, we reported that age was a statistically significant factor (p < 0.001). Younger seemed to have a better local tumor control. In future patient selection, age could be taken into consideration.In our study, of patients with radiographic follow‐up, 1‐year LC rate was 86%. The result was consistent with several previous analysis.We also paid attention to the survival outcomes. We reported that the OS rates at 1‐ and 2‐year were 59% and 52%, respectively. These results are consistent with prior reports in the literature.p = 0.02). With better general condition, patients with spinal metastases would accomplish the treatment and gain the survival benefit from SBRT. Moreover, the presence of other metastases and pain at enrollment were significant factors for OS . In those who experienced pain at enrollment, achieving pain relief could be a predictor for better OS (p < 0.01). As is known to us, for bone metastases, including spinal metastases, the most common symptom was pain. Therefore, with regard to patients with baseline pain, timely and optimal analgesia treatment modality was critical before SBRT. Of course, both analgesics and radiotherapy produced analgesic effects. But there was no denying that we did see better OS among patients who had attained pain relief. In the meanwhile, after the diagnosis of primary cancer, regular physical examination is essential in case of the occurrence of spinal metastases (p < 0.04). It demonstrated that treating site was a significant factor for OS (p = 0.02). Overall, it indicated that cervical vertebrae had a better OS (27 patients), followed by lumbar vertebrae (86 patients), thoracic vertebrae (129 patients), and sacral vertebrae (17 patients). It may be because sacral vertebrae are adjacent to ilium. Therefore, some patients developed myelosuppression after radiation therapy. Through the statistical analysis, there was no significant difference found in radiosensitivity with LC (p = 0.12) and OS (p = 0.11). It could be predicted that spinal SBRT provides a satisfying LC and OS, regardless of radiosensitivity.KPS score was used to evaluate general condition of patients. Obviously, higher KPS score, and better general condition. It is regarded as a predictor for OS (p = 0.04) to be a prognostic factor for pain relief. Younger age could achieve better pain relief. In a way, it may be associated with faster cell proliferation in younger people. When selecting patients to be treated with SBRT, age might be taken into consideration.For these patients, SBRT aims to achieve the pain palliation and delay or even prevent the retreatment. We reported 76.3% of pain relief rate, similar to previous reported rates.To our knowledge, there are no uniformly accepted indications in patient selection for spinal SBRT. The above factors might provide instructions in selecting patients. Moreover, the neurologic, oncologic, mechanical, and systemic (NOMS) frameworkp = 0.045) could decrease the risk of VCF. Therefore, it is necessary to take some preventive measures to avoid the occurrence of VCF after SBRT.The most common toxicity for spinal metastases treated with SBRT was the occurrence of VCF. For patients, VCF would have an influence on the quality of life, such as intolerable bone pain. Hence, fracture prevention is of great importance. As for the toxicity of patients treated with SBRT, we demonstrated a risk of VCF of 8.28%, which is consistent with previous spinal SBRT literatures reporting rates ranging from 5% to 42%.Several strengths of this study deserve mention. First, we categorized tumors with different radiosensitivity. No statistically significant difference was found in radiosensitivity with OS, LC, pain relief, and time to pain relief. Our results might provide a reference for future research. Second, in the study, we analyzed the aspects including OS, LC, pain relief rate, and time to pain relief. Obviously, it included and analyzed comprehensive outcomes. Third, without limited in single fraction, we reported one to six fractions; the results were consistent with previous studies. Moreover, to the best of our knowledge, our study was the first to report the outcomes of spinal metastases treated with SBRT in China. There were a number of limitations in this study. Given the retrospectively collected data, selection biases inevitably existed. Furthermore, assessment of pain response was not prospectively collected. The study is limited because of the experience of single institution, which is needed to be validated in other institutions.5In conclusion, regardless of radiosensitivity, SBRT is a noninvasive intervention that seems to be viable, safe, and effective for patients with spinal metastases. With minimal accepted toxicities, a good tumor control was achieved. Furthermore, patients can be expected to develop durable LC and pain relief on treated lesions. To confirm late toxicities and define patient selection, further studies with large sample sizes and a longer follow‐up are required.Lanlan Guo: Data curation (lead); formal analysis (lead); methodology (lead); resources (lead); software (lead); writing – original draft (lead). Qing‐Qing Xu: Investigation ; methodology ; resources ; software ; writing – original draft . Lixin Ke: Conceptualization ; methodology ; resources ; software ; writing – original draft . Ziwei Wu: Data curation ; formal analysis ; methodology . Ziyi Zeng: Formal analysis ; software ; validation . Lei Chen: Methodology ; project administration ; supervision . Yuan‐Yuan Chen: Methodology ; project administration ; supervision . Li‐Xia Lu: Methodology ; project administration ; supervision ; writing – review and editing .The authors have no conflict of interest to declare.The study was approved by the ethics committee of Sun Yat‐Sen University Cancer Center (number SL‐B2021‐237‐01).


