P = 4.8 × 10−4), suggesting that a female protective mechanism exists for deleterious CNVs and UPDs.Copy number variants (CNVs) are recognized as a crucial genetic cause of neurodevelopmental disorders (NDDs). Chromosomal microarray analysis (CMA), the first-tier diagnostic test for individuals with NDDs, has been utilized to detect CNVs in clinical practice, but most reports are still from populations of European ancestry. To contribute more worldwide clinical genomics data, we investigated the genetic etiology of 410 Han Chinese patients with NDDs  and developmental delay (DD)) using CMA (Affymetrix) after G-banding karyotyping. Among all the NDD patients, 109 (26.6%) carried clinically relevant CNVs or uniparental disomies (UPDs), and 8 (2.0%) had aneuploidies . In total, we found 129 clinically relevant CNVs and UPDs, including 32 CNVs in 30 ASD patients, and 92 CNVs and 5 UPDs in 79 ID/DD cases. When excluding the eight patients with aneuploidies, the diagnostic yield of pathogenic and likely pathogenic CNVs and UPDs was 20.9% for all NDDs (84/402), 3.3% in ASD (5/151), and 31.5% in ID/DD (79/251). When aneuploidies were included, the diagnostic yield increased to 22.4% for all NDDs (92/410), and 33.6% for ID/DD (87/259). We identified a de novo CNV in 14.9% (60/402) of subjects with NDDs. Interestingly, a higher diagnostic yield was observed in females  compared to males  for all NDDs ( Autism spectrum disorder (ASD) and intellectual disability/developmental delay (ID/DD) are the most common NDDs in children and have shared psychiatric behaviors, clinical manifestations, and risk factors, and impair cognitive functions including learning, sociability, and mood4. ASD is one of the childhood-onset NDDs, characterized by impairment in three domains: social interaction, communication skills, and repetitive behavior and restricted interests. Approximately 50% of autistic cases manifest intellectual disability (ID)6. Developmental delay (DD) is the failure to achieve certain developmental milestones at the appropriate age, involving physical, cognitive, communication, social, emotional, and/or adaptive skills3. Both ID (IQ < 70) and DD belong to the clinically heterogeneous NDDs3.Neurodevelopmental disorders (NDDs) are a group of heterogeneous disorders involving developmental dysfunction of the central nervous system, and have an incidence rate of 1–3% in children9. CMA has been demonstrated to improve the diagnostic yield to up to 33%, compared to 3.7% using karyotyping. However, the diagnostic yield can vary widely and largely depends on the cohort population and severity of phenotypes11.The etiology of ASD and ID/DD is complex and overlapping, implicating both genetic and non-genetic factors. Chromosomal microarray analysis (CMA) is a molecular cytogenetic technique that expedites genome-wide detection of clinically significant copy number variants (CNVs), and has been recommended as a first-tier diagnostic tool for patients with ASD, unexplained ID/DD, and multiple congenital anomalies (MCA). CMA can accurately detect different types of CNVs  across a large size range (esp. <5 Mb submicroscopic CNVs), and can also identify uniparental disomies (UPDs)CNV studies have been performed for patients with NDDs worldwide, but additional data from Chinese subjects are needed to delineate the potential differences in CNV distribution in this population, particularly within the clinical setting. Here, we present an investigation of CNVs in a well-characterized clinical cohort with ASD or ID/DD in Shandong, a province in northern China. CNVs were analyzed using the Affymetrix SNP 6.0 or CytoScan HD arrays in combination with deep mining databases, including an updated in-house database, to explore the clinical implication and inheritance of specific candidate CNVs or genes associated with NDDs.Samples from 410 Han Chinese ASD and ID/DD patients were tested, of which 5 with highly suspected trisomy 21 syndrome were analyzed by G-banding karyotyping. Trisomy 21 was detected in these five samples. The remaining 405 samples were analyzed by array and three additional aneuploidies were found: one trisomy 21, one 47,XXY, and one 47,XYY. Thus, aneuploidies were identified in eight subjects (2.0%) in our cohort, with six trisomy 21, one 47,XXY, and one 47,XYY identified.The remaining 402 cases (151 ASD and 251 ID/DD) were further analyzed for the presence of clinically relevant CNVs, which were defined as pathogenic CNVs, likely pathogenic CNVs, and CNVs interpreted as variants of uncertain significance (VUS). We detected 594 high-quality CNVs in our cohort  according to ACMG classification (Table P = 1.0 × 10−7). We found that 12.4% of the CNVs and UPDs were inherited , and 20.6% were of unknown inheritance due to the unavailability of parental samples , four likely pathogenic variants, and three VUS based on ACMG classification Tables  and 3. TTo obtain a more stringent estimate of the diagnostic yield for our cohort, we considered only subjects with pathogenic/likely pathogenic CNVs and UPDs in the calculation. The diagnostic yield was 20.9% (84/402) for all NDDs, and increased to 22.4% (92/410) when subjects with aneuploidies were included. The diagnostic yield was markedly lower for ASD  compared to ID/DD .P = 0.005). We then compared the average size of CNVs and UPDs identified in males and females of both subgroups. There was no statistical difference in the average size of CNVs identified in males and females in the ASD subgroup . In contrast, the average size of CNVs and UPDs was 2.45 Mb ± 2.07 Mb in males and 20.12 Mb ± 12.21 Mb in females in the ID/DD subgroup, indicating a significant difference between male and female ID/DD cases (P = 0.001). The majority of clinically relevant CNVs and UPDs  were smaller than 10 Mb in size  and would not be identified by karyotyping , and his motor, social, and language development were all found to be delayed. His blood biochemical tests, head MRI and heart ultrasound were normal. The second case, 15D3173, was an 8-day-old boy, who was the third child of non-consanguineous healthy parents, and had two healthy sisters of 10 years old and 7 years old, respectively. He was referred to the hospital because of seizures and abnormal development, and presented with facial dysmorphism, specifically small mouth, micrognathia, and high arched palate. His growth delay in utero was found before he was born, and physical examination and ultrasonic cardiogram demonstrated that he had atrioventricular septal defect (AVSD), and pulmonary arterial hypertension. His blood tests showed he had hypocalcemia with calcium 1.38 mmol/L and immunodeficiency with IgA 0.04 g/L , IgG 8.37 g/L , IgM 0.052 g/L . His cryptorchidism and polydactyl were also noticed. The third case, 19D0970, was a 6-day-old girl and the first child of non-consanguineous healthy parents. She was referred to the hospital for seizures and fever, and presented with facial dysmorphism, with features that included small jaw, flat bridge of nose, narrow nasal passages, laryngeal dysplasia with softening of the laryngeal cartilage, and softening of the trachea. She also had growth delay in utero before her birth. Ultrasound examination showed she suffered from congenital heart defects of patent ductus arteriosus, pulmonary hypertension, tricuspid regurgitation, and patent foramen ovala as well as smaller thymus (1.7*1.5*0.6 cm). Her blood tests showed she had lower calcium  and congenital hypothyroidism with TSH 15.22 mIU/L  and FT4 2.53 pmol/L .P = 1.0 × 10−7)  and five de novo CNVs identified in five ASD cases . The proportion of subjects with de novo CNVs was 14.9% (60/402) for all 402 NDD patients (excludes patients with aneuploidies), 3.3% (5/151) for ASD cases and 21.9% (55/251) for the ID/DD cases. The proportion of subjects with a de novo CNVs was significantly higher in the ID/DD subgroup compared to the ASD subgroup  occurred at loci associated with known chromosomal syndromes, including three CNVs identified in ASD cases and 50 CNVs identified in ID/DD cases. The three syndromic de novo CNVs in ASD subjects included Of the 65 de novo CNVs found in ID/DD cases, 50 were associated with known chromosomal syndromes Table . NotablyTRIP12 and a 74 kb maternally transmitted deletion overlapping CTNNA3, both of which were interpreted as VUS. The second ASD case (Y26) was a 3-year-10-month-old girl who harbored two CNVs interpreted as VUS: a 699 kb paternally transmitted duplication overlapping KHDRBS2 and a 76 kb paternally transmitted deletion overlapping PARK2. The 18 ID/DD cases included 15 cases with two pathogenic (or likely pathogenic) CNVs, and three subjects with one pathogenic CNV and a second CNV interpreted as VUS. For example, a 1-year-old girl (16D1511) with DD and facial abnormalities harbored both a 6.5 Mb duplication at 2p25.3p25.2 and a 23.6 Mb duplication at chr14q11.2-q21.2. A 1-month-22-day-old girl (19D0185) with DD, bilateral hearing problem, valgus feet, and cleft palate had both a 17.38 Mb deletion at chr18q21.33q23 and a 9.84 Mb deletion at chr20p13p12.3. A 9.45 Mb duplication at chr4p16.3p16.1 and a 6.84 Mb deletion at chr8p23.3p23.1 were detected in a 19-month-8-day-old boy (19D1091) with DD, speech delay, and hearing problem. We found two cases with Williams–Beuren syndrome deletions who harbored a second clinically relevant CNV. Case (16D2191) harbored a de novo Williams–Beuren syndrome deletion and carried an additional pathogenic CNV, a 5.65 Mb duplication at 22q13.31q13.33. The second case (19D0262) harbored a Williams–Beuren syndrome deletion and a recurrent 1.4 Mb duplication at 16p13.11, which was interpreted as VUS14.There were 20 cases who harbored two clinically relevant CNVs, of which two were ASD cases and 18 were ID/DD cases . Thus, the overall diagnostic yield was 20.9% in our cohort. However, it was significantly lower (3.3%) in subjects with ASD, while remarkably higher (31.6%) for subjects with ID/DD. We identified a de novo CNV in 14.9% of subjects with NDDs. We also found 20 ID/DD cases with more severe phenotypes who harbored two clinically relevant CNVs.20, who identified 127 cases carrying pathogenic CNVs in a cohort of 633 patients, obtaining a diagnostic yield of 20.06% for all NDD patients, 3.7% for isolated ASD, 18.07% for isolated ID/DD, and 34.90% for ID/DD with MCA. The size of CNVs identified in Hu et al. ranged from 223 kb to 102 Mb, and the de novo rate was 16.9%. Lee et al.22 obtained a similar diagnostic yield of 32.2% in 177 patients with unexplained ID/DD. Fan et al.23 observed a yield of 28% in a mixed cohort of 710 Southern Chinese patients with NDDs. The highest yield was found in the subgroup of ID/DD with congenital heart defects (55%), followed by ID/DD with facial dysmorphism (39%), hypotonia (35%), and microcephaly (34%). Pinto et al.24 obtained a