P < 0.001, hazard ratio (HR) 2.8) and splicing and truncating groups . Sensorineural hearing loss was detected in 65.1% of male patients, while hearing survival periods showed a highly significant difference between the non-truncating and truncating groups . In female patients, approximately 20% developed kidney failure at the median age of 50.2 years. The kidney survival was significantly different between the non-truncating and truncating groups . Our findings support the presence of genotype–phenotype correlation not only in male patients but also in female patients with XLAS.The genotype–phenotype correlation of the X-linked Alport syndrome (XLAS) has been well elucidated in males, whereas it remains unclear in females. In this multicenter retrospective study, we analyzed the genotype–phenotype correlation in 216 Korean patients  with XLAS between 2000 and 2021. The patients were divided into three groups according to their genotypes: the non-truncating group, the abnormal splicing group, and the truncating group. In male patients, approximately 60% developed kidney failure at the median age of 25.0 years, and kidney survival showed significant differences between the non-truncating and truncating groups ( Although previous studies suggest a prevalence of approximately 1/50,000 for AS, a recent publication reported significantly higher estimated frequencies of predicted pathogenic COL4A4-COL4A5 variants2. While the most common form of AS inheritance is the autosomal dominant form, which affects about 1 in 106 individuals, the X-linked AS (XLAS) form, which is a more severe phenotype, affects approximately 1/2320 of the population2.Alport syndrome (AS) is a progressive inherited nephropathy that leads to kidney failure and is accompanied by sensorineural hearing loss (SNHL) and ocular abnormalities, such as lenticonus and fleck retinopathy2 or treatment by kidney replacement) (CKD G5)3 by the age of 40 years, with a median age of 25 years4, and exhibit a very strong genotype–phenotype correlation. For example, truncating variants  show a severe phenotype that leads to the earlier development of kidney failure and hearing loss, whereas non-truncating variants (missense and in-frame variants) present a milder phenotype. In the case of splice variants, the overall phenotype was intermediate6. The development of hearing loss and ocular changes showed a trend similar to that of kidney prognosis7. In female patients with XLAS, no genotype–phenotype correlations have been observed as they generally present favorable outcomes, with approximately 25% of cases progressing to CKD G5 throughout their lifetime, with a median age of 65 years9. However, a recent systematic review article10 reported a correlation between severe genotypes and proteinuria. Missense variants are the most common (60%) variants in male patients, and the overall phenotype is favorable, but the prognosis is variable, ranging from mild to severe11. The majority (about 85%) of missense variants are found in the intermediate collagenous domain, and glycine (Gly) substitutions constitute 95% of these variants 11. Glycine substitution adjacent to a noncollagenous (NC) interruption site is known to often be hypomorphic with a milder phenotype12, and other mitigating factors associated with variant location and affected residue have been suggested2. Histologically, the positive expression of the type IV collagen α5 chain in immunofluorescence staining tends to show a milder phenotype12. Here, for the first time, we analyzed the genotype–phenotype correlation in Korean patients of both sexes with XLAS.In male patients, 90% develop chronic kidney disease (CKD) with a glomerular filtration rate (GFR) category 5  affected family members with the same COL4A5 variants as the proband. Therefore, the number of analyzed subjects differed for each parameter because of the missing variable data of the affected family members. All patients and their affected family members analyzed in this study were Korean.This retrospective study was conducted at 12 medical centers in Korea. A total of 124 probands  diagnosed with XLAS between September 2000 and June 2021 were enrolled. The diagnosis of XLAS was primarily based on the detection of pathogenic 13 for patients under 18 years of age and the CKD Epidemiology Collaboration 2021 formula14 for patients aged 18 years and older. CKD stage was determined using the Kidney Disease: Improving Global Outcomes (KDIGO) CKD classification3. Asymptomatic urinary abnormalities (AUA) were defined as the presence of microscopic hematuria and/or proteinuria, detected incidentally during school screening or routine laboratory findings during hospital visits, without any accompanying subjective symptoms. Nephrotic syndrome (NS) was defined as nephrotic-range proteinuria (first morning urine protein to creatinine ratio (UPCR) ≥ 2.0 mg/mg or ≥ 3 + dipstick) and serum albumin < 3.0 g/dL according to the KDIGO 2021 guideline15. The occurrence of hearing impairment was defined as subjective symptoms or according to pure tone audiometry results based on the World Health Organization classification16. Patients with other potential causes of hearing impairment, such as ear infections or medications, were excluded from the analysis. Ocular lesions included maculopathy, lens abnormalities, corneal opacities, cataracts, myopia, keratoconus, and astigmatism18.The estimated GFR (eGFR) was calculated using the creatinine-cystatin C-based Schwartz 2012 equationThis study was approved by the institutional ethics committee of each hospital, including the Seoul National University Bundang Hospital, Seoul National University Children’s Hospital, Asan Medical Center, Chonnam National University Hospital, Chungnam National University Hospital, Ewha Womans University Hospital, Inha University Hospital, Korea University Hospital, Kyungpook National University Hospital, Pusan National University Yangsan Hospital, the Catholic University of Korea, Bucheon St. Mary’s Hospital, and Wonju Severance Christian Hospital, which waived the need for informed consent because only retrospective study data was collected. All procedures were performed in accordance with the Declaration of Helsinki.COL4A5 in most probands, except for four female probands in which targeted exome sequencing (TES) (three patients) and whole-exome sequencing (WES) (one patient) were used. Family members were screened using Sanger sequencing if they presented with clinical symptoms related to AS, such as hematuria, proteinuria, CKD, or hearing loss. The detailed procedures of Sanger sequencing19, TES20, and WES21 have been described in previous literature. Sequences were compared with the reference mRNA sequences (GenBank Accession: NM_000495.4). The interpretation of variants followed the American College of Medical Genetics and Genomics and the Association for Molecular Pathology guidelines, and variants classified as pathogenic or likely pathogenic were considered disease-causing variants . Descriptive statistics, including the median (interquartile range [IQR]) or frequency counts (percentage), were used to describe the sample population. Categorical variables were analyzed using the Chi-square test or Fisher’s exact test. Continuous variables were compared using the Kruskal–Wallis test or the Mann–Whitney U test. The Kaplan–Meier method and the log-rank statistic were used to present the occurrence of events (age at CKD G5 and age at detection of SNHL). The hazard ratio (HR) was analyzed using the Cox proportional hazards model. Robust statistical tests were used for the comparison between groups and intrafamilial correlationsThe detailed clinical kidney presentations and outcomes are summarized in Table In male patients, UPCR at the initial hospital visit at a median age of 8.9 (IQR 4.1–14.3) years was 1.6 mg/mg (IQR 0.5–4.0 mg/mg), and during follow-up, almost all patients except for one developed overt proteinuria (UPCR > 0.2 mg/mg). More than 90% of female patients developed overt proteinuria during follow-up. All patients exhibited hematuria. Treatment with renin-angiotensin system inhibitors (RASi) was initiated in all male patients at a median age of 9.5 years, except for two patients already in CKD G5 at the initial presentation. Nearly 90% of the female patients started taking RASi at the same median age as the male patients.Approximately 60% of male patients had reached CKD G5 at the median age of 25.0 ] 23.5–26.5) years, which was estimated by the Kaplan–Meier method Fig. , and neaKidney biopsy was performed in 52.3% (68 of 130 patients) of male patients at a median age of 10.4 (IQR 7.1–14.3) and 41.9% (36 of 86 patients) of female patients at a median age of 10.6 (IQR 7.0–22.9) years. The pathological diagnosis was AS in 59 (86.8%) male and 20 (55.6%) female patients, while the remaining patients were diagnosed with immunoglobulin A nephropathy, mesangial proliferative glomerulonephritis, or thin basement membrane disease. On the second biopsy, AS was diagnosed in four male and three female patients.The