Extramammary Paget's disease (EMPD) is rare. There are no standard treatments due to its rarity and few clinical trials.The objective of this multicenter study was to investigate treatment outcomes of Korean patients with advanced/metastatic EMPD. Data were collected retrospectively from 14 institutions participating in Korean Cancer Study Group (KCSG) Rare Cancer Committee.n = 22) achieved an objective response rate (ORR) of 45.5% and a median progression‐free survival (PFS) of 7.89 months. Taxane‐based chemotherapy (n = 8) achieved an objective response rate of 62.5% and median PFS of 9.73 months. In second‐line chemotherapy, platinum‐based chemotherapy (n = 4) had a disease control rate (DCR) of 75.0% and median PFS of 3.45 months. Taxane‐based chemotherapy (n = 8) had a DCR of 75.0% and a median PFS of 8.67 months. Six patients received anti‐human epidermal growth factor receptor 2 (HER2) antibody during first‐ and second‐line chemotherapy. Overall, systemic chemotherapy combined with anti‐HER2 antibody had an ORR of 100% and a median PFS of 13.31 months. The ORR and PFS with systemic chemotherapy combined with trastuzumab was better than platinum‐ and taxane‐based chemotherapy only.A total of 37 patients were identified. Of these 37 patients, 6 received locoregional therapy as a first‐line treatment. In 31 patients who received systemic chemotherapy as a first‐line treatment, platinum‐based chemotherapy  still has no established standard treatment and little data on clinical outcomes. In this study, we found that there is no survival difference between platinum‐based chemotherapy and taxane‐based chemotherapy, and trastuzumab with taxane has longer survival than trastuzumab monotherapy or conventional platinum‐ or taxane‐based chemotherapy. It is mainly manifested as either a primary cutaneous adenocarcinoma, but it can also be manifested as secondary cutaneous involvement from cancers originating in the urinary tract or lower gastrointestinal tract. The cell of origin for primary cutaneous EMPD still remains controversial. While it is reported that adenocarcinoma originating from underlying apocrine or eccrine glands has spread to the epithelium, it has also been reported as originating from pluripotent stem cells or Toker cells.EMPD usually presents in the form of eczema‐like plaques with well‐defined boundaries and occurs predominantly in the anogenital region. Occasionally, it manifests as multifocal and bilateral lesions. The vulva is the predominant site of occurrence and, according to report, accounts for up to 65.0% of all cases of EMPD.Most patients with EMPD are diagnosed and treated in the stage of carcinoma in situ.The prognosis for patients with distant metastases is very poor.Nevertheless, there is still no established standard treatment for advanced or metastatic EMPD. Studies on real‐world results of current practice are also rare. In this regard, we planned a multicenter retrospective study to investigate current treatment patterns and compare clinical outcomes of Korean advanced or metastatic EMPD patients.22.1A total of 14 medical center affiliated with Rare Cancer Committee of Korean Cancer Study Group (KCSG) participated in this study. As a retrospective study, medical records of 14 participating centers were searched from January 2004 to December 2018. Fifty‐three patients with advanced or metastatic EMPD was found. Ten patients who refused treatment after initial diagnosis or did not receive any kind of treatment for his or her recurrent disease were excluded. Six patients who had secondary EMPD were also excluded. Four cases were related to rectal cancer. One case was related to bile tract cancer and one case was related to ureter cancer. Clinical characteristics were retrospectively collected from medical records including age, gender, primary site, relapse/metastatic sites, HER2 status, laboratory data, the type of treatments, treatment regimens, the start & end date of treatment, outcomes of treatment, and survivals. The study protocol was approved by the Institutional Review Board of each participating hospital.2.2Responses to treatment were determined by investigators at each participating institution according to RECIST criteria. Scheduled follow‐up with computed tomography was performed every 3 or 4 cycles of chemotherapy or whenever clinically indicated in accordance with policies of participating centers. Objective response rate (ORR) was determined by the percent of patients who achieved a complete response or partial response to the treatment. Progression‐free survival (PFS) was