diagnostic yield of 3.4% in a cohort of 2446 subjects with ASD and a de novo rate of 4.7%, but this was a strictly research cohort. This is comparable to our diagnostic yield of 2.6% in ASD subjects and de novo rate 3.3%. Ho et al.18 tested 10,351 NDDs cases and observed a yield of 5.4% for ASD/or combining with any other testing indications, which was also comparable to our ASD data. While their yield of 12.5% for subjects with ID/DD and 8.6% for all NDDs was lower than that observed in our study, it is comparable to some published data25. For example, Zarrei et al.8 obtained a yield of 10.5% in 1838 NDDs cases. A higher yield of 11.4% was observed in the ASD cases in this study. Uddin et al.25 also obtained a lower yield of 10.15% in a cohort of 10,619 subjects with NDDs. We suppose that the difference resulted from the constitution of cases with NDDs, which can include subjects with ASD, ADHD (attention deficit hyperactivity disorder), OCD (obsessive-compulsive disorder), and SCZ (schizophrenia) without many comorbid constructive defects. Our data further confirm that diagnostic yield is related positively with severities and comorbid conditions of NDDs, such as co-occurring facial dysmorphism and congenital heart diseases which could increase the yield markedly21.The diagnostic yield and de novo CNV rate of our cohort is comparable with some previous reports Table . Our res17. The specialties of the referring pediatricians who are responsible for selecting patients to undergo genetic testing constitutes the first bias to the diagnostic yield in a clinical setting19. In this study, a diagnostic yield of 31.5% was obtained for the patients with ID/DD presenting clear clinical features, some of whom suffered from more severe and complex phenotypes. These patients were mostly (96%) diagnosed by senior developmental pediatricians or pediatric neurologists at the Pediatric Health Care Institute and Rehabilitation Center, and a few (4%) by senior and experienced neonatologists at the Neonatology Department in our hospital. Their specialty and experiences in recognizing the patients’ indications and severities is crucial to elevating the yield when referring them for genetic testing.The diagnostic yield of a cohort can be affected significantly by multiple factors that include but are not limited to: referring physician specialty, gender of patients, age of patient at testing, and referring indication (or combination of indications) for testing32. In our cohort, a higher diagnostic yield of pathogenic and likely pathogenic CNVs was observed in females (31.3%) compared to males (16.1%) when considering all NDDs, indicating a significant difference (P = 4.8 × 10−4). Similarly, in the ID/DD subgroup, a higher yield of 37.5% was observed in females compared to that of 27.2% in males, though this difference was not statistically significant. Jacquemont et al.26 investigated the molecular basis of the sex-based difference in a cohort of 15,585 probands with NDD, and found a significant increase in deleterious autosomal CNVs and single-nucleotide variants (SNVs) in female probands compared to males with NDDs. Jacquemont et al. also found that maternal transmission of deleterious CNVs and SNVs was observed more frequently in females than in males in an independent ASD cohort of 762 families. These data support the “female protective model”, suggesting a higher “mutational burden” is required for females with NDDs to manifest clinical features. In our study, the CNV size in females was larger than that in males in the ID/DD subgroup (20.12 Mb ± 12.21 Mb versus 2.45 Mb ± 2.07 Mb), demonstrating a significant difference between male and female patients (P = 1 × 10−3). This result is comparable to previous studies26. For example, Polyak et al.27 discovered that girls carried a higher burden of large CNVs and in both ASD and ID/DD cohorts. Han et al.28 found a significant excess of large (≥500 kb), rare (<1%) CNVs in females compared to males in both NDD cases and controls. Desachy et al.29 observed a similar phenomenon of large, rare CNVs in females in the population and ASD families, suggesting a female protective mechanism exists for deleterious CNVs that may go beyond NDDs phenotypes and contribute to decreased female fetal loss in the population. Roberts et al.32 observed a higher detection rate of abnormal CNVs in females (27%) than in males (18%). Roberts et al. also found that the average size of CNVs in ID/DD was much larger than that in ASD (2.90 ± 2.87 Mb versus 966 ± 1464 kb). Consistently, in our cohort, the average size of CNVs in ID/DD cases was 4.14 Mb ± 3.77 Mb, which was much larger than that of ASD cases (802.5 kb ± 394.5 kb). The difference is potentially related to the genetic cause of ID/DD and ASD, with smaller CNVs implicating a single gene in ASD versus larger CNVs involving more than one gene in ID/DD.It is documented that the CNV burden differs between males and females in both NDD patients and the general population21. Xu et al.33 investigated CNVs identified in 434 patients with ASD and ID/DD. The yield for patients under 2-year-old was 70%, which was significantly higher than those over 5 years old. Most of the younger patients under 2-year-old suffered from comorbidity with severe medical problems, such as microcephaly, macrocephaly, hypotonia, and other systemic abnormalities like asphyxia of the newborn, malnutrition and anemia, which may have influenced the pediatricians to recommend genetic evaluation for these patients with CMA. Moreover, similar yields of 12% and 14.7% were obtained for both subgroups of ASD and ID/DD under 2-year-old in this study. In order to illustrate the impact of patients’ age on the diagnostic yield, we stratified the diagnostic yields by age for both subgroups in our study, and found that the 2–5-year-old patients had the highest diagnostic yield of 3.5% (4/114) in ASD subgroup, while the highest yield of 40.3% (25/62) was observed in the 1–2-year-old cases in the ID/DD subgroup (Table P = 1 × 10−3), being 4-year-1-month for ASD and 2-year-11-month for ID/DD, which may have contributed to the difference in yield between the two subgroups.It has been noticed that the age of patients also affects the detection rate of CNVs26. To better assess the advantages of CMA for identification of clinically relevant CNVs in ASD and ID/DD with clear phenotypes in northern China, the patients with aneuploidy such as trisomy 21, 47XXY, 47 XYY syndromes were excluded at first. In this study, 4 CNVs in ASD subgroup were associated with known chromosomal syndromes, including Kleefstra syndrome, AUTS2 syndrome, 15q24 microdeletion syndrome, and MECP2 duplication syndrome. In the ID/DD subgroup, 60 CNVs occurred at loci associated with 37 known chromosomal syndromes. Recurrent pathogenic CNVs were most frequently detected at 7q11.23, corresponding to the Williams–Beuren syndrome deletion which was observed in 11/251 (4.4%) ID/DD patients. Other chromosomal syndromes observed in multiple patients with ID/DD included partial trisomy 9p (duplication at chr9p24), 15q11q13 duplication syndrome, 18q deletion syndrome34, Prader–Willi syndrome, 22q11 deletion syndrome (DiGeorge syndrome), 8p23.1 microdeletion syndrome, 22q11.2 duplication syndrome, and MECP2 duplication syndrome.Aneuploidy is the gain or loss of an entire chromosome and is the leading genetic cause for developmental abnormality31. By analyzing CNVs interpreted as VUS in this cohort, the diagnostic yield of ASD subgroup increased from 3.3% (5/151) to 21.2% (32/151). The 27 CNVs interpreted as VUS in the ASD subgroup included 17 duplications with size of 56 kb to 1.7 Mb and 10 deletions with size of 74 kb to 1.2 Mb. These CNVs impacted some genes related to ASD/DD and were considered as new CNV candidates for association with ASD after analyzing data from databases and the literature. For example, a 141 kb duplication at 2q14.1 involving DPP10 was detected in a 3-year-old autistic boy. DPP10 has been reported to be related to synaptogenesis and ASD susceptibility in several studies of autism37. However, Mak et al. recently proposed that DPP10 duplication is likely a benign CNV polymorphism enriched in Southern Chinese with a population frequency of ~1% by genotyping 258 Southern Chinese ASD patients38. In DECIPHER, a CNV of the same size was reported in a patient with autistic behavior and mild global developmental delay. More samples, especially Chinese from northern China, are needed to clarify the genotype-phenotype relationship of this CNV. A second example is a 477 kb duplication at 2q14.3 involving CNTNAP5 that was detected in a 2-year-4-month girl. Rare deletion of CNTNAP5 was suggested as a novel genetic factor that might confer ASD susceptibility39. However, duplications of CNTNAP5 have not been studied. Last, a 115 kb maternal duplication at 2q36.3 was identified in a 2-year-4-month female autistic patient with ASD, and overlaps TRIP12, which has been reported to be associated with ASD40. An 180 kb duplication at the 5′ portion of TRIP12 has been reported in an individual with macrocephaly42. Two additional duplications on 2q36.3 with similar sizes were found in two cases with ID and DD in the DECIPHER database.It has been recommended that variants of uncertain significance be considered in the diagnostic yield of ID/DD, particularly ASD, as many CNVs of VUS will change to pathogenic CNVs following the accumulation of clinical evidence in databases45.In this study, we investigated the genetic etiology of a clinical cohort of NDD subjects who presented with ASD or ID/DD. The cohort was comprised of Han Chinese subjects from Shandong province, a northern region of China, who presented with typical phenotypes and were diagnosed by experienced pediatricians or pediatric neurologists. In our cohort, the patients with ID/DD were of a younger age than the patients with ASD. The high diagnostic yield observed in our cohort may have been influenced by the clinical experience of the referring pediatricians, the phenotypic severity of the cohort, gender, and age. Genome sequencing is expected to provide a higher yield on this clinical cohortThe study was approved by the Ethics Committee of Qilu Children’s Hospital of Shandong University. Informed written consent was obtained from the patients’ parents. The information of the patients’ and their families was anonymized prior to genotyping and analysis. All the procedures performed in the study were in accordance with the Declaration of Helsinki.A total of 410 probands with ASD or unexplained ID/DD with or without other congenital anomalies who were referred for genetic services in our institute from January 2014 to December 2018 were enrolled in this study. Their parents were also enrolled in the study. The cohort consisted of 282 male and 128 female patients  with mean age of 