expression of the type IV collagen α5 chain was examined by immunofluorescence microscopy in 23 male and 17 female patients. In male patients, the expression was completely absent in 17 (73.9%), weak in 3 (13.0%), and normal in 3 (13.0%) patients. In female patients, 8 (47.1%) showed a mosaic pattern, 7 (41.2%) showed a normal pattern, and 2 (11.8%) showed a total loss.In male patients, 65.1% developed SNHL at the median age  of 19.9 (95% CI 13.8–26.0) years, while 14.1% of female patients developed SNHL at the median age of 53.4 (95% CI 47.5–59.2) years, which was estimated by Kaplan–Meier analysis  had missense variants, 23 (18.5%) had abnormal splicing, 19 (15.3%) had nonsense variants, 21 (16.9%) had short frame-shifting insertion or deletion variants, and 5 (4.0%) had other types of variants Table . Among tP = 0.023, odds ratio [OR] 3.3), and AUA was significantly less prevalent  in Group 3 patients when compared to Group 1 or 2 patients  and between Group 2 and Group 3 , which was estimated by Kaplan–Meier analysis. However, there was no difference between Groups 1 and 2. The kidney outcomes according to variant type are described in Table When stratified according to variant types, approximately 50% of Group 1 patients and 70% of Group 3 patients developed CKD G5 at the median age  of 30 and 20 years, respectively. The kidney survival period showed a significant difference between Group 1 and Group 3  did not affect the severity of the kidney phenotypes. Furthermore, the difference in the amino acid substitution for Gly did not correlate with the kidney phenotypes (data not shown).In 15 families, there were at least two (between two and four) male patients who progressed to CKD G5. Intrafamilial homogeneity in CKD progression (less than 15 [0–10.3] years of age at CKD G5) was observed in 13 families. Conversely, intrafamilial heterogeneity (15 or more [between 16 and 22.9] years of age at CKD G5) was observed in the remaining two families.P < 0.001, OR 7.6 [95% CI 2.3–24.8])  and in Group 2 than in Group 1 . However, there was no difference between Groups 2 and 3.  and in Group 2 than in Group 1 (P < 0.001) (Table SNHL was detected more commonly in Group 3 patients when compared to Group 1 patients (P = 0.029) and Group 2 (P = 0.005), and Group 3 patients presented AUA less frequently than other groups (P = 0.037) , as well as Groups 1 and 2  (Table The age of onset was lower in Group 3 than in Group 1 (7) Table . Fourtee7) Table .Table 4GThe prevalence of SNHL did not differ among the three groups. Ocular phenotypes were not analyzed owing to data limitations.23. In most previously reported studies23, cases with truncating variants developed CKD G5 earlier than cases with non-truncating variants. The kidney prognosis of male patients in our study was similar to that of a European study5. In contrast, the overall median age at CKD G5 in our study was earlier than that in the USA and Japanese cohort studies23  present with microscopic hematuria, with or without macroscopic hematuria, proteinuria can be recognized at an early stage of childhood, sometimes leading to nephrotic syndrome5. More than half of the patients with hearing loss required a hearing aid at the time of diagnosis, which means that the onset of hearing loss might be earlier. Hearing loss can occur even at preschool age in patients with severe variants32. Among female patients, 14.1% were found to have SNHL, which is higher than in the Japanese study (5.5%) but lower than in the European cohort (28%)9. The median age of the SNHL was 53.4 years, which is an earlier age than in the European cohort (more than 80 years). Despite these findings, there is limited research on hearing loss in females, so further studies are needed to better understand this condition. Moreover, early detection and proper management of SNHL are required to improve developmental, educational, and cognitive outcomes, particularly in children and adolescents33.SNHL was detected in 65.1% of male patients in the present study; male patients with missense variants developed hearing problems significantly later than those with other variants, which is consistent with previous reports9 showed that female patients with XLAS, showed far more benign kidney outcomes compared to male patients: only 12–15% and 30–40% of patients developed CKD G5 by 40 and 60 years of age, respectively, without genotype–phenotype correlations. However, in a smaller study of 24 female patients with XLAS34, patients with non-missense variants showed a higher frequency of early proteinuria and a higher risk of developing CKD. Moreover, a recent systemic review10 provided more supportive evidence for a correlation between severe genotype and proteinuria, with proteinuria likely leading to kidney failure in female patients. The review found that proteinuria detected before 15 years of age progressed rapidly to kidney failure10 . Even female patients with truncating variants had significantly poorer kidney survival than patients with other variants. These findings support the presence of genotype–phenotype correlation not only in male patients but also in female patients with XLAS.In this multicenter retrospective study of Korean patients with XLAS, missense variants (mostly Gly substitutions) were the most common variant in both male (46.2%) and female (46.5%) patients. Despite using RASi in most patients, 57.9% of male and 20.9% of female patients developed CKD G5 at a median age of 25.0 and 50.2 years, respectively. Furthermore, SNHL was detected in 65.1% of male and 14.1% of female patients at a median age of 19.9 and 53.4 years, respectively. Among male patients, those with truncating variants had a shorter kidney survival period and higher frequency of SNHL than those with other types of variants (Supplementary Tables.


This cohort study investigates the incidence of colorectal cancer and prevalence of adenomas and other precursor lesions among adults younger than 50 years in Austria. What is the trend in colorectal cancer (CRC) incidence among younger adults in Austria and what are the trends for adenomas, advanced adenomas, and serrated lesions in adults younger than age 50 years?In this cohort study of 296 170 patients who received a screening colonoscopy, CRC incidence decreased in Austria in those aged 50 years or older but increased among males aged younger than 50 years and decreased in females aged younger than 50 years. Adenoma prevalence increased across age groups, while advanced adenoma prevalence increased in patients aged younger than 50 years but decreased in those aged 50 years or older.This study found increasing incidence of CRC in younger adults, suggesting the importance of targeted screening efforts, especially for males aged younger than 50 years. Incidence of colorectal cancer (CRC) is increasing among younger adults. However, data on precursor lesions in patients who are asymptomatic, especially those aged younger than 50 years, are lacking.To analyze the prevalence and number needed to screen (NNS) for adenomas, advanced adenomas, and serrated lesions, as well as the incidence of CRC in patients older than age 20 years.This cohort study was conducted among 296 170 patients who received a screening colonoscopy within a national screening colonoscopy registry from 2012 to 2018 in Austria, including 11 103 patients aged younger than 50 years. CRC incidence was analyzed using data from Statistic Austria from 1988 to 2018. Data were analyzed in September 2021.The prevalence of adenomas and other lesions and the incidence of CRC in individuals aged 20 years or older were assessed.Among 296 170 patients included in the study , 11 103 patients (3.7%) were aged younger than 50 years and 285 067 patients (96.3%) were aged 50 years or older. Among patients younger than age 50 years, 1166 individuals  had adenomas and 389 individuals  had at least 1 advanced adenoma, while among those aged 50 years or older, 62 384 individuals  had adenomas and 19 680 individuals  had at least 1 advanced adenoma. Among 1128 males aged 40 to 44 years, 160 individuals  had at least 1 adenoma, and among 1398 females aged 40 to 44 years, 114 individuals  had at least 1 adenoma. The prevalence of adenomas for individuals aged 45 to 49 years vs 50 to 54 years was 490 of 2879 males  vs 8269 of 40 935 males  and 284 of 2792 females  vs 4997 of 40 303 females , respectively. Prevalence of adenomas changed from 61 of 498 individuals (12.4%) in 2008 to 150 of 1064 individuals (14.1%) in 2018 among those younger than 50 years and from 2646 of 12 166 individuals (21.8%) to 10 673 of 37 922 individuals (28.2%) among those aged 50 years and older. The prevalence of advanced adenomas changed from 20 individuals (4.0%) in 2008 to 55 individuals (5.2%) in 2018 in individuals younger than 50 years and from 888 individuals (7.3%) in 2008 to 2578 individuals (6.8%) in 2018 among those aged 50 years and older. Among individuals younger than age 50 years, CRC incidence per 100 000 individuals changed from 9.1 incidents in 1988 to 10.2 