calculated from the date of the initiation of treatment to the date of disease progression or death from any cause. Overall survival (OS) was calculated from the date of the initiation of first‐line treatment for recurrence or metastasis to the date of death from any cause.2.3p < 0.05. All data were analyzed with the Statistical Package for Social Sciences 24.0 (IBM Corp.) and MedCalc 20.014 .Descriptive statistics was used to analyze clinical data. The association between clinical characteristics and response to chemotherapy was determined using Fisher's exact test. PFS and OS were analyzed using the Kaplan–Meier method and compared with the log‐rank test. Statistical significance was defined by 33.1Clinical characteristics of the 37 patients with primary EMPD are summarized in Table 3.2In 37 patients, three patients received palliative radiation therapy only, three patients received locoregional therapy, and 31 patients received systemic chemotherapy  had of PFS and OS of 58.4 months. The patient was alive at the time of manuscript was written.p = 0.292 and p = 0.643, respectively) . The remaining one patient received a combination of platinum and taxane. The patient received carboplatin+docetaxel chemotherapy, and he had a stable disease with a PFS of 6.24 months and an OS of 8.05 months until loss to follow‐up. Overall PFS and OS of those treated with first‐line chemotherapy are shown in Figure Thirty‐one of 37 patients initially received systemic chemotherapy as a first‐line treatment. The overall ORR was 48.4% 15 of 31). The median PFS was 8.51 months . The median OS was 21.06 months (95% CI: 18.75–23.37). In 31 patients who were initially treated with systemic chemotherapy  achieved PR and a PFS of 4.93 months. Of two patients who received docetaxel monotherapy, one patient had PD and a PFS of 1.84 months, and the other patient had SD and a PFS of 6.74 months. The patient who received etoposide monotherapy achieved PR and a PFS of 2.99 months. The patient who received doxorubicin monotherapy achieved SD and a PFS of 6.97 months. Six patients experienced disease progression during third‐line chemotherapy. Three of these six patients received fourth‐line chemotherapy  and all initially had PD at best response with PFS of 2.99, 1.84, and 0.26 months, respectively. One of the three patients received fifth‐line chemotherapy with etoposide after trastuzumab monotherapy. The patient had PD at best response and a PFS of 1.41 months. Summarizing the treatment results of third‐line, fourth‐line, and fifth‐line chemotherapy, there were objective responses in 3 out of 10 treatments, and the median PFS of 10 treatment was 2.42 months.Systemic chemotherapy combined with anti‐HER2 antibody (trastuzumab or trastuzumab biosimilar) was used in six patients with HER2‐positive EMPD: three in first‐line, three in second‐line, and one in fourth‐line Table . In six N = 19 vs. 4, 8.87 [95% CI: 7.40–10.34] vs. 3.88 [95% CI: 0–8.16], p = 0.032). In first‐line chemotherapy, three patients who received chemotherapy combined with trastuzumab had numerically longer PFS than those received platinum‐ and taxane‐based chemotherapy . In 12 patients who had HER2‐positive EMPD, nine patients received first‐line chemotherapy. In these nine patients, patients who received chemotherapy combined with trastuzumab had longer PFS than those received platinum‐ and taxane‐based chemotherapy . Of the 31 patients receiving chemotherapy, none received radiotherapy or surgery other than palliative purposes that could affect the determination of response during chemotherapy. Outcomes of serial systemic chemotherapy in primary EMPD in 31 patients showed in Appendix In 31 patients treated with first‐line systemic chemotherapy, treatment response was not associated with clinical factors including age, performance status (PS), primary sites, disease status, LN station, the sites of metastasis, HER2 positivity, the type of treatment (platinum vs. taxane), and CK7/CK20/CEA positivity  male predominance in Taiwan patients.In our study, platinum‐based chemotherapy was preferred to docetaxel‐based chemotherapy as first‐line treatment. More than a half of patient (22 of 31) received platinum‐based chemotherapy for first‐line chemotherapy. Taxane‐based chemotherapy was used in eight patients for first‐line treatment. Because taxanes are not covered by Korean Health Insurance, clinicians might have preferred platinum‐based chemotherapy as their first‐line prescription. Numerically, the PFS of taxane‐based chemotherapy (docetaxel monotherapy) seems to be better than that of platinum‐based