2-years-11-months, including 151 unrelated ASD patients  with mean age of 4-years-1-month (ranged from 1-year-10-months to 8-years-2-months) and 259 ID/DD patients  with mean age of 1-year-10-month (ranged from 1 day to 10-year-3-month)  following the manufacturer’s instructions. Potential RNA contamination was removed by RNaseA . The DNA was quantified using the NanoDrop ND-1000 spectrophotometer . The genomic DNA was genotyped using the Affymetrix Human Genome-Wide SNP Array 6.0 or Affymetrix CytoScan HD Arrays . DNA digestion, ligation, fragmentation, labeling, hybridization, staining and scanning were performed following the manufacturer’s protocols .The data were analyzed with Command Console 3.1  or Chromosome Analysis Suite (ChAS) version 3.1.0.15 . Data quality was evaluated with contrast quality control (CQC). The default CQC threshold (≥0.4) was used for analyzing each sample. Samples with a CQC < 0.4 were excluded from the study. The QC call rates of all the samples were greater than 96%. The reporting threshold was set at 50 kb (markers ≥ 20) for deletions and duplications.http://projects.tcag.ca/variation), CAG database , University of California Santa Cruz Genome Browser , Online Mendelian Inheritance in Man , DECIPHER database (http://decipher.sanger.ac.uk), ISCA (https://www.iscaconsortium.org), and PubMed (http://www.ncbi.nlm.nih.gov/pubmed) were used. The control data of 1679 non-ASD Chinese subjects from multiple sources were used to distinguish rare copy number variations in our cohort. The control data included 919 samples from Singapore database46, 103 samples from the HapMap project47, 451 samples from Lu et al.48, and 206 parents from Gazzellone et al.49. The frequency of prioritized CNVs was computed against the aforementioned controls. CNVs with >50% reciprocal overlap were deemed identical50. Rare CNVs were defined as those not being present in more than 1% of 1679 ethnically-matched non-ASD control samples. We further restricted rare CNVs to those not being present in more than 1% of subjects in the Database of Genomic Variants (DGV)51. We analyzed CNVs overlapping <70% of their total length with segmental duplications and repeat-rich loci of the human genome. All CNVs were classified as pathogenic, likely pathogenic, variants of uncertain significance (VUS), likely benign, and benign according to the American College of Medical Genetics and Genomics guidelines52. In brief, CNVs were considered as pathogenic if they were documented as clinically significant in multiple peer-reviewed publications, or large CNVs unreported in the literature but overlapped a smaller interval with established clinical significance; CNVs were regarded as likely pathogenic if they were described in a single case report but with well-defined breakpoints and phenotype associated with NDDs, or involved a gene with a very compelling function-related and specific to NDDs. Other classes of CNVs were considered variants of uncertain clinical significance (VUS), likely benign or benign CNVs. Pathogenic, likely pathogenic, and VUS CNVs were considered to potentially affect gene function associated with the phenotypes of ID/DD or ASD in the study and were further validated by MLPA/qPCR.To evaluate the pathogenic associations of CNVs, the Database of Genomic Variants —and were synthesized by Shanghai Invitrogen Biotechnology Company  (Supplementary Data GAPDH) copies in samples. Both male and female genomic DNA samples from unaffected pooled samples stored in our laboratory were used simultaneously as male and female control samples. Each qPCR was carried out in triplicate with the SYBR Premix Ex Taq II PCR reagent kit  following the manufacturer’s protocol.MS-MLPA was performed using SALSA MLPA kits ME028 and ME030  to identify PWS/AS, and Silver–Russell syndrome, separately, according to the manufacturer’s instructions. The data were analyzed using Coffalyser software. qPCR with SYBR Green chemistry were utilized to verify the potentially clinically relevant CNVs in the cases and their parents. The primer sets for qPCR were designed to target different fragments within variant regions using an online primer designing tool—Primer 3 (P value was <0.05 and the confidence interval was 95%.Statistical analysis was performed with SPSS 16.0 software. Two-sided Fisher’s test was used to test significance of CNVs in different groups. Results were considered statistically significant when the Further information on research design is available in the Supplementary InformationReporting SummarySupplementary Data 1Supplementary Data 2Supplementary Data 3Supplementary Data 4Supplementary Data 5Supplementary Data 6


This study examined differences in the pathway to diagnosis of Alzheimer's disease and related dementias (ADRD) between Black and White older adults. Using electronic health records from a large health system, we included 2,085 non-Hispanic Black and 6,269 non-Hispanic White older adults with a final/primary diagnosis of ADRD between 2014 and 2020. Black older adults were more likely to receive the ADRD diagnosis from a primary care provider (35.4% vs. 29.8%), during a hospital admission (19.5% vs. 13.6%), or during an emergency department visit (4.2% vs. 2.0%); but were less likely to be diagnosed by an ADRD specialist (31.6% vs. 45.2%). Black older adults had nearly twice as many clinical encounters in the two years prior to the ADRD diagnosis than their White counterparts (43 vs. 26). Despite having more clinical encounters, Black older adults were more likely to be at a later stage when diagnosed than White older adults.


Patients and Methods. A retrospective review of enucleated/eviscerated eyes that underwent surgery between 2006 and 2020 at the Department of Ophthalmology of Semmelweis University, Budapest, Hungary, due to ocular trauma as the primary indication for enucleation/evisceration. For each subject, clinical history, B-scan ultrasound report, and histopathology results were reviewed.  To analyse the demographic and clinical characteristics of ocular traumas resulting in enucleation/evisceration in a large tertiary referral center in a developed country (Hungary) over a period of 15 years. n = 96; 77.4%), ocular burns , traumatic optic neuropathy , bulbar avulsion , traumatic cataract , retinal ablation , and traumatic carotid-cavernous fistula . Among the 124 patients, 98 (79.0%) underwent enucleation and 26 (21.0%) evisceration. Patients who underwent primary enucleation/evisceration (n = 24 19.4%) were significantly older at the time of the injury (57.7 ± 22.7 years) than people who underwent secondary eye removal (32.4 ± 24.4 years) (p < 0.0001). The mean time interval between trauma and enucleation/evisceration was 114.9 ± 163.5 months. The main clinical indications for anophthalmic surgery were atrophia/phthisis bulbi , acute trauma , painful blind eye due to glaucoma , endophthalmitis , and cosmetic reasons . One patient (0.8%) had sympathetic ophthalmia.  There were 124 enucleated/eviscerated eyes from 124 patients ). The mean age at the time of trauma was 37.3 ± 26.0 years while the mean age at the time of enucleation/evisceration was 46.9 ± 20.3 years. The main clinical diagnoses after ocular trauma were open globe injury ( Primary enucleation/evisceration was performed in one-fifth of all ocular trauma-related anophthalmic surgeries in our tertiary eye care center with enucleation being the most common procedure. Atrophia/phthisis bulbi was the most frequent immediate clinical indication for enucleation/evisceration. Ocular trauma is a leading indication for bulbar enucleation and evisceration worldwide . EnucleaAlmost every third severe ocular injury leads to blindness in the USA . PrimarySeveral previous studies have analysed ocular injuries that have resulted in enucleation/evisceration in different countries –7, but tThe primary aim of this study was to analyse the demographic and clinical characteristics of ocular traumas that resulted in enucleation/evisceration, as well as the frequency of enucleation versus evisceration, and the frequency of primary versus secondary enucleation/evisceration in a tertiary eye care center in a European developed country (Hungary) over a period of 15 years.This retrospective study was undertaken at a tertiary eye care center to analyse demographic and clinical characteristics of patients who suffered ocular trauma and later underwent enucleation/evisceration in Hungary. The study was approved by the Regional and Institutional Committee of Science and Research Ethics of Semmelweis University, Hungary (No. 243/2020). The study was performed in accordance with the Declaration of Helsinki Guidelines for Human Research.In total, 729 eyes underwent enucleation/evisceration over a period of 15 years (between January 2006 and December 2020) at the Department of Ophthalmology of Semmelweis University. Among these, 124 eyes of 124 patients were removed due to ocular trauma. Our study was conducted on these 124 eyes.For each subject, the clinical data were reviewed including patient demographics, clinical history, presenting visual acuity at the time of ocular injury and enucleation/evisceration, clinical indication for enucleation/evisceration, B-scan ultrasound reports , operative details, and results of the histopathological analysis following enucleation/evisceration. Paraffin sections stained with haematoxylin-eosin and histopathological charts were available for 119 (96.0%) globes. Visual acuity data were converted from Snellen chart values to LogMAR format.Our study was performed in a retrospective fashion and many patients were referred to our clinic only weeks, months, or years after the trauma, as our department is a tertiary eye care center. Therefore, we could not examine the complete course of all cases, as documentations were incomplete. As a result, this classification could not be performed either using the Birmingham eye trauma terminology system  or the Sp value lower than 0.05 was considered statistically significant.Statistical analysis was performed with Statistica 8.0 . Data were expressed as mean with standard deviation (SD). Chi square test was used for differences in proportions of categorical variables. To compare the two groups regarding age, time interval between trauma and enucleation/evisceration, visual acuity, number of preexisting ocular factors and systemic diseases, and number of surgeries, we used the student's t-test in case of normal distribution and the nonparametric Mann–Whitney U test for not normally distributed variables. A p=0.148) regarding proportion of primary enucleations and eviscerations. There was no significant difference between primary and secondary enucleation/evisceration groups regarding sex (p=0.938) and laterality (p=0.415). The mean age of the patients was 37.3 ± 26.0 years  at the time of ocular