incidents in 2018 among males  and from 9.7 incidents in 1988 to 7.7 incidents in 2018 among females, with a nonsignificant AAPC . Among individuals aged 50 years or older, CRC incidence per 100 000 individuals changed from 168 incidents in 1988 to 97 incidents in 2018 among females , and 217 incidents in 1988 to 143 incidents in 2018 among males .In this study, CRC incidence decreased after 1988 in Austria among individuals older than 50 years, while among patients younger than 50 years, incidence increased among males but decreased among females. Prevalence of adenomas increased in all age groups, while advanced adenoma prevalence increased among patients younger than 50 years but decreased in patients aged 50 years and older. At the same time, an increase in mortality and incidence rates among younger patients was noticed.2Given that the incidence of CRC increases around age 50 years within a mean-risk population, screening programs have focused on this population so far. The American Cancer Society recommends that the age for individuals at mean risk undergoing first-time screening colonoscopy should be lowered to 45 years.3With the purpose of detecting and removing precancerous lesions, such as adenomas, within the same investigation, colonoscopy is the criterion standard for CRC screening. While having a higher risk of progression to CRC, adenomas are divided into nonadvanced (tubular adenomas <10 mm) adenomas and advanced  adenomas (AAs), and transition rates from AA to CRC were reported to greatly increase with age but were similar between male and female patients.4 In a study by Ferlitsch et al,5 the incidence of CRC and precursors in males aged 45 to 49 years was comparable with that of females 10 years older.In addition to age, patient sex should also have an influence on the age at which a screening colonoscopy is recommended given that several studies have found that male sex is an independent factor associated with CRC.6 showed that CRC among individuals aged 40 to 45 years was diagnosed at a more advanced stage compared with in 1990. This indicates a real increase of CRC incidence and not only a shift in age at diagnosis. Despite the evidence of an increase in CRC incidence among younger adults,8 data about the prevalence of precursor lesions, such as adenomas, among younger individuals, especially those without symptoms, are still missing.Meester et alTherefore, the aim of our study was to assess the prevalence of adenomas and AAs among younger adults without symptoms within the Austrian CRC screening program. Furthermore, the incidence of CRC within younger adults was evaluated and trends since 1988 were analyzed using data from Statistic Austria.STROBE) reporting guideline.This cohort study was approved by the local ethics committee of the Medical University of Vienna. All patients had to sign written informed consent giving permission for data submission. The study was conducted following the Strengthening the Reporting of Observational Studies in Epidemiology  was added to the report form in 2012. In 236 of 463 endoscopists participating in the quality assurance program (51.0%), participating physicians were using high-definition endoscopes. Further descriptions of this project have been reported elsewhere.Data were provided from 305 229 screening colonoscopies between 2008 and 2018, mostly involving patients aged 50 years and older. However, younger individuals were allowed to undergo a screening colonoscopy within this program if they were asymptomatic and the reason for the examination was patient fear of cancer. Patients with a positive family history, inflammatory bowel disease (IBD), or cancer symptoms were excluded from this study. Information regarding CRC incidence in Austria was provided by Statistic Austria for 1988 until 2018.Endoscopists with fewer than 30 screening colonoscopies  and examinations with poor bowel preparation (8499 examinations) were excluded from this study, resulting in 9059 exclusions. A total of 296 170 screening colonoscopies remained after exclusion for study analyses within the screening program.2 test to evaluate differences between groups. We divided all patients into age groups by steps of 5 years and calculated the prevalence of adenomas and AAs and the number needed to screen (NNS) for each group. AAs were defined as adenomas 10 mm or greater in size, with high-grade dysplasia, or with villous histology. Prevalences over time for adenomas and AAs were analyzed from 2008 to 2018. Information regarding serrated lesions, including sessile serrated lesions (SSLs) and traditional serrated adenomas (TSAs) were added to the colonoscopy report in 2012. Prevalence of serrated lesions was analyzed between 2012 and 2018. Austrian data on CRC incidence from 1988 to 2918 were provided by Statistics Austria. Piecewise linear regression models were fitted using the segmented R package version 1.2. The number of breakpoints was limited to 1. We used the average annual percentage change (AAPC) to analyze trends in the incidence of CRC and precursor lesions. Statistical significance was denoted as P ≤ .05. Analyses were conducted as 2-sided tests using R statistical software version 4.1.0 . Data were analyzed from January 2012 to December 2018.Patient characteristics were described using median and IQR and categorical variables by absolute and relative frequencies. We used the χA total of 296 170 patients underwent a screening colonoscopy within the Austrian quality assurance program between 2008 and 2018 and were included in this study . There were 11 103 patients (3.8%) aged younger than 50 years  and 285 067 patients (96.3%) aged 50 years or older  .Cecum was reached in 287 585 patients (97.1%). In 640 patients (0.2%), complications were registered, including 42 perforations (<0.1%). The median (IQR) detection rate was 21.4% (17.6-26.1%) for adenomas and 6.6% (4.2%-9.0%) for AAsData from Statistic Austria showed that CRC incidence per 100 000 individuals among males younger than 50 years changed from 9.1 incidents in 1988 to 8.5 incidents in 1998, 8.6 incidents in 2008, and 10.2 incidents in 2018 . Incidence per 100 000 individuals among females in the same age group was 9.7 incidents in 1988, 7.0 incidents in 1998, 7.8 incidents in 2008, and 7.7 incidents in 2018, with a nonsignificant AAPC . Among males older than 50 years, rates per 100 000 individuals changed from 217 incidents in 1988 to 220 incidents in 1998, 199 incidents in 2008, and 143 incidents in 2018 . Incidence per 100 000 female patients aged 50 years or older was 168 incidents in 1988, 166 incidents in 1998, 132 incidents in 2008, and 97 incidents in 2018 CRC incidence per 100 000 individuals among males aged 40 to 44 years changed from 14.4 incidents in 1988 to 15.1 incidents in 1998, 12.5 incidents in 2008, and 16.2 incidents in 2018, for a nonsignificant AAPC . In females in this age group, incidence per 100 000 individuals was 11.7 incidents in 1988, 10.2 incidents in 1998, 11.9 incidents in 2008, and 16.5 incidents in 2018, for a nonsignificant AAPC . Among individuals aged 45 to 49 years, the incidence per 100 000 individuals changed from 92 incidents in 1988 to 77 incidents in 2018 among males  and from 84 incidents in 1988 to 53 incidents in 2018 among females, for a nonsignificant AAPC . Among males aged 50 to 54 years, incidence of CRC per 100 000 individuals changed from 112 incidents in 1988 to 155 incidents in 2018 . Among females, incidence per 100 000 individuals was 95 incidents in 1985 and 134 incidents in 2015 . Among individuals aged 55 to 59 years, incidence per 100 000 individuals changed from 213 incidents in 1988 to 223 incidents in 2018  among males and from 139 incidents in 1988 to 135 incidents in 2018  among females .P < .001). Among patients younger than age 50 years, 1166 individuals  had adenomas, whereas among patients aged 50 years or older, 62 384 individuals  had adenomas (P < .001). Among 5359 males younger than age 50 years, 710 individuals  had adenomas, and among 5744 females younger than age 50 years, 456 individuals  had adenomas. In patients aged 50 years or older, 62 384 individuals overall  had adenomas, while 38 384 of 139 998 males  and 24 000 of 145 069 females  had adenomas. Among individuals younger than age 50 years, the prevalence changed from 61 of 498 individuals (12.4%) in 2008 to 150 of 1064 individuals (14.1%) in 2018 overall, 38 of 226 males (16.8%) in 2008 to 97 of 512 males (19.0%) in 2018, for a nonsignificant AAPC , and 23 of 272 females (8.5%) in 2008 to 53 of 552 females (9.7%) in 2018, for a nonsignificant AAPC . Among individuals aged 50 years or older, the prevalence changed from 2646 of 12 166 individuals (21.8%) in 2008 to 10 673 of 37 922 individuals (28.2%) in 2018 overall, 1626 of 5840 males (27.8%) in 2008 to 6313 of 18 461 males (34.2%) in 2018 , and 1020 of 6326 females (16.1%) in 2008 to 4360 of 19 461 females (22.4%) in 2018   had at least 1 adenoma; 39 094 males  and 24 456 females  had adenomas (to 2.5%) .Among 2526 individuals aged 40 to 44 