chemotherapy (FP). However, taxane‐ or platinum‐based chemotherapy had no statistical difference in survival as a first‐line treatment. Because our comparison included only eight patients treated with taxane‐based chemotherapy, the numerical difference should be re‐evaluated with a larger number of patients. Although these two regimens are the most commonly used in advanced/metastatic EMPD, only 5 of 19 patients who received FP as a first‐line chemotherapy received docetaxel monotherapy for second‐line chemotherapy. None of the eight patients who received docetaxel monotherapy as a first‐line chemotherapy received platinum‐based chemotherapy for second‐line chemotherapy. Therefore, in this study, it is not possible to determine which chemotherapy is better as first‐line chemotherapy.Our results of platinum‐ and taxane‐based chemotherapy are comparable to those of previous studies. Kariya et al. have reported a beneficial effect of low‐dose 5‐fluorouracil/cisplatin regimen in one patient with metastatic EMPD.Our data demonstrate that most patients underwent median 2 treatment‐line . Most patients received only first or second line of chemotherapy. There was no standard regimen after second line of chemotherapy. After second line of chemotherapy, the response was also poor . Considering that about half of patients just underwent one or two lines of chemotherapy and that a few people receive third or more line chemotherapy, to improve patient’ survival, we should focus on developing more efficacious regimen and its application on early line of treatment before patient's deterioration.Histologically, EMPD has very similar characteristics to breast Paget's disease. In breast Paget's disease, HER2 tends to be amplified or overexpressed in most patients.Contrary to results of previous study with trastuzumab monotherapy,We performed a statistical analysis to compare clinical factors and clinical outcomes, but most of the data had many missing values, making it difficult to properly process statistics. Therefore, it should be considered that some of our statistical results have biases and limitations in interpretation. In this study, no specific clinical factor influenced the clinical outcomes except the well‐known prognosticator—PS. However, due to small sized and the nature of the retrospective study, this result needs to be confirmed through another large sized study. Several other cytotoxic chemotherapeutic regimens were tried at various lines of treatment. However, outcomes of these regimens were not superior to those of platinum‐ or taxane‐based chemotherapy used in first‐line or second‐line treatment. Therefore, there is no reason to prefer these regimens to platinum‐ or taxane‐based chemotherapy without compelling indications. Recently, pyrotinib, a tyrosine kinase inhibitor, have been attempted in patients harboring HER2 mutations. Immune checkpoint inhibitors in PD‐L1 positive cancer are being attempted. They might be helpful in the treatment of metastatic EMPD.In summary, platinum‐ and taxane‐based chemotherapy showed similar efficacy in advanced/metastatic EMPD. However, there was no further improvement in treatment or clinical outcomes with conventional cytotoxic chemotherapy so far. To improve the patient's outcomes, it is urgent to introduce new treatment strategy such as targeted therapies and immune checkpoint therapies. The combination of anti‐HER2 antibody could be a turning point in the treatment for patients with advanced/metastatic EMPD. To improve the patient's outcomes, effort to introduce new treatments is mandatory and its application on early line of treatment before patient's deterioration.Byeong Seok Sohn: Conceptualization ; data curation ; formal analysis ; resources ; writing – original draft (lead). Jeongeun Kim: Data curation ; writing – review and editing . Miso Kim: Data curation ; writing – review and editing . Jung Yong Hong: Data curation ; writing – review and editing . Jieun Lee: Data curation ; writing – review and editing . Song Ee Park: Writing – review and editing . Hyojeong Kim: Data curation ; writing – review and editing . Hyo Jin Lee: Data curation ; writing – review and editing . Eun Joo Kang: Data curation ; writing – review and editing . Soon Il Lee: Data curation ; writing – review and editing . In Hee Lee: Data curation ; writing – review and editing . Seok Jae Huh: Data curation ; writing – review and editing . Jeongmin Jo: Data curation ; writing – review and editing . Ho Young Kim: Data curation ; writing – review and editing .All authors declare no conflict of interests.