trauma and 46.9 ± 20.3 years  at the time of enucleation/evisceration. Twenty-four subjects (19.4%) had primary and 100 (80.6%) had secondary enucleation/evisceration. Patients who underwent primary enucleation/evisceration (n = 24 19.4%) were significantly older at the time of the injury (57.7 ± 22.7 years) than people who underwent secondary eye removal (32.4 ± 24.4 years) (p < 0.0001). Among patients with primary enucleation/evisceration, best corrected distance visual acuity was NLP in 20 (83.3%) cases and light perception (LP) in 4 (16.7%) cases.The demographic and medical characteristics and age distribution of the patients are shown in Associated preexisting systemic diseases, social factors, and preexisting ophthalmological factors are shown in n = 96; 77.4%), ocular burns , traumatic optic neuropathy , bulbar avulsion , traumatic cataract , retinal ablation , traumatic carotid-cavernous fistula , and unclassifiable due to incomplete documentation . In the open globe injury group, 47 eyes (49.0%) had a corneal, 26 (27.1%) had a scleral, and 23 (23.9%) had a corneoscleral laceration.The main clinical diagnoses after ocular trauma were (in decreasing order) open globe injury (The injury occurred at home in 57 cases (46.0%), at the workplace in 17 cases (13.7%), in a violent act in 13 cases (10.5%), in a traffic accident in seven cases (5.6%), and in a sports accident in three cases (2.4%). The circumstances of the injury were not determinable in 27 (21.8%) cases. Gunshot injury occurred in two cases (1.6%), both of them at home, as an accident. Intraocular foreign body was found in 17 (13.7%) and intraorbital foreign body was detectable in 2 (1.6%) eyes. Primary enucleation/evisceration was performed within 24 hours in 21 patients (16.9%) and within one week in three cases (2.4%).Most frequently performed ocular surgeries in order to manage ocular trauma before enucleation/evisceration are shown in Immediate clinical indications for enucleation/evisceration  are displayed in Among four patients who underwent primary enucleation/evisceration with a visual acuity of LP, two had total corneal melting with endophthalmitis, one had total corneal melting without endophthalmitis, and one had buphthalmos with extensive scleral laceration.B-scan ultrasound examinations showed retinal detachment in 34 (27.4%) eyes, atrophia/phthisis bulbi in 29 (23.4%), choroidal detachment in 13 (10.5%), normal posterior segment in 12 (9.7%), vitreous haemorrhage in 11 (8.9%), silicon oil in 9 (7.3%), endophthalmitis in 7 (5.6%), optic disc cupping in 4 (3.2%), subretinal haemorrhage in 2 (1.6%), mild vitreous inflammation in 2 (1.6%), suprachoroideal haemorrhage in 1 (0.8%), optic nerve damage in 1 (0.8%), crystalline lens dislocation in 1 (0.8%), empty scleral shell in 1 (0.8%), and intravitreal foreign body in 1 (0.8%). B-scan reports were not available in 25 (20.2%) cases.Histopathological diagnoses after enucleation/evisceration are shown in Only one patient (0.8%) had sympathetic ophthalmia in our sample, who was referred to our clinic with granulomatous panuveitis on the right eye and phthisis bulbi on the left eye 50 years following open globe injury on the left eye.Among the 124 patients who underwent enucleation/evisceration, 50 (40.3%) received a primary orbital implant at the time of eye removal. The type of implant was silicone in 26 (52.0%), aluminium-oxide ceramic in 5 (10.0%), and hydroxyapatite in 19 (38.0%) cases.We analysed the demographic, etiological, and clinical details of ocular trauma cases that led to loss of the eye over a 15-year period at a tertiary eye care center in Hungary. To the best of our knowledge, this is the first study to report on the characteristics of ocular injuries leading to enucleation/evisceration in Europe.The incidence of ocular trauma leading to enucleation is reported to be 1.1% among patients with ocular trauma in China . Ocular In our sample, mean age at the time of enucleation/evisceration due to ocular trauma 46.9 years) was similar to the findings of de Gottrau et al. in Germany   , primarySimilar to the study by Sigurdsson et al. in Iceland , most ofThe order of frequency of most common immediate clinical indications and pathological diagnoses for enucleation/evisceration in our sample were the same as reported by de Gottrau et al.  in Germany  thirty yPreference for enucleation over evisceration may be related to the well-known supposition in the international literature that evisceration does not eliminate the risk of sympathetic ophthalmia after ocular trauma . NeverthSimilar to evisceration, enucleation was also most commonly performed as a secondary procedure in our patients. Ophthalmologists are rather careful and tend to avoid enucleation as a primary procedure after ocular trauma, as every eye deserves a chance.In the present study, the number of known preexisting systemic and ocular diseases was ten times lower in patients with trauma than in subjects with enucleation/evisceration due to corneal ulcer in the same institution, in a previous study . This maLimitations of our study include that it was performed in a retrospective fashion; our department is a tertiary eye care center, and for this reason, we could not examine the complete course of these cases and many patients were only referred to our clinic when the eyes could no longer be salvaged.Secondary enucleation/evisceration was performed more frequently after ocular trauma in our department than primary anophthalmic surgery. Atrophia/phthisis bulbi was the most frequent immediate clinical indication for enucleation/evisceration.


A troponin I cut-off level of ≥60 pg/mL predicted moderate to severe HIE with a specificity of 81.1% and a negative prediction rate of 76.9%. A troponin I cut-off level of ≥180 pg/mL was significantly  = 33.1, p = 0.001, odds ratio 96.8) related with hypotension during first admission and significantly  = 5.3, p = 0.021, odds ratio 4.53) related with abnormal neurodevelopmental outcomes at 1 year. Early troponin I level may be a useful biomarker for predicting moderate to severe HIE, and initialization of hypothermia therapy.Troponin I is a biomarker for cardiac injury in children. The role of troponin I in neonatal Hypoxic–Ischemic encephalopathy (HIE) may have valuable clinical implications. Troponin I levels were measured within 6 h of birth to determine their relationship to HIE stage, short-term cardiac functional outcomes, and neurodevelopmental outcomes at 1 year. Seventy-three patients were divided into two groups: mild HIE and moderate to severe HIE. Troponin I levels within 6 h of birth were obtained in 61 patients, and were significantly higher in patients with moderate to severe HIE than in patients with mild HIE (Mann–Whitney U test, U = 146,  Birth asphyxia is a physiological disorder in newborn infants resulting from a prolonged or profound mismatch between oxygen demand and oxygen delivery . Birth aStudies have shown that therapeutic hypothermia in neonatal HIE is effective to prevent long-term neurodevelopmental consequences ,9,10,11 Although hypothermia is effective in moderate and severe neonatal HIE, possible side effects include the risk of intracranial hemorrhage and cardiopulmonary instability . The advTroponin contains three protein subunits: troponin C, troponin T, and troponin I. The heart is essentially a muscle, and damage to the heart causes it to release troponin into the bloodstream. Troponin I levels in the blood are very low (<30 pg/mL in newborns) , but injHypothermia in newborns may induce adverse effects ,12,23. Tn = 7), premature birth before 36 weeks preterm (n = 9), or confirmed genetic defects  of each patient was reviewed. Ninety patients were enrolled. Seventeen patients were excluded due to congenital anomalies  by the chemiluminescence immunoassays, and creatine phosphokinase (CK). Troponin, CK, and CKMB levels within 6 h of birth were determined for neonates with HIE. Following hypothermia therapy in stage II and III HIE patients, a series of examinations were conducted before discharge, including head ultrasound (HUS) and magnetic resonance imaging. To investigate the differences in blood biomarkers for cardiopulmonary function, an experienced pediatric neurologist and a neonatologist consultant divided patients into two groups according to their Sarnat stages: mild (stage I) and moderate to severe (stage II). Differences in troponin, CK, and CKMB were compared between groups .The data of patients with parenchymal lung diseases were reviewed. Parenchymal lung diseases can be broadly divided into those that create an abnormal increase in density (lung consolidation or collapse) on a chest radiograph and those that cause increased lucency (pneumothorax or pneumomediastinum). Hypotension was defined as a mean blood pressure < gestational age in weeks .Neurodevelopmental outcomes were evaluated at the corrected age of 1 year either through clinical evaluations conducted by an experienced pediatric neurologist or using the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III).Ethical approval was provided by the Chung Shan Medical University Hospital Internal Review Board (IRB #: CS2-14003), and the study was performed in accordance with relevant guidelines. Patient charts were retrospectively reviewed in all cases.t-test to compare the means of two independent groups or a chi-squared test between categorical variables. The Fisher exact test was used when sample sizes was small. Logistic regression was to conduct when the dependent variable is binary. Hedges’ g (effect size) provides a measure of effect size where there are different sample sizes, and is determined by the mean difference between two groups, dividing the result by the standard deviation. The odds ratio (OR) is the association between a variable and an outcome, and is calculated by dividing the odds of the first group by the odds in the second group. If the sample distribution was nonparametric, a Mann–Whitney U test was performed. Significance was set at p < 0.05. All statistical tests were carried out using SPSS .Significant differences between groups were evaluated using an independent Overall, 73 patients had HIE after excluded 17 cases, 28 (38.4%) of 73 patients had stage I (mild) and 45 (61.6%) of 73 had stage II–III (moderate to severe) HIE receiving therapeutic hypothermia .t (72) = 2.88; p = 0.005) and 5 min (t (72) = 3.62; p = 0.001) were significantly different between the two groups  = 7.50, p = 0.006,) compared with patients with stage I HIE; and higher  = 6.63, p = 0.011) in parenchymal lung disorders before discharge in stage II-III HIE compared with patients with stage I HIE. The number of clinical cardiopulmonary presentations was higher in patients with stage II–III HIE related to hypotension during first admission   = 16,11; p < 0.001) than