years, adenomas were found in 274 individuals  overall, 114 of 1398 females , and 160 of 1128 males  . Within Among 5671 individuals aged 45 to 49 years, 774 individuals overall , 490 of 2879 males , and 284 of 2792 females  had adenomas . Among mAmong 81 238 individuals aged 50 to 54 years, 8269 of 40 935 males  and 4997 of 40 303 females  had adenomas . In thisP < .001). Among individuals younger than age 50 years, 389 individuals overall , 229 males  and 160 females  had AAs. Among individuals aged 50 years or older, 19 680 individuals overall , 12 042 males , and 7638 females  had at least 1 AA. The proportion of patients with an AA detected differed statistically significantly by age group (<50 vs ≥50 years: P < .001).AAs were detected in 20 069 patients overall , 12 271 males , and 7798 females   in 2008 to 55 individuals (5.2%) in 2018 overall, 21 males (9.3%) in 2008 to 42 males (8.2%) in 2018, and 7 females (2.5%) in 2008 to 2 females (3.9%) in 2018. Among patients aged 50 years and older, the prevalence changed from 888 individuals (7.3%) in 2008 to 2578 individuals (6.8%) in 2018 overall, 329 females (5.2%) in 2008 to 817 females (4.2%) in 2018, and 555 males (9.5%) in 2008 to 1514 males (8.2%) in 2018 .Among patients aged 40 to 44 years, AAs occurred in 98 individuals overall , 66 males , and 32 females . Within the age 45 to 49 years group, AAs occurred in 144 males  and 112 females . In this age group, AAs occurred in 6 males (5.5%) in 2008 and 11 males (4.0%) in 2018 and 4 females (3.0%) in 2008 and 9 females (3.1%) in 2018.In patients aged 50 to 54 years, 2374 males  and 1451 females  had AAs. Within this age group, 77 males (5.3%) had at least 1 AA in 2008 compared with 249 males (4.6%) in 2018, while 45 females (3.0%) in 2008 and 169 females (3.1%) in 2018 had at least 1 AA. Among patients aged 55 to 59 years, the prevalence changed from 96 males (7.6%) in 2008 to 241 males (6.3%) in 2018 and 59 females (4.3%) in 2008 to 120 females (3.0%) in 2018.Serrated polyps, including SSLs and TSAs, were detected in 5410 individuals (1.8%) overall, 165 patients aged younger than 50 years (1.6%), and 5245 patients aged 50 years or older (1.8%). Among patients younger than age 50 years, 79 males (1.6%) and 86 females (1.7%) had serrated polyps, while among those aged 50 years or older, serrated lesions were detected in 2578 males (1.8%) and 2667 females (1.8%).Within the ages 45 to 49 years group, 110 individuals overall (1.9%), 58 females (2.1%), and 52 males (1.8%) had serrated lesions. Among individuals aged 50 to 54 years, 1462 individuals overall (1.8%), 685 females (1.7%), and 777 males (1.8%) had serrated lesions.From 2012 to 2018, the prevalence of serrated lesions changed from 241 of 24 109 patients (1.0%) to 1325 patients (3.4%) overall, 114 of 12 653 females (0.9%) to 700 females (3.5%), and 114 of 11 456 males (1.0%) to 626 males (3.3%). Among patients younger than age 50 years, prevalence from 2012 to 2018 changed from 10 of 861 patients (1.2%) to 26 patients (3.0%) overall, 5 of 409 males (1.2%) to 21 males (4.1%), and 5 of 452 females (0.9%) to 17 females (3.1%). Among individuals aged 50 years or older, the prevalence from 2012 to 2018 changed from 232 of 23 248 individuals (1.0%) to 1289 individuals (3.4%), 110 of 11 047 males (1.0%) to 609 males (3.3%), and 110 of 12 201 females (0.9%) to 681 females (3.5%) .12 found that the miss rate for adenomas larger than 10 mm was 5.8%, showing that high-risk lesions have a relatively small risk for not being detected during colonoscopy. In our study cohort, we additionally found that the prevalence of AAs and the incidence of CRC were increasing, which cannot be explained only by quality improvement of screening colonoscopy. However, the prevalence of AAs, which have a higher risk of progression to CRC, changed from 4.0% in 2008 to 5.2% in 2018 among patients younger than age 50 years, while it decreased from 7.3% to 6.8% in patients aged 50 years or older.This large cohort study of 296 170 screening colonoscopies among patients who were asymptomatic, including 11 103 patients (3.7%) younger than age 50 years, found an increased prevalence of adenomas among younger adults since 2008. However, this trend was seen in all age groups. Therefore, these findings may not necessarily reflect a general increase in the presence of adenomas within younger adults but rather an improvement in screening quality and adenoma detection rate in general, as well as better equipment, which may be associated with higher numbers of detected adenomas. A study by Ahn et alDespite the increase in adenomas, the incidence of CRC in Austria decreased from 1988 to 2018 in males and females aged 50 years and older. This is likely associated with trends of the opportunistic screening program in Austria. The incidence in males younger than age 50 years increased. The incidence per 100 000 individuals of CRC in females younger than age 50 years changed from 9.7 incidents in 1988 to 7.7 incidents in 2018. However, the AAPC within this group was −0.2%, which suggests that the incidence in this group decreased when every year of this period is statistically taken into account.Looking at different age groups, an increase of CRC incidence was noticed within males aged 40 to 44 years, while the AAPC within males aged 45 to 49 years declined. Within females aged 40 to 44 years, we also found an increase in CRC incidence, although the AAPC of 0.1% was not statistically significant, while the incidence within females aged 45 to 49 years decreased, although the AAPC of −0.9% was not statistically significant. In Austria, the age to start with screening colonoscopy was 50 years during the period analyzed in this study. Nevertheless, an increase in CRC incidence in younger adults was greater within males aged 40 to 44 years.However, in 10.5% of patients younger than age 50 years, adenomas were found. The NNS of 9 represents that 9 patients younger than age 50 years need to be screened to find 1 adenoma. The NNS in those aged 45 to 49 years was almost comparable with that of those aged 50 to 54 years in this study.5 showed that the prevalence and NNS of AA in women were comparable to those in women aged 10 years younger. Our study found that the prevalence was higher and the NNS lower within males aged 40 to 44 years  than that among males aged 45 to 49 years . Thus, the NNS within males aged 40 to 44 years was comparable to that in females aged 20 years older (aged 60-64), with a prevalence of 5.5% and an NNS of 18.A study by Ferlitsch et al13 CRC incidence increased within individuals aged 20 to 49 years, especially those aged 20 to 39 years. However, the reason for undergoing screening colonoscopy within those patients is unknown, and the trend of increasing incidence may be due to a selection bias. Furthermore, no increase in mortality was found. A study by Sehgal et al14 showed that a colonoscopy was associated with a decrease in the risk of CRC by 50% when given at ages 45 to 49 years and of 68% when given at ages 50 to 54 years. However, most study patients were referred to colonoscopy due to symptoms, so outcomes associated with lowering the age to start screening colonoscopy within this age group remain unclear.Some studies reported an increase of CRC in younger adults. In a study by Vuik et al,15 However, a limitation of our study was that we did not have data regarding lifestyle factors or comorbidities.To our knowledge, our study is the first to evaluate trends in the incidence of CRC and precursor lesions within a large cohort of younger adults without symptoms, with a total of 11 103 screening colonoscopies in patients younger than age 50 years. Patients with IBD, cancer or CRC symptoms, or a positive family history of CRC were excluded from the study. The main reason for screening within those patients was patient fear of cancer. Additionally, the reason for the increasing prevalence of precursor lesions among younger adults is still unknown. Lack of physical activity, obesity, and other lifestyle factors are associated with an increased risk of CRC and adenomas.Moreover, our data also showed an increased incidence of serrated lesions, including SSLs and TSAs, from 2012 to 2018 in individuals aged younger than 50 years and 50 years or older. However, serrated legions were found in a total of 165 patients younger than age 50 years, not allowing for conclusions regarding the AAPC in this group. Starting in 2012, we have included sessile and traditionally serrated lesions in our report forms. Through our regular benchmark distributions and educational sessions, there has been an increasing emphasis on serrated lesions, which may account for the observed increase over the years.The prevalence for adenomas in males aged 40 to 44 years in this study was 14.0%, suggesting that a screening colonoscopy finds an adenoma in every seventh male patient. Individuals aged 45 to 49 years already have access to screening colonoscopy in many countries. However, the NNS of 6 within males in this group is almost comparable