Prostatic stromal sarcoma is an extremely rare malignancy of the prostate with a poor prognosis.A 65‐year‐old man presented with dyschezia, and computed tomography showed a large prostate mass. The diagnosis was prostate stromal sarcoma by transrectal needle biopsy. Magnetic resonance imaging suggested rectal infiltration. The patient underwent 4 courses of neoadjuvant chemotherapy with gemcitabine and docetaxel hydrate followed by total pelvic exenteration.No recurrence has occurred at 5 years after the surgery. This is the first report of complete resection in prostate stromal sarcoma after neoadjuvant chemotherapy with gemcitabine and docetaxel hydrate. ACadjuvant chemotherapyACTactinomycinAWDalive with diseaseCDDPcisplatinCPT‐11irinotecanCTcomputed tomographyCThchemotherapyDODdead of diseaseDOXOdoxorubicinDRdistant recurrenceDTXdocetaxel hydrateDxdiagnosisERestrogen receptorsGEMgemcitabineIFOifosfamideLRlocal recurrenceMMCmitomycin CMRImagnetic resonance imagingn.r.not reportedNACneoadjuvant chemotherapyNCI CTCAENational Cancer Institute Common Terminology Criteria for Adverse EventsNEDno evidence of diseasePgRprogesterone receptorsPIRApirarubicinPRpartial responsePSPUMPproliferation of uncertain malignant potentialPSSprostate stromal sarcomaRCPradical cystoprostatectomyRPradical prostatectomyRTradiotherapySDstable diseaseSTUMPstromal tumors of uncertain malignant potentialVCRvincristineVp‐16etoposidePSS is an extremely rare malignancy with a poor prognosis. Surgical resection is considered the treatment of choice as the effectiveness of NAC is unknown. Here, we report a case of PSS, in which the tumor was completely resected after NAC with GEM and DTX.PSS is an extremely rare malignancy of the prostate with a poor prognosis. In 1998, PSS was classified into 2 types: PSS and STUMP. Surgical resection is the treatment of choice, as the effectiveness of NAC is unknown.A 65‐year‐old man presented with dyschezia and was admitted to a local hospital in Thailand.2 mass with rectal invasion, mainly in the right lobe of the prostate , indicating PSS. Whole‐body CT showed no lymph nodes or distant metastases.The patient was diagnosed with PSS.2  and DTX 70 mg/m2 (day 1) was administered. After two courses of CTh, MRI showed that the volume of the mass was reduced by 48% to 36 × 36 mm, indicating a PR to the CTh  and DTX . Neutropenia [grade4 by NCI CTCAE] occurred on days 13–16 of treatment. MRI showed that the tumor had reduced by 75% from the initial examination . Although most initial symptoms of PSS are dysuria, hematuria, and urinary retention, PSS has no specific clinical symptoms.There are no specific imaging findings for PSS; however, in the present case, MRI detected rectal invasion. PSS may not increase PSA levels, which were normal in the present case.Compared to STUMP, PSS shows greater cellularity, mitosis, necrosis and stromal overgrowth.While immunohistochemistry can help diagnose PSS, it does not provide a definitive Dx.The treatment of PSS is mainly surgical resection, with extended resection selected according to the degree of tumor growth.It is not known whether radiation therapy or CTh can prolong survival.In the present case of PSS, NAC using GEM and DTX and total pelvic exenteration resulted in survival without recurrence at 5 years after surgery, suggesting the effectiveness of multidisciplinary treatment for PSS.Naoto Hodotsuka: Writing – original draft. Yasutomo Suzuki: Supervision. Kyota Suzuki: Writing – review and editing. Yuichiro Honda: Writing – review and editing. Shuma Endo: Writing – review and editing. Eigo Kuribayashi: Writing – review and editing. Kotaro Obayashi: Writing – review and editing. Tadaaki Minowa: Writing – review and editing. Tsutomu Hatori: Visualization. Yukihiro Kondo: Supervision.The authors declare no conflicts of interests.Not applicable.The patient provided informed consent for publication of this case report.Not applicable.