stage I HIE with abnormal neurodevelopmental outcomes at the age of 1 year. Among stage I patients, four (14.3%) had mild developmental delays at the age of 1 year. In the 45 stage II–III patients treated with hypothermia therapy, two (4.4%) died before discharge due to pulmonary pneumothorax and 26 (57.8%) had abnormal neurodevelopmental outcomes at the age of 1 year (o 27.60) . Twenty-n = 22) patients, the blood troponin I level was 50.6 ± 36.7 pg/mL. This was significantly lower  than the troponin I levels of stage II–III patients (n = 39) (325.1 ± 754.5 pg/mL). CK and CKMB were not significantly different between the two groups. We found that troponin I levels were significantly higher in moderate to severe HIE than in mild HIE  between stage I and stage II patients and between stage I and stage III  patients. No difference in troponin I level was observed between patients with stage II and III HIE (Sixty-one patients had the troponin I level within 6 hours of birth . Among smild HIE . Troponi III HIE . p = 0.005)  than patients without adverse neurodevelopmental outcomes  . No sign= 0.005) . No diff2  = 13.0, p = 0.001; odds ratio 7.14), with the prediction of moderate to severe HIE in a positive prediction rate (PPV) of 81.1%, a negative prediction rate (NPV) of 62.5%, a specificity of 68.2%, and a sensitivity of 76.9%. A troponin I cut-off level of ≥120 pg/mL could predict moderate to severe HIE  = 13.0, p = 0.005; odds ratio 9.50) with a higher PPV of 90.9% and a specificity of 90.5%, and a lower NPV of 50.0% and a lower sensitivity of 48.7%  = 33.1, p = 0.001; odds ratio 96.8) with hypotension during first admission  = 33.1, p = 0.001; odds ratio 96.8) with abnormal neurodevelopmental outcomes or death at 1 year  = 5.3, p = 0.021; odds ratio 4.53) with a PPV of 66.7% and a higher specificity of 89.5%, and a NPV of 69.4% and a lower sensitivity of 34.8% . On the basis of these results, troponin I level can act as a blood biomarker for the early prediction of moderate to severe HIE, for which hypothermia therapy has been shown to be beneficial. This study found that CK and CKMB were not useful biomarkers of neonatal HIE staging. A troponin I cut-off of ≥120 pg/mL could be used to predict HIE stage as well as for the prediction of hypotension during first admission. However, the troponin I level ≥180 pg/mL was a biomarker for predicting neurodevelopmental outcomes in patients with neonatal HIE at 1 year.The findings indicated that troponin I is a biomarker for cardiac cell injury and reflects the staging of HIE. One study revealed that early troponin I levels may be correlated with the severity of neonatal HIE and could predict residual encephalopathy in newborns at discharge . These fResults from previous studies on troponin I levels in neonatal HIE have been inconsistent  21,22,2,27,28. OThe long-term neurological outcomes in newborns with HIE are a critical issue for clinicians. Choosing an appropriate cut-off level of troponin I is difficult and maybe biased. In this study, troponin I levels within 6 h were higher in the patients with moderate to severe HIE than in the patients with mild HIE. The troponin I levels were also higher in the patients with abnormal neurodevelopmental outcome than the level in patients with unremarkable neurodevelopmental outcomes at the age of 1 year. This was not in disagreement with the findings that the cut-off 60 pg/mL and 120 pg/mL could not predict the neurodevelopmental outcomes. An appropriate cut-off level is noteworthy. In patients treated with hypothermia therapy, neonatal hypotension could have caused secondary damage and further brain consequence. In a recent study, troponin-I levels, especially at levels >0.3 ng/mL, after therapeutic hypothermia was an independent factor for increased risk of acute kidney injury in asphyxiated newborns .The proportion of abnormal neurodevelopmental outcomes was still half in moderate to severe HIE patients treated with hypothermia. This finding is comparable to those of other studies, which have demonstrated a risk of death or moderate to severe disability in 45–55% of treated infants for moderate to severe HIE ,8,10. EaTroponin I levels within 6 h of birth can be a useful biomarker for determining the stage of neonatal HIE and initialize early hypothermia therapy for moderate to severe HIE. Higher troponin I ≥120 pg/mL levels were associated with hypotension during first admission. The results suggest to carefully monitor for blood pressure during hypothermia therapy. Long-term neurodevelopmental follow-up of patients is warranted. Further study to enroll a large number of neonatal mild HIE and to define an adequate cut-off troponin I level to provide early and precise management is suggested.


Journal of Hip Preservation Surgery (JHPS) is not the only place where work in the field of hip preservation may be published. Although our aim is to offer the best of the best, we continue to be fascinated by work that finds its way into journals other than our own. There is much to learn from it so JHPS has selected six recent and topical subjects for those who seek a summary of what is taking place in our ever-fascinating world of hip preservation. What you see here are the mildly edited abstracts of the original articles, to give them what JHPS hopes is a more readable feel. If you are pushed for time, what follows should take you no more than 10 min to read. So here goes …The The authors  from DaeThe post-operative centre-edge angle, the alpha angle and the offset decreased significantly compared with the preoperative measurements. The outcome scores before surgery and at 1 and 2 years after surgery for mean mHHS were 62.19, 86.70 and 87.89; the mean iHOT-12 scores were 30.44, 73.56 and 73.77 and the mean VAS scores were 6.07, 1.93 and 1.59, respectively. There was a significant improvement in the mean mHHS, iHOT-12 and VAS scores at 1 and 2 years after surgery. The mHHS score at 2-year follow-up after surgery was significantly higher than that at 1 year after surgery. One patient with severe acetabular and femoral articular cartilage damage underwent total hip replacement 11 months after index surgery.The authors concluded that the hip arthroscopy considerably improved hip symptoms and function in Chinese FAI patients who were 50 years or older and did not have severe radiographic osteoarthritis. The conversion to total hip arthroplasty (THA) and complications were reported to be low. Adherence to strict surgical indications and appropriate surgical strategies were considered important in order to lay the foundation for satisfactory post-operative results in elderly patients with FAI.et al. [Flores et al.  from theThe authors reported that a total of 131 hips were included  in the study. Women had a smaller mean preoperative alpha angle than men  and lower acetabular cartilage injury grade . Both women and men achieved equivalent significant improvements in PRO scores after surgery (scores increased 18.4–45.1 points for mHHS and HOOS). Women and men both reached PASS for mHHS at similar rates . MCID was also achieved at similar rates between women and men for all scores  except the activities of daily living (ADL) subscale of the HOOS, in which a significantly greater percentage of women reached MCID compared with men (79.2% versus 62.7%). Additional stratification by age group using the median cohort age of 34 years showed no significant differences in PRO improvement based on age group for each gender. The authors concluded that women can achieve clinically meaningful improvements in PRO scores after hip arthroscopy for FAI. Compared with men, women demonstrated equivalent high rates of achieving MCID and PASS at 2 years after surgery.et al. [In this retrospective cohort study, Lee et al.  report mThe authors report that the mean preoperative and final mHHS and HOS-ADL improved significantly from 61.2 and 60.6–79.5 and 81.8, respectively, while the VAS pain score decreased significantly from 6.3 to 3.2. Although the mean range of internal rotation and flexion increased from 14.2° and 100.7° preoperatively to 30.4° and 110.6° at 1-year postoperatively, they decreased slightly to 27.4° and 105.4° at the final follow-up, respectively. Eight cases (4.2%) underwent revision arthroscopic surgery and three cases (1.6%) were converted to THA. The authors noted that the patients with early-stage osteoarthritis of various diagnoses achieved improved clinical outcomes. Therefore, using hip arthroscopy in middle-aged patients with early osteoarthritis, it is possible to achieve good surgical outcome.The authors  from CalIt was reported that the mean follow-up time was 4.9 years, the mean age was 37.2 years (range 10–88), and 57% were female. During the follow-up period, 82 patients underwent a THA within 2 years of their arthroscopies (5.3%), after a median time of 9 months after the initial arthroscopy. Increasing age was highly predictive of early THA conversion. Although other predictors showed significant bivariable associations with early failure, body mass index (BMI), race, sex and prior arthroscopy did not add meaningful independent predictive information.The authors concluded that the risk of conversion to THA within 2 years after hip arthroscopy increased substantially with patient age at the time of the procedure. BMI, race, sex, and prior arthroscopy were not important independent predictors of conversion beyond the information contained in patient age.et al. [Martinez et al.  aimed toIn the final result they included 185 patients with a mean age of 36.7 years. Patients participating in rotational running sports and flexibility sports had a significantly greater proportion of rim chondral injuries than those participating in endurance sports or asymmetric-overhead sports. Ligamentum teres tears were significantly associated with flexibility sports. A total of 84.7%, 67.7%, 67.2% and 71.2% of patients met MCID levels for the mHHS, the hip outcome score questionnaire with ADL, the sports subscale (HOS-SSS) and the iHOT-12, respectively; 94.9%, 66.2% and 62.7% met the PASS for mHHS, HOS-ADL and HOS-SSS, respectively; 86.7%, 48.5%, 47.8% and 32.4% found substantial clinical benefit for mHHS, HOS-ADL, HOS-SSS and iHOT-12, respectively.The authors highlighted that the rotational running sports were significantly associated with rim chondral injuries. While the flexibility sports were significantly associated with rim chondral injuries and ligamentum teres tears. Athletes participating in these sports are more likely to have intra-articular hip injuries than those in the other sports categories.et al. [In this study, Lee et al.  note thaThe authors concluded in the light of their findings that implementing an obturator nerve block into SI-FICB can reduce the post-operative opioid consumption in hip arthroscopy.None declared.