with that of males aged 40 to 44 years, but those individuals do not have easy access to screening. The prevalence of AAs in males was higher within those aged 40 to 44 years than those aged 45 to 49 years, which raises the question of whether we should start at age 40 years, especially in males. Our data show that incidence within males increased more than that in females and the sex-specific gap is now even higher. These findings suggest that not only age but also sex should be considered for further recommendations. Our findings suggest that screening at age 40 years for males and age 50 years for females warrants thoughtful consideration.16 screening colonoscopy reduced the risk of CRC, but there was no effect on CRC mortality. One reason could be that it takes more time to see the effects of screening on CRC mortality. However, that study included only patients older than age 50 years, and studies evaluating the effect of screening colonoscopy on CRC incidence and mortality in younger adults are still lacking.Despite increasing incidence of adenomas and AAs among younger adults, the incidence of CRC increased only slightly among younger adults in general, which was mostly due to increasing incidence within males. In a 2022 study by Bretthauer et al,Given that a screening colonoscopy is a procedure that depends on operator performance, quality improvement of screening should continue. Organized screening programs should be established in all countries with the aim of offering high-quality screening endoscopy and preventing progression to colorectal cancer.Our study has several limitations, including that it is primarily a descriptive study. Furthermore, this study did not analyze factors associated with CRC. We lacked data regarding comorbidities, such as smoking, diabetes, fatty liver disease, or body mass index. Therefore, further studies are necessary to evaluate the reasons for increasing incidences of CRC in younger adults, particularly males. Additionally, serrated lesions were added to our report form in 2012, so data on these types of lesions from 2008 to 2012 are missing. Given that the total number of SSLs and TSAs was quite low, another limitation of this study is that we did not have the AAPC of the prevalence of serrated lesions.This cohort study found that the prevalence of adenomas and AAs increased among younger adults in Austria. The NNS of 18 for the prevalence of AAs in males aged 40 to 44 years was lower than in males aged 45 to 49 years (NNS = 20). CRC incidence has increased since 1988 in males but not females younger than age 50 years. These findings suggest that patient sex should be considered as a factor when determining the age for starting screening in further recommendations. Based on this study, screening should have started at age 40 years for males and age 50 years or even later, around age 55 years, for females.


There is an increasing aging population. The goal of our study was to look at how frailty impacts discharge from acute hospitalization as well as long term function at 1 year following their burn.After IRB approval, all patients over age 50 who were admitted September 2019-2021 were considered for enrollment. Exclusion criteria included, a non-survival burn and underlying co-morbidities that would affect long term outcomes independent of a burn. Data collected included: age, gender, TBSA, surgical intervention, Canadian Health and Aging Frailty Score (CFS), discharge disposition, Barthel index, and a functional questionnaire. Follow-up phone calls were completed 6 month-1.5 post.Follow up data obtained via phone call for 30 subjects; the average age was 71 (10.8) years old with 8.6 % (16.5) TBSA, with a CFS average of 2.89 (1.5). 20 (40%) were lost to follow-up. 90 % of patients returned to their baseline and prior living environment. Of the patients who did not return to their prior functional status all had impaired Bartel index prior to their burn injury as well as higher CFS >5, as well as longer LOS (26 day), and were older. Discharge was assessed based on enrollment sample size (n=50), average age 71 yo (10.4), burn size of 7.4% TBSA (13.2), CFS of 3.4 (1.64), and length of stay 20 (25.09) days. 13 patients (26%) were discharge to an IRF, 10 patients (20%) to a SNF, and 27 patients (54%) to home. Patients who discharge home had Lower CFS 2.2, lower age, 69 y.o., and lower TBSA 5.6% compared to patients who were discharged to SNF and IRF. Patients who were discharge to an IRF were older (77yo), had larger TBSA (13.5) and a lower CFS (3) compared to patients who were discharged to a SNF. 80% of patients who discharge to a IRF returned to their prior level of function compared to 40 % who discharged to a SNFThis work helps structure discussions with the geriatric population about expectations to return to their prior level of function. Frailty appears to be associated with outcomes and discharge as lower CFS, older age and larger TBSA were more likely to discharge to IRF and recover to their baseline compared to patients with higher frailty score who were more likely to discharge to a SNF despite younger age and smaller TBSA. This shows that even relatively small burns (8% TBSA) in the elderly can affect ability to care for oneself and ability to go into the community 1 year after their injury.This can be used by physicians and therapists to aide in discussions about discharge from the hospital as well as long term outcomes expected following their burn injury.


Male breast cancer (MBC) is one of the rare malignancies that account for less than 1% of all malignancies in males. However, the clinicopathological characteristics of MBC are not entirely similar to female breast cancer; but still, it is treated in line with the female breast cancer protocols.To retrospectively analyse trends in MBC as to its distribution, presentation, treatment, and outcome.A total of 106 patients with MBC from 1991 to 2020 were analysed retrospectively. Frequency distribution analysis of the demographic and clinicopathological data and treatment variables was done.Median age of presentation was 57 years; ranging from 30 to 86 years. Either of the sides was almost equally affected with an R: L ratio of 1.2:1. The average duration of complaint was 26.2 months (range 1–240 months). History of gynaecomastia was noted in 18 patients, significant benign prostate hypertrophy in 13, and hypertension needing medical treatment in 14 patients. The majority of the patients were smokers (72/106) and alcoholics (43/106). Five patients reported positive family history. 21 patients had metastatic disease at presentation and received palliative treatment. Stage II was seen in 36.8%, stage III in 43.4%, and stage IV in 19.8% of patients. Node positives were 63.2%. Pathology was invariably (90.5%) infiltrative ductal carcinoma. Radiation was administered in 85.8% of the patients, chemotherapy in 72.6% of patients, and hormonal treatment was given in 47.2% of patients. The median overall survival (OS) was 78 months. OS at 5 and 10 years was 78% and 58% respectively.Despite the possibility of MBC being apparent at an early stage, patients present with locally advanced disease. Radical surgery with adjuvant/neoadjuvant chemotherapy and adjuvant radiotherapy remains the gold standard. Cancer education campaigns must be run to catch the early disease and to radically treat the disease. Male breast cancer (MBC) occurs all over the world, but the highest incidence is seen in sub-Saharan countries . MBC is There are some lacunae with regard to the ideal management of MBC and its treatment has been extrapolated to a great extent from research led on female breast cancer. Studies that focus on MBC should subsequently recommend the standard of care, but till now they have not been able to address all important questions regarding MBC. There are no randomised studies because of the low number of patients continued in any institution and retrospective studies are additionally not very many. Initial trials proposed that MBC had a poor prognosis in comparison to breast cancer in females –9. The MIndications for postmastectomy radiotherapy (PMRT) in MBC are in accordance with the guidelines for female breast cancer. PMRT seems to decrease locoregional recurrence (LRR) in MBC; in any case, the effect on overall survival (OS) is unknown –13. Few A total of 8,154 breast cancer cases were registered from 1991 to 2020, out of which 106 MBC cases were identified constituting 1.3% of total breast cancer cases. These were retrospectively analysed for patient‑related characteristics such as age, comorbidity, family history, tumour size, nodal status, stage, histology, oestrogen/progesterone, and human epidermal growth factor receptor 2 (HER‑2) status  and 2. Ap < 0.05. Statistical analysis was performed using Statistical Package for Social Sciences software’s recent version.PMRT was delivered to patients with a T3 tumour, close/positive margins, and positive nodes. Standard two tangential opposed fields were used to irradiate the chest wall (CW). Radiotherapy was delivered with 50 Gy in 25 fractions over 5 weeks to CW. The dose was prescribed at the midpoint of the central axis. For supraclavicular fossa, the dose delivered was 50 Gy in 25 fractions over 5 weeks with a single‑incident field. Radiation therapy was delivered using a Cobalt-60 machine. Tamoxifen was prescribed to estrogen receptor (ER)/progesterone receptor (PR)‑positive patients for 5 years as per female breast cancer guidelines and letrozole which was prescribed for a further 3–5 years in females, was not prescribed in MBC cases [2, Methotrexate 40 mg/m2, and 5‑FU 600 mg/m2) in 24.7% patients in the early part of the study period till 1996, FAC  in 49.4% patients till 2008, and anthracyclines and taxanes in 25.9% patients from 2008 afterwards , respectively (p = 0.022) (p < 0.05 (significant). 