Few population‐based studies have described allergic rhinitis (AR) according to the Allergic Rhinitis and its Impact on Asthma (ARIA) classification, and none have assessed the impact of asthma on this classification. Our aims were to 1) describe AR according to four ARIA classes and 2) within each of the four ARIA classes, compare participants with AR alone versus those with AR and asthma.Cross‐sectional analyses were performed using data from the 2014 annual follow‐up questionnaire of the French adult population‐based cohort Constances. Current AR was defined by the report of sneezing, runny, or blocked nose in the last 12 months and the report of nasal allergies. Following ARIA recommendations, rhinitis was classified according to its severity (mild or moderate‐severe) and duration (intermittent or persistent). Ever asthma was also defined by a questionnaire.Among the 4675 participants with AR , 44% were classified as mild/intermittent, 16% mild/persistent, 25% moderate‐severe/intermittent, and 15% moderate‐severe/persistent. Within each of the four ARIA classes, compared to participants with rhinitis alone, participants with rhinitis and asthma had significantly more severe symptoms, more conjunctivitis, a higher mean eosinophil count and more treatments with intra‐nasal corticosteroids and oral antihistamines co‐medication.This is a paradigm shift study as for the first time this large population‐based study in adults showed that asthma status has a profound effect on the ARIA classification. Rhinitis alone and rhinitis with asthma represent two distinct phenotypes. These results reinforce the need to include asthma status in the ARIA classification and guidelines. Our specific objectives were to 1) describe AR according to four ARIA classes and 2) within each of the four ARIA classes, compare participants with AR alone versus those with AR and asthma.22.1A cross‐sectional study was carried out with the data from the 2014 annual follow‐up questionnaire of the Constances cohort among participants reporting current AR. We first describe AR according to the two major criteria of ARIA that is, severity and duration and then we studied the impact of asthma on these ARIA classes concerning clinical features, eosinophils and medication needs.2.2https://www.constances.fr/index_EN.php). The participants were enrolled from 2012 to 2020 in 20 administrative districts. At inclusion, participants completed several standardized questionnaires and had a complete medical examination.Constances is a population‐based cohort of 220,000 adults aged 18–69 at inclusion, randomly selected from social security affiliates in France ), the National Council for Statistical Information , the National Medical Council , and the Institutional Review Board of the National Institute for Medical Research‐INSERM (authorisation no. 01–011). All participants signed a written informed consent.2.3During your lifetime, have you ever had a problem with sneezing, or a runny, or a blocked nose when you did not have a cold or the flu?”, to “Have you had these problems in the last 12 months?”, and to “Have you ever had nasal allergies in your lifetime, including hay fever?”.As specific Immunoglobulin E (IgE) and Skin Prick Tests (SPTs) are not available in Constances, we used a definition of AR based on a questionnaire, as published previously.Following the ARIA recommendations,Allergic rhinitis was defined as persistent if symptoms occurred more than 4 days per week and more than four consecutive weeks. Otherwise, AR was defined as intermittent.Have you ever had asthma?” at inclusion or answered “asthma” to: “Here is a list of health problems. Indicate here the ones you have suffered from in the last 12 months ” at the 2014 follow‐up questionnaire.Participants were considered as having ever‐asthma if they answered yes to “Other variables of interest are described in the supplement.2.4Analysis in complete‐cases, that is, by excluding participants with missing data, was carried out, and no imputation was performed.We described AR according to the ARIA classification of severity (mild versus moderate‐severe) and duration (intermittent versus persistent) separately. The severity and duration of rhinitis were then combined into four classes according to the ARIA classification: mild/intermittent, mild/persistent, moderate‐severe/intermittent, and moderate‐severe/persistent. Then, we