Similarly, the study showed that riders who often or always wore a safety vest suffered significantly fewer spinal injuries (p = 0.017) and had significantly fewer injuries per 1000 riding hours (p = 0.031) than riders who did not wear a safety vest. Based on the present results, there should be an extension of the general helmet requirement and a requirement to wear safety vests in show jumping in general.This retrospective cross-sectional epidemiological study deals with sport-specific injury patterns in show jumping. A total of 363 show jumpers of all levels (S) answered a retrospective questionnaire about injuries and overuse damages which occurred in the course of their careers. Demographic data and information on injuries in various body regions were collected. In addition to descriptive analysis, significance tests were performed. For better statistical comparability with other sports, exposure time was extrapolated with total career duration and weekly training hours, and injuries per 1000 jumping hours were calculated. The study included 251 (69%) women and 112 (31%) men, who were on average 26.9 ± 10.9 years old. The injury rate for the entire collective was 3.7 per 1000 h of exposure. The most frequently affected body region was the head (31%). Overuse complaints play a subordinate role and mainly affect the upper extremities (65%). The riders of the professional lower performance levels are less likely to injure themselves per 1000 h than riders of the higher performance levels. Riders who often or always wore a helmet suffered significantly fewer head injuries ( Show jumping is a discipline of equestrian sport in which various obstacles in a marked area as a course must be overcome in a specified sequence and in a specified time by horse and rider ,2. The hEquestrian sport in general is associated with multiple possibilities for injury and the competitive sport in particular can be classified as a risky sport. Show jumping ranks as one of the most accident-prone disciplines ,5. SerioSince January 2021, a general helmet obligation has been introduced for almost all equestrian disciplines ,7.Research on current publications related to horseback riding revealed some general research on horseback riding injuries of all riding disciplines. To date, there is hardly any literature considering injuries specific to show jumping and different riding levels in show jumping ,9. LechlThe aim of this study is to record and evaluate sport-specific overuse and injury patterns of all body regions and injured structures in show jumpers of all performance levels, as well as differences between genders and protective equipment. The collected data should lead to a further development of preventive as well as protective measures to make the sport safer.The retrospective cross-sectional epidemiological study was carried out using a questionnaire analogous to previous studies in accordance with the Helsinki Declaration and after review by the responsible ethics committee of the University of Duisburg-Essen 09-4123-BO) ,11,12. T3-BO ,11,U test was used in each case. For the multilevel variables riding experience and performance class, Kruskal–Wallis tests were performed first in each case. If this revealed a significant difference between at least two groups, pairwise Mann–Whitney U tests were then calculated to investigate between which groups there were significant differences in the number of injuries. Values of p < 0.05 were considered as significant.The statistical evaluation was carried out using IBM SPSS Statistics 25 software . Within the context of descriptive statistics, a calculation of the mean value and the standard deviation (M ± SD) was performed. All values were tested for normal distribution with the Kolmogorov–Smirnov test. In addition to the descriptive evaluation of the number of injuries in the different body areas, the influence of the variables, gender and performance level, on the number of injuries per body area was also investigated. For this purpose, the sum of the injuries was first calculated for each body area from the number of injuries relevant to the body area in each case. Subsequently, significance tests were performed with this sum variable. Due to the non-normal distribution of the sum variable, non-parametric tests were used. For the dichotomous variable gender, a Mann–Whitney 2. The respondents practiced show jumping for a mean of 12.7 ± 9.9 years. In total, 1,832,558 riding hours (=exposure time) were reported. The average exposure time per rider was 5048 h. On all indicated variables an injury rate of 3.7 per 1000 riding hours can be found. The distribution of the study participants according to performance level is shown in p < 0.001). From S 5 to S 2, the number of riding hours increases significantly. S 1 rides significantly less than S 2  female and 112 (30.9%) male riders. The mean age of all participating athletes was 26.9 ± 10.9 years, that of the female participants 25 ± 8.5 years and that of the male participants 31.3 ± 14.2 years. The mean body weight was 66.4 ± 3.2 kg and the mean body mass index was 22.1 ± 3.2 kg/mthan S 2 . The injp < 0.001).The injury location and frequency showed that 326 (89.8%) athletes had been injured at least once since they started practicing the sport. A total of 6768 injuries and overuse injuries were reported in the entire collective. The most common location was the head, followed by the trunk. Variables classified as overuse accounted for only 4.4% (296) of all mentions. In the following, all injuries and overloads are considered by body region with significance testing of the number of injuries per performance level. The consideration of the mentioned variables regarding the total riding duration was carried out in advance. With 11,648.5 ± 19,069.3 h on average, men rode significantly more hours than women with 2103.3 ± 5125.4 h (p < 0.05). There are also significant differences in the number of head injuries ever in the performance level (p < 0.001). Significantly more injuries are shown in S 1 than in S 3 to 6, significantly more in S 2 than in S 5 and 6 and significantly more in each of S 3 and 4 than in S 6. Considering 1000 h of exposure, no significant differences can be shown (p > 0.05). In summary, riders in better performance levels have more head injuries  riders sustained at least one head injury during their career. Based on the complete study collective, this results in an average of 5.7 ± 11.3 head injuries. injuries .p < 0.05). For every 1000 h of exposure, women are significantly more likely to sustain truncal injuries (p < 0.05). Divided into performance levels, there are significant differences regarding the number of truncal injuries over the course of the entire career (p < 0.001). There were no significant differences between S 1 to S 3 over the entire riding career and significantly fewer injuries in each case compared to S 4–6. The S 4–6 do not differ significantly from each other. In summary, riders in the lower performance levels sustain more truncal injuries than riders in the higher performance levels  athletes injured their trunk at least once in their career. On average, every athlete sustains a truncal injury 4.4 ± 7.6 times in his career. e levels .The number of injuries to the remaining body regions are shown in n = 74) of the samples. More than half were tendinitis of the elbow (51.3%), followed by carpal tunnel syndrome (14.3%). Comparing genders, there were no significant differences in neither complete career (p > 0.05) nor 1000 h of exposure (p > 0.05). The same applies to the performance levels ever (p > 0.05). The age categories differ significantly in the number of overloads in the entire career (p < 0.05), especially for more overloads in the over 51-year-olds compared to all under 40-year-olds. For the whole career, there were significant differences in riding experience (p < 0.05). Riders with a career of more than 20 years had significantly more overloads than riders with less than 10 years of riding experience.Contusions and skin injuries were the most common types of injuries in show jumping, followed by distensions and distortions. All injury types are shown in The injury-related training breaks for all participants in total amount to 2418.1 weeks. On average, each athlete had to take a break of 6.7 ± 17.0 weeks in their career due to injuries. The longest downtime was 214 weeks. On average, each rider had to take an injury-related break of 0.5 ± 1.2 weeks per career year. Spinal injuries accounted for the longest downtime, at 27.3% of total downtime. Lower leg and foot injuries at 15.6% and knee injuries at 14.5% combine for about another third of all injury time off. In descending order, shoulder injuries (11.4%), pelvic and thigh injuries (10%) and head injuries (9.2%) are similarly likely to trigger riding breaks. Hand (7.4%) and elbow injuries (4.5%) accounted for the lowest percentage of all injury-related breaks.p = 0.008). Similarly, the present study shows that riders with helmets reported a significantly (p = 0.006) lower total injury duration (15.1 ± 28.5 days) than riders without helmets (26.2 ± 32.8 days). No significant difference was seen in the number of days of training lost due to head injuries for riders with or without helmets (p = 0.318). Regarding to the total number of injuries per 1000 h of riding, no significant difference was shown between the groups of riders with and without helmets (p = 0.744).Of the 363 jumpers surveyed, 86 (24%) reported to never or occasionally wear a helmet and 277 (76%) riders reported to often or always wear a helmet. In the present study riders with helmets suffered 4.7 ± 10.1 head injuries and riders without helmets suffered 9.1 ± 14.1 head injuries. This indicates that riders who often or always wear a helmet suffer significantly fewer head injuries than riders who do not or only occasionally wear a helmet (p = 0.017). In the total number of injuries per 1000 riding hours, riders without a safety vest also had significantly more injuries than riders with a safety vest (p = 0.031).Always or often wearing a safety vest was reported by 50 (14%) riders and 313 (86%) never or occasionally wear a safety vest. Riders with safety vests suffered a mean of 2.9 ± 4.3 and riders without safety vests suffered 4.7 ± 7.9 spinal injuries. Thus, riders who often or always wore a safety vest suffered significantly fewer spinal injuries than riders who occasionally or never wore a safety vest , followed by injuries to the trunk (23.8%). The most commonly reported injury types are contusions and skin injuries (47.4%). Minor injuries such as contusions and skin injuries are the leading injury type in general equestrian sports and account for 44% to 51% of injuries ,22. In tIn the present study the trunk injuries were the second most frequently injured region with 24% and lead to the longest injury break time. Compared to other studies, this injury is underrepresented in our study ,24,25.According to the literature, most injuries involve the upper extremity in equestrian sports ,13,26. Ip < 0.05). On the one hand, this could be related to the fact that men are presumably more risk averse than women and that men are less likely to wear a helmet than women [In the present study, significantly more men than women were injured in the head region . Similarly, riders with helmets had a significantly lower total injury duration than riders without helmets (p = 0.006). Regarding the total number of injuries per 1000 h of riding, no significant difference was shown between the groups of riders with and without helmets (p = 0.744). This is related to the fact that the protective equipment only protects one body region at a time. In 2010, a general helmet requirement was introduced in almost all equestrian sports [The risk of injury can be relevantly reduced by wearing protectors in sports ,7. In eqp = 0.017). Moreover, in the total number of injuries per 1000 