10-year DFS for stage II was 72% versus 41%, for stage III – 55% versus 26% and for stage IV – 19% versus 11%, with and without PMRT, respectively, p < 0.05 (significant). Hormonal therapy also significantly improved DFS and OS at 10 years  (The median follow‑up was 60 months (range of 4–278 months). For the entire cohort, LRR occurred in 9.4% and distant metastasis in 19.8% of patients. PMRT reduced LRR, and improved OS and DFS in low‑ as well as high‑risk patients. For the entire cohort, the median DFS was 43 months, and the 5 and 10‑year survival rates were 78% and 58%, respectively. The median OS was 78 months. DFS at 10 years was 54% and 24% with and without PMRT (ectively . OS at 1= 0.022) . The OS = 0.022) . Statistctively) . Only 1 et al [et al [et al [et al [et al [et al [The incidence of MBC patients in the present study was 1.3%, which was slightly higher than the worldwide average of 1%, but it is in close relation to the Indian study from Patna, Bihar by Pawar et al . Howeverl [et al  , but there was no survival difference (p = 0.72) [In our institution, PMRT is prescribed to patients when indicated like in T3/T4 tumour, close/positive margins, and positive nodes . In thiset al.  from Canet al. , 34, 35.et al. , 4.7% wi. [et al , 6.9%–10l [et al , 11.3% wl [et al  from Turl [et al . Cutuli l [et al  reportedl [et al  reportedl [et al  demonstrl [et al –43. The  = 0.72) . Our out = 0.72) , 42.p = 0.66). Additionally, OS at 10 years with and without neoadjuvant chemotherapy was 64% and 59%, respectively (p = 0.77). A total of 77 (72.6%) patients went through chemotherapy in this study. Recurrence rates were lower in patients who got both chemotherapy and hormonal treatment contrasted to chemotherapy alone 35% versus 78%. Giordano et al [Neoadjuvant chemotherapy showed no advantage in DFS or OS. DFS at 10 years with and without neoadjuvant chemotherapy was 62% and 57%, respectively  were getting hormonal treatment. Of four different studies with a limited number of patients and follow-ups from India, three announced that ER/PR was communicated in 77%–89% of MBC patients –30, 46. The strength of our study is that it is the largest data set from India on MBC with a good median follow‑up of 60 months in all patients treated on a cobalt machine with conventionally fractionated radiotherapy. The recurrence rate in MBC patients in this study is equivalent to female BC patients , 48. TheMBC patients present at a locally advanced stage with a long median duration of symptoms despite the possibility of being diagnosed at an early stage. Radical surgery with chemotherapy and post-mastectomy radiation treatment remains the standard practice as in the females. Patients in this study were younger as compared to the Western series. PMRT reduced the LRR rate in MBC. PMRT and hormonal therapy significantly improved DFS and OS in MBC patients. However, ER/PR-positive patients might have been responded better to hormonal treatment. Chemotherapy had no impact on DFS and OS. However, future prospective trials with a large sample size may enlighten the path to successful treatment with minimal recurrence. This study necessitates health education and cancer awareness in the rural parts of India as 70% of the population of India belongs to a rural background. So, effective cancer education campaigns and/or programs must be run for early presentation and better cure of MBC.Nil.Nil.


Survival significance of the number of positive lymph nodes (LNs) in parotid adenoid cystic carcinoma (ACC) remains unknown; thus, this study aimed to determine the impact of the number of positive LNs on the prognosis of parotid ACC.Patients with surgically treated parotid ACC were enrolled from the SEER database. The number of positive LNs was analyzed using three models , its hazard ratios on disease specific survival (DSS) and overall survival (OS) were assessed using univariate and multivariate Cox analyses.A total of 1,689 patients were included. In all models, the number of positive LNs was independently related to DSS and OS, model 3 had the highest C-index for DSS [0.83 (95% CI: 0.81–0.85)] and OS [0.82 (95% CI: 0.80–0.84)]. Compared with the 0/1 positive LN group, the 2–4 positive LN group had an HR of 2.81 (95% CI: 1.73–4.56) for DSS and 2.36 (95% CI: 1.58–3.54) for OS. The 5+ LN group had an HR of 20.15 (95% CI: 7.50–54.18) for DSS and 14.20 (95% CI: 5.45–36.97) for OS. No overlap existed in the 95% CI of the HR.The three prognostic categories based on the number of positive LNs (0/1 vs 2–4 vs 5+) could stratify the DSS and OS in parotid ACC without overlap. Adenoid cystic carcinoma (ACC) is one of the most common malignancies among all parotid tumors. It is characterized by distant metastasis and perineural infiltration , making Novel LN stagings have been proposed based on the number of positive LNs and/or LN size , 7, in wTherefore, this study aimed to clarify the impact of the number of positive LNs on the prognosis of parotid ACC.th American Joint Committee on Cancer (AJCC) classification, extranodal extension (ENE), distant metastasis, operation type, radiation, chemotherapy, number of positive LNs, and follow-up were extracted and analyzed.All data was obtained from the Surveillance, Epidemiology, and End Results database, which provides information on cancer statistics to reduce the cancer burden among the United States population . The proEthical approval was not required because the data is publicly accessible.The disease grade was classified into low, moderate, and high. A low grade was defined as well differentiated; a moderate grade was defined as moderately differentiated; and a high grade was defined as poorly differentiated or undifferentiated. The tumor size was determined based on the Tumor Size Summary (2016+), Collaborative Stage tumor size (2004–2015), and extent of disease (EOD) 10-size (1988–2003). The tumor extension was defined as extracapsular invasion and evaluated based on the Derived EOD 2018 T (2018+), Collaborative Stage extension (2004–2015), and EOD 10-extent (1988–2003). The tumor stage was extrapolated based on the tumor size, tumor extension, and Derived AJCC classification. ENE was formulated based on Derived EOD 2018 N (2018+), Derived AJCC classification, RX Summ–Scope Reg LN Sur (2003+), EOD Regional Nodes (2018+), CS lymph nodes (2004–2015), and EOD 10 - nodes (1988–2003). Distant metastasis was confirmed using the Derived AJCC classification. The type of operation consisted of non-total and total parotidectomy and was decided based on the RX Summ–Surg Prim Site (1998+). The number of positive LN was calculated based on the Regional nodes examined (1988+), Regional nodes positive (1988+), and RX Summ–Scope Reg LN Sur (2003+). The time to surgery (TTS) was defined as the duration between the diagnosis and treatment.Missing data patterns were evaluated on whether they occur at random using the method previously introduced and imputed using multiple imputation by fully conditional specifications, which was implemented using multiple imputation by chained equations , 9.The primary outcome variable was disease-specific survival (DSS) and overall survival (OS). The time of DSS was calculated from the date of surgery to the date of cancer-caused death or last follow-up. Meanwhile, the time of OS was calculated from the date of surgery to the date of overall death or last follow-up.Three models were constructed using different cutoffs for the number of positive LNs to detect the optimal cutoff. In model 1, the impact was compared between the 0 and 1+ groups. In model 2, the impact was analyzed among the 0, 1, 2, 3, 4, 5, and 6+ groups. In model 3, the impact was determined among the 0/1, 2–4, and 5+ groups.via the Kaplan-Meier method and compared with the logrank test, univariate Cox analysis was used to assess the variables that affect survival significantly. Subsequently, these variables were further validated through multivariate Cox analysis for detecting independent factors. The three models were evaluated using C-index. All statistical analyses were performed using R program version 3.4.3. Statistical significance was set at p < 0.05 (two-sided).In all three models, estimated survival functions were