compared participants with AR and never asthma versus those with AR and ever asthma within each of the four ARIA classes.t test/analysis of variance comparison of variances for continuous variables were used. We computed effect size measures.Pearson Chi‐2 tests for categorical variables and Student All analyses were performed using SAS 9.4 software (SAS Institute).33.1n = 735) were excluded from the analyses. Among participants with current AR, participants with missing data regarding severity (n = 1031), duration (n = 100), or ever asthma (n = 91) were also excluded. Finally, 4584 participants with AR were included  of them completed the 2014 follow‐up questionnaire. Participants with missing data regarding the definition of AR . Participants with moderate‐severe AR had a higher mean eosinophil count  and a higher TNSS4 score  as well as an earlier age of onset of rhinitis symptoms  than those with mild AR. Compared to participants with mild AR, those with moderate‐severe AR reported more multi‐morbidities: ever asthma , ever conjunctivitis , and/or ever eczema . They also reported more nasal symptoms: rhinorrhea , nasal congestion/obstruction , nasal itching , sneezing  and associated‐eye symptoms . Participants with moderate‐severe AR reported more triggers of rhinitis symptoms: dust mites or house dust , animals , air pollution , change in weather , tobacco , pollens , cold air  or other triggers , and more persistent rhinitis  than those with mild AR. Regarding treatments, participants with moderate‐severe AR reported more co‐medication  + Intranasal Corticosteroids (INCS)) than those with mild AR . Large effect sizes were observed for TNSS4 as expected, medium effect sizes for the congestion/obstruction symptom and the number of reported symptoms and small effect sizes for asthma, duration, rhinorrhea, nasal itching, sneezing, associated‐eye symptoms, the number of reported triggers and co‐medication.The characteristics of participants with AR according to its severity are presented in Table 3.4p = 0.001), a higher TNSS4  and reported more moderate‐severe rhinitis  than those with intermittent AR. Participants with persistent AR also reported more ever asthma  and ever conjunctivitis . Regarding treatment, participants with persistent AR reported more co‐medication (OA + INCS) than those with intermittent AR . Small effect sizes were observed for TNSS4, severity, and co‐medication.The characteristics of participants with AR according to its duration are presented in Table 3.5The characteristics of participants with AR according to the four ARIA classes are presented in Table 3.6Eight sub‐classes were defined according to the ARIA classification and the ever asthma status in each subclass Table , with th3), but more marked differences between classes were observed in participants with ever asthma (range from 231 to 291 cells/mm3). The results of the multivariate logistic regressions after adjustment for age, gender, smoking, diploma, conjunctivitis and eczema are presented in the Table Whatever the ARIA subclass considered, within each ARIA subclass, asthma multimorbidity further separated participants, showing significant differences for most outcomes. In particular, ever conjunctivitis was higher by 10%–20% in AR and ever asthma in comparison to AR alone for all 4 ARIA classes . In each category, the largest effect size between participants without ever asthma and with ever asthma was for the age of onset of rhinitis. The age of onset of rhinitis ranged from 16.1 years (moderate‐severe/intermittent AR + ever asthma) to 26.0 years . Importantly, co‐medication (OA + INCS) was reported from 18.8%  to 64.1% (moderate‐severe AR + ever asthma). The prevalence of reported symptoms was always higher in the AR + ever asthma group regardless of the ARIA class. Reported triggers of rhinitis symptoms were far higher in AR + ever asthma than AR alone for mites or house dust and animals. Eosinophil counts were significantly higher for all ARIA classes in participants with asthma than in those with rhinitis alone . Of note, mean eosinophil counts varied little across the ARIA classes in participants without asthma  participants were randomly selected from the affiliated of the National Health Insurance Fund . In France, the General Health Insurance Fund administered by CNAM is compulsory for salaried workers, even during unemployed periods and their families; it covers about 85% of the population living in France. Individuals not covered by this scheme are those belonging to the agricultural scheme, which provides social protection for farmers and agricultural workers, the schemes for the liberal professions, and special schemes . As a result, some of the workers associated with these professions could not be included in Constances. 