riding hours, riders without a safety vest had significantly more injuries than riders with a safety vest (p = 0.031). A general recommendation to wear a vest has not yet been made. Authors should discuss the results and how they can be interpreted from the perspective of previous studies and of the working hypotheses. The findings and their implications should be discussed in the broadest context possible. Future research directions may also be highlighted.Another form of protection is the safety vest. In this study, 86% (313) of the riders reported to never or occasionally wear a safety vest. These figures are consistent with those in the literature ,25. ReasIn the present study, we were able to obtain a good overview of injuries and overuse injuries in show jumping. The injury rate for show jumping was higher than in comparable studies on equestrian sports but lower than in other sports such as contact sports, with 3.7 injuries per 1000 h of riding. ,21. The p = 0.008) and had a significantly lower total injury duration than riders who did not wear a helmet (p = 0.006). Similarly, the study showed that riders who often or always wore a safety vest suffered significantly fewer spinal injuries (p = 0.017) and had significantly fewer injuries per 1000 riding hours (p = 0.031) than riders who did not wear a safety vest. In general, these results confirm the introduction of mandatory helmet use in show jumping competitions. However, based on the present results, there should be an extension of the general helmet requirement and a requirement to wear safety vests in show jumping in general. According to the present study, this could prevent many injuries in show jumping.This study was able to show that riders who often or always wore a helmet suffered significantly fewer head injuries (


This cohort study investigates the association of exposure to ambient fine particulate matter air pollution with kidney transplant outcomes. 2.5) air pollution associated with increased risk of adverse posttransplant outcomes among patients with kidney transplants?Is exposure to increased levels of ambient fine particulate matter  air pollution are associated with increased risks for detrimental health outcomes, but risks for patients with kidney transplants (KTs) remain unknown.Increased levels of ambient fine particulate matter  and mean PM2.5 level in the year before KT  in quartiles, as well as baseline annual mean PM2.5 level (in 10 μg/m3).Exposures included post-KT time-dependent annual mean PM2.5 levels greater than the Environmental Protection Agency recommended level of 12 μg/m3 was estimated.Acute kidney rejection , time to death-censored graft failure, and time to all-cause death. Multivariable logistic regression for kidney rejection and Cox analyses with nonlinear assessment of exposure-response for death-censored graft failure and all-cause death were performed. The national burden of graft failure associated with PM2.5 level was 9.8 (8.3-11.9) μg/m3. Increased baseline PM2.5 level, compared with quartile 1 baseline PM2.5 level, was not associated with higher odds of acute kidney rejection for quartile 2  but was associated with increased odds for quartile 3  and quartile 4 . Nonlinear assessment of exposure-response for graft failure and death showed no evidence for nonlinearity. Increased PM2.5 levels were associated with increased risk of death-censored graft failure  and all-cause death . The national burden of death-censored graft failure associated with PM2.5 above 12 μg/m3 was 57 failures  per year among patients with KTs.Among 112 098 patients with KTs, 70 522 individuals (62.9%) were older than age 50 years at the time of KT, 68 117 (60.8%) were men, and the median (IQR) follow-up was 6.0 (3.9-8.9) years. There were 37 265 Black patients (33.2%), 17 047 Hispanic patients (15.2%), 48 581 White patients [43.3%]), and 9205 patients (8.2%) of other race or ethnicity. The median (IQR) baseline PM2.5 level was an independent risk factor associated with acute rejection, graft failure, and death among patients with KTs. These findings suggest that efforts toward decreasing levels of PM2.5 concentration may be associated with improved outcomes after KT.This cohort study found that PM The etiology of kidney disease may be mediated by an increase in systemic inflammation and oxidative stress associated with air pollutants.15 It also has been found that particulate matter inhaled through the respiratory tract and cleared by the kidney may be associated with direct damage to renal tissue.16 Furthermore, air pollutants and PM2.5 are associated with insulin resistance,18 attenuated flow-mediated arterial dilation,19 and systemic hypertension,22 which are important factors that may be associated with kidney function.In the field of kidney disease, epidemiological studies from 2016 to 20202.5 levels and health outcomes, few studies have examined the association between PM2.5 levels and the outcomes of solid organ transplantation. Among patients with lung transplants, Bhinder et al23 found that increased PM2.5 levels were associated with an increased risk of chronic lung allograft dysfunction and overall mortality. Similar findings have been observed among individuals with heart transplants.24 Among individuals with kidney transplant (KT), studies26 found that exposure to air pollutants was associated with an increased risk of cardiovascular mortality, but associations of PM2.5 levels with other important transplant outcomes have not been examined to date, to our knowledge. With the identified knowledge gap in the association of PM2.5 levels with KT outcomes, this study aimed to determine whether PM2.5 concentration is an independent risk factor associated with kidney rejection, graft failure, or overall mortality among patients with KTs.Despite the existing evidence for an association between PMSTROBE) reporting guideline for cohort studies.Exemptions for study approval and informed consent were obtained for this cohort study from the Washington University in St. Louis School of Medicine Institutional Review Board because the study was secondary analyses of deidentified data. This report follows the Strengthening the Reporting of Observational Studies in Epidemiology . Transplant outcomes were followed up until March 2021. Detailed descriptions of OPTN data were described elsewhere.31 ADI summarizes factors for the theoretical domains of income, education, employment, and housing quality.32 Data on population density were obtained from the US Bureau of Census 2010 Zip Code Tabulation Area to tract Relationship File.33 Data on remaining contextual characteristics were obtained from 2011 to 2015 American Community Survey 5-year estimates accessed through ArcGIS Living Atlas of the World.34We obtained recipient characteristics, including age, sex, race and ethnicity , body mass index , insurance status, and zip code of residence at the time of KT, as well as clinical data on panel reactive antibodies (PRA), diabetes, chronic obstructive pulmonary disease, etiology of kidney disease, and duration of dialysis closest to transplant. Race and ethnicity were among the many recipient and donor characteristics  that we used to adjust for recipient and donor characteristics. We also collected donor characteristics, including age, sex, race and ethnicity, BMI, kidney donor profile index, donor type, and history of hypertension, as well as transplant factors, including donor-recipient cytomegalovirus seropairing, level of human leukocyte antigen (HLA) mismatch, and cold ischemia time. Patient zip codes of residence were mapped to zip code–level data to obtain contextual characteristics, including area deprivation index (ADI), population density , median income, high school graduation and unemployment rates, and proportion of residents below the federal poverty line. Data on ADI were obtained from the University of Wisconsin School of Medicine and Public Health’s Neighborhood Atlas.2.5 concentration in micrograms per cubic meter in the recipient residential zip code area to reflect changing levels of PM2.5 over time after KT. Data on annual mean PM2.5 concentration (1 × 1 km) in the contiguous United States were obtained from aerosol optical depth retrievals from the NASA Moderate Resolution Imaging Spectroradiometer, Multi-Angle Imaging Spectroradiometer, and Sea-Viewing Wide Field-of-View Sensor calibrated using geographically weighted regression.36 The years of availability were 2001 to 2018. The overlap of 1 × 1–km resolution PM2.5 grids and zip code area produced surface area–weighted PM2.5 levels for each zip code.11The exposure was post-KT time-dependent annual mean PM2.5 level, defined as the annual mean PM2.5 level in the year before KT for a patient’s residential zip code area, was also considered as baseline PM2.5 level in 10 μg/m3 increments and baseline PM2.5 level categorized in quartiles.Baseline PMThe outcomes included acute kidney rejection reported at 1 year after KT (yes or no), death-censored graft failure , and all-cause death , with all data from the OPTN. The latter 2 transplant outcomes were followed up until March 2021 unless otherwise specified.The cohort included patients who underwent KT from 2004 to 2016. We excluded patients aged younger than 18 years at KT, patients receiving kidneys from living donors, patients with a previous KT, and patients with missing data on zip codes or continuous covariate variables.2.5 level quartiles in percentages for categorical variables and in medians (IQRs) for continuous variables. To compare between baseline PM2.5 level quartiles, χ2 tests were performed for categorical variables and Kruskal-Wallis tests were performed for continuous variables. Survival curves for time-to-event transplant outcomes  stratified by baseline PM2.5 level quartiles were adjusted for recipients' age, sex, race and ethnicity, dialysis status and duration, and ADI.Recipient characteristics, donor characteristics, transplant factors, and contextual factors were stratified by baseline PM2.5 concentration with time-to-event transplant outcomes were analyzed by multivariable Cox models. Robust sandwich variance estimators for Cox models were used.38 Follow-up was censored at the end of 2018 because data on annual mean PM2.5 concentration were available only up to 2018. The covariates in these multivariable models were selected from all recipient demographics, donor characteristics, transplant factors, contextual factors  was analyzed using multivariable logistic regression.The associations of post-KT PM2.5 level quartiles,39 and the statistical significance of spline terms was assessed for nonlinearity of spline terms. When there was no evidence of deviation from linearity, patients residing in areas with the lowest 1%  and the highest 1%  baseline PM2.5 levels were excluded from the analytic cohort, and multivariable-adjusted hazard ratios using the aforementioned Cox models were estimated using 3.7 μg/m3 as the reference level. These multivariable-adjusted hazard ratios (HRs) were plotted against the baseline PM2.5 level from 3.7 μg/m3 to 16.9 μg/m3 with the background of the histogram distribution of baseline PM2.5 level for the included analytic cohort.11To plot the exposure-response function for death-censored graft failure and all-cause death, cubic spline analyses were first performed in multivariable Cox models with knots placed at baseline PM2.5 levels greater than the Environmental Protection Agency (EPA) recommended PM2.5 concentration of 12 μg/m3 was plotted using the population attributable fraction (PAF) multiplied by incidence of graft failure per 100 000 patients with KTs per year from 2004 to 2016. PAF was the proportional reduction of the condition in the KT population that would occur if exposure to PM2.5 was decreased to 12 μg/m3. PAF was computed using piecewise constant hazard models for graft failure incidence.41Geographic distribution of the estimated national burden