generated A total of 1,689 patients were included with a mean age of 52 ± 17 years, in which 665 (39.4%) were males and 1,024 (60.0%) were females. Caucasian patients accounted for 76.1% of the total population. During the initial treatment, 59.0% of the patients were married. Low-, moderate-, and high-grade disease occurred in 427 (25.3%), 611 (36.2%), and 446 (26.4%) patients, respectively. The tumor stages were distributed as T1/2 in 604 (35.8%) patients and T3/4 in 955 (56.5%) patients. ENE was present in 49 (2.9%) patients. Distant metastasis was present in 90 (5.3%) patients during diagnosis. Total parotidectomy was performed in 1,157 (68.5%) patients. A total of 1,294 (76.6%) and 107 (6.3%) patients received radiotherapy and chemotherapy, respectively.LN metastasis occurred in 534 (31.6%) patients, in which 282 patients had one positive LN, 108 patients had two positive LNs, 62 patients had three positive LNs, 24 patients had four positive LNs, 16 patients had five positive LNs, and 42 patients had six or more positive LNs.In model 1, the presence of LN metastasis statistically decreased DSS and OS in the univariate and multivariate Cox analyses and was associated with an additional nearly two- and 1.5-fold risk for cancer-caused and overall death, respectively 4. The 1In model 2, the univariate Cox analysis reported the statistical association between DSS/OS and the number of positive LNs. In the multivariate Cox analysis, compared with no LN metastasis, one positive LN did not provide additional compromise to DSS, while two or more positive LNs were related to worse DSS. The 10-year DSS rates of the 2, 3, and 4+ LN groups were 51% (95% CI: 41–61%), 54% (95% CI: 36–72%), and 50% (95% CI: 30–70%), respectively. Their HR was comparable, and their 95% CI greatly overlapped. In the 5 and 6+ positive LNs groups, the median DSS time was 37.0 (95% CI: 31.7–42.3) and 25.0 (95% CI: 9.3–40.6) months, respectively. Their 95% CI also apparently overlapped. As for the OS, a similar trend was observed , 60% (95% CI: 54–66%), and 50% (95% CI: 48–52%), respectively, the difference was significant (p<0.001). The 10-year OS rates in the 0/1, 2–4, 5+ positive LN groups were 63% (95% CI: 59–67%), 50% (95% CI: 44–56%), and 9% (95% CI: 1–17%), respectively, the difference was significant (p<0.001) 4. The CThe main finding was that LN metastasis was an important prognostic factor for both DSS and OS; however, the negative impact was only observed when at least two positive LNs were present. The three prognostic categories based on the number of positive LNs (0/1 vs 2–4 vs 5+) could predict oncologic outcomes in parotid ACC without overlap and ultimately help triage high-risk patients who may benefit from more aggressive adjuvant therapies.Model 1 confirmed that LN metastasis is an independent predictor of DSS and OS. However, it referred to the metastasis of intraparotid or neck LN, both of which significantly decrease survival. Han et al.  analyzedModel 2 provided a more interesting finding. Firstly, this was the first to report that the presence of only one positive LN did not pose any additional compromise in survival compared with the absence of LN metastasis. In many solid cancers, prognosis would be decreased by up to half although there was only one positive LN . The obvth AJCC classification could not present a satisfactory OS stratification. However, the new LN system, which was developed based on the number of positive LNs (0 vs 1–3 vs 4+) and/or their maximum diameter (< 20 mm vs 20+ mm) showed better accuracy in OS prediction. In another similar study  ENE may demonstrate little influence on survival; (2) intraparotid LN should be taken into consideration in nodal staging; (3) an LN staging based on the number of positive LNs could be a good surrogate for the current system; and (4) the optimal cutoff for the number of positive LNs varied with the histologic type. Our three prognostic categories provided an accurate discrimination for low-, moderate-, and high-risk patients and could be used as a central predictor of mortality in parotid ACC.Nevertheless, this study still has some limitations. First, this was a retrospective study; hence, there may be inherent bias. Second, data on lymphovascular invasion and margin status were not available. Third, we only enrolled patients with parotid ACC, it remained unknown whether current finding was suitable for parotid cancers of other histologic types.In summary, LN metastasis significantly impacts survival in parotid ACC; however, the effect is not apparent until at least two positive LNs are present. Our three prognostic categories based on the number of positive LNs (0/1 vs 2–4 vs 5+) could be used to screen patients with different risks and plan for more aggressive treatment for high-risk patients.The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found in the article/supplementary material.Ethics approval was not required owing to public access of the data.The author confirms being the sole contributor of this work and has approved it for publication.


Here we present an optimized procedure for resin activation that minimizes the use of SOCl2 as the activation reagent and reduces the activation time. Additionally, we demonstrate the feasibility of reusing the 2-CTC resin when following the activation protocol, achieving comparable results to the first usage of the resin. Moreover, we achieved different degrees of resin activation by varying the amount of SOCl2. For instance, the use of 2% SOCl2 in anhydrous dichloromethane (DCM) allowed up to 44% activation of the resin, thereby making it suitable for the synthesis of longer peptides. Alternatively, employing 25% SOCl2 in anhydrous DCM resulted in up to 80% activation with a reaction time of only 5 min in both cases.Used in solid-phase peptide synthesis (SPPS) for peptides with an acid termination, the 2-chlorotrityl chloride (2-CTC) resin is highly susceptible to moisture, leading to reduced resin loading and lower synthetic yields. It is therefore recommended that the resin be activated with thionyl chloride (SOCl The 2-chlorotrityl chloride (2-CTC) polystyrene resin is used in solid-phase peptide synthesis (SPPS) to obtain peptides with an acid termination. Although its initial purpose was to obtain protected peptides for use in convergent synthesis, this resin proved also to be quite useful for synthesizing fully unprotected peptides . 2-CTC r2 in DCM 1+ of each AA, using a 30 to 100% ACN gradient in 3.5 min. Column: XSelect 3.5 μm, 4.6 × 50 mm. Solvent: water 0.1% formic acid and ACN 0.07% formic acid. Wavelength Detection: 220 nm. Flow: 1.6 mL/min.2. Finally, Tukey’s multiple comparison test is used for pairwise comparison. A p < 0.05 is considered statistically significant. The statistical analysis is performed with GraphPad Prism version 9.0 .Two-way standard multiple comparison analysis of variance (ANOVA) is used to compare loadings at different times and different % SOCl2 concentration and the activation time on resin loading and activation was determined at three concentrations and four different times, as indicated in The effect of the SOCl2 in anh. DCM and the addition of H2O at different steps:2O alongside the activation solution of 50% SOCl2 -Thr(tBu)-OH. The yield was calculated in terms of resin gain weight, and the % purity was evaluated by integrating the main peak in the corresponding chromatogram .Due to the increased demand of peptides for both research and industrial purposes , peptide2, a loading of 1.34 mEq/g (84.5%) was achieved within 5 min of reaction time. Extending the reaction time to 60 min brought about only a modest increase of 10.3% in the loading, which reached 94.8%. The most significant differences in resin loading were obtained between the 5- and the 40- or 60-min treatments. In terms of concentration, significant differences occurred between 2% and 25% or 50% SOCl2 at each time point, but no significant differences were observed between 25% and 50% SOCl2. The use of 2% SOCl2 to activate the 2-CTC resin produces a minor increase in loading values, ranging from 30.7% to 44.0%  and the resin loading measured before activation (0.35 mEq/g) . This co2O was added during the resin activation step (Experiment 2), the loading reached only 49.7%. On the other hand, when 5% H2O was added during the coupling step  and 0.69 mEq/g (44%), which can be used in the synthesis of short peptides and allows a considerable reduction in the amounts of required reagents.The resin load was verified after the incorporation of the first amino acid under different conditions. Furthermore, it was confirmed by evaluating the synthesis yield of a test tripeptide. Three concentrations of SOClOptimizing the activation of 2-CTC resin using anh. DCM allowed a reduction in the use of reagents, as well as in reaction time. Furthermore, the feasibility of resin recovery for reuse after activation was demonstrated for the described procedure. These findings were validated through the successful synthesis of a test tripeptide.