2) some geographical areas of France were not included. In addition, about 20% of participants had missing data for rhinitis severity. Compared to the participants included in the analysis population, the participants with missing data had a lower level of education and a higher average age, and we cannot exclude that they may have a particular rhinitis profile.As specific IgE and SPTs are not available in Constances, we used a definition of AR based on a questionnaire. We acknowledge that defining AR by questionnaire may be considered a limitation, even if we have used validated and standardized questions.4.2et al.,The percentage of patients with moderate‐severe rhinitis was lower in Constances than in the patient cohorts both in primarySeverity impacts more the characteristics of AR than duration, as shown by the higher effect sizes observed for severity than for duration. This was already observed in patients consulting for rhinitis in primary care.The ARIA classification has been criticized for only considering the severity of rhinitis in a dichotomous way: indeed, the large prevalence of moderate‐severe rhinitis found in patient cohorts suggests an important heterogeneity in this disease severity group.The major novel finding is the impact of asthma on rhinitis in all four ARIA classes. For most important outcomes, asthma has a significant impact . The effect size was often moderate, except for treatment (INCS + OA) and the age of onset where it was stronger, and the results persisted after adjusting for age, gender, smoking, diploma, conjunctivitis and eczema. An extremely important data is the treatments reported. For oral anti‐histamines, asthma does not make any difference. More patients without asthma reported intra‐nasal corticosteroids. On the other hand, there was a major impact on asthma by increasing the use of combined intra‐nasal corticosteroid and oral anti‐histamine by around 20% for the four ARIA classes. It has been found in real‐world data of over 10,000 patients that patients with rhinitis using this combination are less well controlled than those using intra‐nasal corticosteroids. These findings were observed in both cross‐sectional and longitudinal studies.In conclusion, for the first time in a large population‐based study in adults, the characteristics of AR according to the four ARIA classes were described. This result confirms what has been observed in clinical practice and highlights the interest of using the ARIA classification to define AR in the general population. Furthermore, asthma status added important information to the ARIA classification. These findings indicate that ARIA or other rhinitis guidelines should make a distinction between rhinitis alone and rhinitis with asthma for AR management. This critical information is already considered in the development of ARIA 2024.Marine Savouré: Conceptualization, methodology, formal analysis, writing – original draft, visualization. Jean Bousquet: Conceptualization, methodology, writing – review & editing. Bénédicte Leynaert: Review & editing. Céline Ribet: Resources, review & editing. Marcel Goldberg: Resources, review & editing. Marie Zins: Resources, review & editing. Bénédicte Jacquemin: Conceptualization, methodology, writing – review & editing, supervision. Rachel Nadif: Conceptualization, methodology, writing – review & editing, supervision.Dr. Bousquet reports personal fees from Cipla, Menarini, Mylan, Novartis, Purina, Sanofi‐Aventis, Teva, Uriach, other from KYomed‐Innov, and other from Mask‐air‐SAS, outside the submitted work. The other authors have nothing to disclose.Our findings strongly indicate for the first time that rhinitis guidelines should make a distinction between AR alone and AR with asthma for AR management.For the first time in a large population‐based study in adults, AR according to the four AR and Its Impact on Asthma classes was described. Asthma status added important information to the classification.Supplementary MaterialClick here for additional data file.