of graft failure associated with PM2.5 concentration was computed using ArcGIS Pro software version 2.7.0 (Esri). Data were analyzed from April 2020 through July 2021.All tests were 2-sided, and results were considered statistically significant at α = .05 or when 95% CIs did not cross 1 for odds ratios and hazard ratios. All statistical analyses were performed using SAS statistical software version 9.4 (SAS Institute) and R statistical software version 4.0.2 . Zip code–level PM11 Cities were defined as core-based (including metropolitan and micropolitan) statistical areas, which were obtained from the US Census Bureau33 and linked to patient residential zip codes. Additionally, for the acute kidney rejection outcome, multivariable logistic regression was performed adjusting for city clustering.To account for variations in city characteristics that could confound the association, sensitivity analyses for all 3 outcomes were conducted using multilevel models and adapting city-adjusted and within-city models. These models were detailed elsewhere.Among 214 317 patients who received KTs from 2004 to 2016 in the United States , while 37 265 patients (33.2%) were Black, 17 047 patients (15.2%) were Hispanic, and 9205 patients (8.2%) were of other race or ethnicity. Most patients had obesity or overweight BMI and were on dialysis more than 24 months before KT. Most patients received kidneys from donors who were aged 18 to 50 years (69 483 patients [62.0%]), men (67 284 patients [60.0%]), and White , while 15 550 patients had donors who were Black (14.0%), 15 189 patients had donors who were Hispanic (14.0%), and 3851 patients had donors who were of other race or ethnicity (3.4%). Most patients received kidneys from donors with a BMI from 18.5 to 24.9 (38 504 patients [34.4%]) or 25.0 to 29.9 (34 735 patients [30.99%]). Among transplant factors, most patients had a level of HLA mismatch of 3 to 6 hours and 12 to 24 hours of cold ischemia time. The median (IQR) ADI of patient residential zip code areas was 53.7 (31.1-72.3), and the median (IQR) population density was 0.00076 (0.00013-0.00186) individuals per square meter.2.5 level was 9.8 (8.3-11.9) μg/m3. Baseline PM2.5 concentration ranged from 1.2 μg/m3 to less than 8.3 μg/m3 among 28 025 patients in the first quartile, from 8.3 μg/m3 to less than 9.8 μg/m3 among 28 024 patients in the second quartile, from 9.8μg/m3 to less than 11.9 μg/m3 among 28 025 patients in the third quartile, and from 11.9 μg/m3to less than 22.4 μg/m3 among 28 024 patients in the fourth quartile. All recipient demographics, donor characteristics, transplant factors, and contextual factors were statistically significantly different across PM2.5 level quartiles except for sex for recipients and donors. Factors that decreased with PM2.5 level quartiles included proportion of recipients aged older than 50 years  and the proportion who were White  (The median (IQR) baseline PM < .001) .2.5 levels by quartile were associated with increases in acute kidney rejection , death-censored graft failure , and all-cause death   . The adjuartiles A-B demon2.5 level   and all-cause death . Using continuous baseline PM2.5 exposure .Risks for adverse KT outcomes increased with levels of post-KT time-dependent PM14-1.28) B left. Uexposure B, right,2.5 was reduced to the EPA recommended level of 12 μg/m3 was 3.99% (95% CI 3.32%-4.65%). The national burden of graft failure associated with increased levels of PM2.5 over 12 μg/m3 was estimated to be 57 failures  among 8623 patients with KTs per year from 2004 to 2016. The map illustrating the geographic distribution of the burden of graft failure (per 100 000 patients with KTs) associated with increased levels of PM2.5 over 12 μg/m3 is presented in 2.5 level, increased baseline PM2.5 level quartiles were associated with increased risk of acute kidney rejection, graft failure, and all-cause death (eTable in the The PAF for graft failure if exposure to PM2.5 concentration during post-KT follow-up or in the year before KT (by quartile or quantity), our study consistently found that PM2.5 concentration was an independent risk factor associated with acute rejection, death-censored graft failure, and all-cause mortality among recipients of KTs. These results were robust when different statistical models (with or without adjustment for city variations) were used. We also found linear exposure response associations between baseline PM2.5 concentration and risks for death-censored graft failure and all-cause death. These findings suggest that consistent exposure to fine particulate matter air pollution is associated with increased risk of worse transplant outcomes among recipients of KTs, including kidney rejection, kidney graft failure, and all-cause death.This cohort study is one of the first studies, to our knowledge, to assess the association of ambient fine particulate matter air pollution with outcomes among recipients of KTs. Using annual mean PM2.5 over 12 μg/m3 suggests that the highest burden was concentrated in areas with high population density and a high degree of air pollution, such as the Southwest and East North Central regions. The map showing areas with increased burden is consistent with that in Goodkind et al,42 in which the authors illustrated the estimated monetary marginal damages at every emission source location on a map.42The geographic distribution of the burden of graft failure associated with increased levels of PM2.5 concentration was associated with increased risk of kidney graft failure. This finding is consistent with those in previous reports finding increased risks for CKD and ESRD among individuals with native kidneys.43 Additionally, using multiple definitions of exposures, Bowe et al11 found an association between exposure to PM2.5 and risk for incident CKD and ESRD in a cohort of US veterans. In an earlier study, Mehta et al13 found that 1-year exposure to increased PM2.5 concentration was associated with an annual decrease in kidney function. Globally, it was estimated that PM2.5 concentration is associated with 3.3 million cases of incident CKD and 122.4 million cases of prevalent CKD.43 However, our finding is not supported by the finding in a Feng et al,44 which found that risk of death-censored graft failure was increased with increased PM2.5 concentrations, although this change was not statistically significant. This deviation could be associated with a shorter follow-up time .One highlight of this study is the finding that increased PM47 We found a 13% increase in odds of rejection within the first year of KT among recipients residing in areas with the fourth quartile of baseline PM2.5 levels, compared with the first quartile. This finding is consistent with that in Feng et al44 and suggests an alloimmune etiology as a possible pathway for rejection that may be associated with increased risk of graft loss. The exact mechanism of increased risk of rejection with PM2.5 has not yet been elucidated. We hypothesize that this could be associated with increased systemic inflammation and activation of the innate and adaptive immune systems. This hypothesis is based on a growing body of literature suggesting that the organic compounds, free radicals, and transition metals contained in PM2.5 are associated with increased oxidative stress, as well as the gene and protein expression of proinflammatory mediators, such as tumor necrosis growth factor α, monocyte chemoattractant protein 1, macrophage inflammatory protein 2, interleukin 6, interleukin 1β, and interleukin 8.48 Studies have also found that PM2.5 is associated with increased expression of adhesion molecules like vascular cellular adhesion molecule 1 and the adhesion of monocyte cells to endothelial cells.50 In lung transplant, aryl hydrocarbon receptor is considered as a pathway to changing naive T cells to inflammatory T helper 17 cells and promoting chronic inflammation and chronic rejection.51Kidney graft rejection is a major risk factor associated with graft loss.3 increase in PM2.5 level, similar to the finding of Feng et al (15% increase per 10 ug/m3 increase in PM2.5 level).44 Prior studies among recipients of KTs have found increased risk of cardiovascular mortality from exposure to air pollutants.26 The increased mortality risk has also been reported among individuals with heart transplants: 26% to 43% increases in mortality risk per 10 ug/m3 increase in time-dependent PM2.5 concentration.24 In patients with lung transplants, the increase in mortality risk was not statistically significant, as reported by Bhinder and colleagues,52 possibly associated with the exposure definition  and a smaller sample size . As for mortality among patients with CKD, it was estimated at 211 019 deaths associated with CKD associated with PM2.5 exposure globally.43 However, similar to the situation in the general nontransplant population, it is likely that most of these deaths are associated with detrimental cardiovascular outcomes of PM2.5 exposure.53Our study found a 21% increase in mortality risk among individuals with KTs for every 10 ug/m2.5 levels with acute rejection, graft failure, and death in a large national cohort of individuals with KTs. Second, our analyses benefited from merges of multiple databases to comprehensively account for potential confounding, including patient, donor, and transplant factors, as well as contextual characteristics . Third, multiple exposure definitions were used to ensure the robustness of study findings. Fourth, the robustness of the findings was strengthened by sensitivity analyses adjusting for city variations. We note that PM2.5 concentration generally decreased over time. As a consequence, using time-dependent exposure is particularly important to capture the association of decreasing PM2.5 levels over time with transplant outcomes. Furthermore, this trend was associated with changes in included recipient and donor characteristics, transplant factors, and contextual factors, as well as transplant outcomes when recipients were grouped by baseline PM2.5 level quartiles, as presented in the This study has several strengths. First, to our knowledge, it is one of the first studies on the association of PM2.5 concentration was available up to 2018 at the time of the study, limiting follow-up time. Nonetheless, we were able to include a follow-up of 2 to 15 years. Third, the most up-to-date residential zip codes for recipients of KTs were recorded at the time of KT. Time-dependent analyses may be biased if the patients moved to another zip code area after KT. However, this bias may be decreased if patients who moved after KT were not systematically more likely to move to areas with higher or lower levels of PM2.5 compared with their area of residence at KT. Fourth, composition and toxic content of PM2.5 may change over time and by geography; consequently, use of PM2.5 level alone may underestimate risk.54 Fifth, indoor air pollution was not accounted for in this study. Sixth, although we controlled for as many covariates as possible and adjusted for city variations, residual confounding may remain, which could bias the estimated association.Nonetheless, this study has several limitations that should be noted. First, like most retrospective studies, the results rely on the accuracy of the recorded data from multiple databases. Second, although time-dependent analyses allowed for capturing the exposure after KT, the most updated annual mean PM2.5 were independently associated with increased risk of acute rejection, graft loss, and death. Our findings suggest that efforts toward cleaner air may be associated with decreased burden of adverse outcomes after KT. In clinical practice, suggesting that recipients of KTs reside in areas with lower levels of PM2.5 concentration may be associated with improved transplant outcomes.To our knowledge, this is one of the first studies in a national cohort of recipients of KTs that found that increased levels of PM