P = 0.021). The main manifestation of tumor was ground glass opacity (GGO) in 18–35 years group, while most showed non-GGO in 36–45 years group (P = 0.003). The proportion of minimally invasive adenocarcinoma was higher in 18–35 years group, while the invasive adenocarcinoma was higher in 36–45 years group (P = 0.004). Univariate analysis showed that asymptomatic, stage I–II, surgery, women, with few or no metastatic organs had longer OS. Multivariate analysis showed that the independent factors affecting the OS of young patients were tumor stage and more metastatic organs.Lung cancer is rare in young people, but the incidence and mortality are on the rise. We retrospectively analyzed the data of young patients aged ≤45 years diagnosed as lung cancer in our hospital from 2014 to 2021. The purpose was to explore the clinicopathological characteristics of young patients, and the risk factors affecting overall survival (OS) time. The results showed that the young patients were mainly female, had no smoking history, asymptomatic at initial diagnosis, with a high proportion of adenocarcinoma and stage I–II. We divided all patients into two groups according to age and found that the proportion of stage I–II in 18–35 years group was significantly higher than that in 36–45 years group ( Non-sma2in situ was excluded [1. The clinical data of patients diagnosed with NSCLC aged 18–45 years in our hospital from January 2014 to December 2021 were retrospectively analyzed, with a total of 298 cases. All cases were confirmed by pathology. According to the latest classification of adenocarcinoma, carcinoma excluded . Adenoca2. All statistical analyses were performed using the SPSS19.0 software. Qualitative variables were described using counts and percent and compared by the Chi-square test. Kaplan–Meier method with log-rank tests were used for OS comparisons in univariate analysis. Multivariate analysis of survival was performed using the Cox proportional hazards regression to identify independent prognostic factors. The level of significance was set as 5%. The true effect of univariate analysis is easily covered by the influence of confounding factors, so we take the results of multivariate analysis as an independent risk factor affecting survival.33.1A total of 298 young patients with lung cancer were included in the instant study, most of whom were female (65.1%) and had no smoking history (87.2%). The most common pathological type is adenocarcinoma (90.0%), including MIA (28.9%) and IA (61.1%). In addition, squamous cell carcinoma accounted for 4.7% and other types accounted for 5.3%. In terms of CT manifestations of tumors, 37.6% of cases showed as ground glass opacity (GGO), and non-GGO (solid nodule or mass or other) accounted for 62.4%. At the initial visit, most patients were asymptomatic (60.7%), 29.2% of them had cough/expectoration/sputum blood/asthma or fever, and other clinical symptoms were relatively rare. In respect of tumor staging, patients with stage I were the most (59.4%), followed by 71 patients with stage IV (23.8%), while patients with stage III and stage II accounted for 11.8 and 5.0%, respectively. Stage I–II was 192 (64.4%) in total, and stage III–IV was 106 (35.6%). Of all patients, 227 (76.2%) had no metastasis, 62 (20.8%) had 1–2 metastatic organs, and nine (3.0%) had three or more metastatic organs . In 71 p3.2P = 0.003). There were statistical differences in the distribution of pathological types between the two groups (P = 0.004). Adenocarcinoma accounted for the most in both groups. However, the proportion of MIA in the 18–35 years old group was higher than that in the 36–45 years old group (42.5% vs 23.9%), while the proportion of IA in the 36–45 years old group was higher (66.9% vs 45.0%). Lung CT manifestation in the two groups had statistical difference (P = 0.003). The 18–35 years old group mainly showed GGO, while those in the 36–45 years old group mainly showed non-GGO. There was no significant difference between the two groups in gender, smoking history, surgery or not, the number of distant metastatic organs, and clinical manifestations at the initial diagnosis . The number of distant metastatic organs was significantly lower than that in the 2014–2017 group (P < 0.05) , asymptomatic (70.5% vs 31.1%), MIA (37.9% vs 1.4%), GGO (48.2% vs 5.4%), and surgical treatment (78.1% vs 56.8%) during 2018–2021 was significantly higher than that in 2014–2017 ( < 0.05) .3.4P = 0.046).Asymptomatic patients had longer OS than symptomatic patients (P < 0.001). Patients in stage I–II had better prognosis than stage III–IV (P < 0.001). Patients receiving surgery have had better prognosis than those without surgery (P < 0.001). Patients without distant metastasis or with 1–2 metastatic organs had longer OS than patients with metastatic organs ≥3 (P < 0.001). The survival curves are shown in P = 0.029) and the number of distant metastatic organs   .3.5P = 0.289 (There were 71 patients with stage IV in this study. The most common distant metastasis site is bone (46.5%), followed by intrapulmonary (43.7%), pleural (29.6%), and brain (14.1%) . Patient = 0.289 .4Recent studies show that occupations with high exposure risk, smoking, and family history of lung cancer are risk factors for lung cancer in young people ,9. YoungThis study showed that females are in the majority, mainly adenocarcinoma (90.0%), and most patients have no smoking history, which is consistent with many literature reports ,11,12. TIn terms of tumor stage, this study shows that young patients with lung cancer in stage I–II is more common (64.4%), and stage III–IV only accounts for 35.6%, which is different from other literatures that young patients are mainly in advanced stage . We consThere were statistical differences between the two groups (18–35 years old group and 36–45 years old group) in TNM stage, pathological type, and CT manifestation of the tumor. Compared with the 36–45 years old group, there are more patients with stage I–II and the tumors mainly showed as GGO in the 18–35 years old group. Although adenocarcinoma accounted for the most in both the groups, the proportion of MIA in the 18–35 years old group was relatively higher than in 36–45 years old group (42.5% vs 23.9%), while the proportion of IA in the 36–45 years old group was relatively higher (66.9% vs 45.0%). There was no significant difference between the two groups in gender, smoking history, surgery or not, the number of distant metastatic organs, and clinical manifestations. Therefore, we believe that patients in the 18–35 years old group had unique clinicopathological characteristics, including that lung lesions were more manifested as GGO, with early stage at the initial diagnosis, and the pathological type was mainly MIA.Among 71 patients with stage IV, the most common metastasis site was bone (46.5%), followed by intrapulmonary (43.7%), pleural (29.6%), and brain (14.1%).The results were similar to one study on young patients with NSCLC , which sThere were few relevant studies on the prognosis of young patients with lung cancer, and the obtained results have been controversial. A study  shows thP < 0.05), which is consistent with literature report [P = 0.029) and the number of distant metastatic organs .The univariate analysis of this study shows that females, asymptomatic patients, and those who underwent surgery had longer survival time in young patients with lung cancer  in 36–45 years old group. Adenocarcinoma accounted for the most in both the groups, but the proportion of MIA in the 18–35 years old group was relatively higher than in 36–45 years old group, while the proportion of IA in the 36–45 years old group was relatively higher. The independent risk factors affecting the OS of young patients with NSCLC are TNM stage and the number of distant metastatic organs. There was no statistical difference in terms of OS whether there was bone metastasis in stage IV patients.


Plasmodium falciparum in the placenta hampers the diagnosis of malaria in pregnant women, leading to microscopy or conventional rapid diagnostic tests (RDTs) false-negative results. Although mainly asymptomatic, maternal malaria remains harmful to pregnant women and their offspring in endemic settings and must be adequately diagnosed. Ultra-sensitive RDTs (uRDTs) are thought to be more sensitive than RDTs, and their diagnostic performance was assessed in the current study in pregnant women living in Kinshasa, a stable malaria transmission area in the Democratic Republic of the Congo.Low peripheral parasitaemia caused by sequestration of To assess and compare the diagnostic performances of both RDTs and uRDTs, 497 peripheral blood samples were tested using microscopy and quantitative polymerase chain reaction (qPCR) as the index and the reference tests, respectively. The agreement between the different diagnostic tests assessed was estimated by Cohen's Kappa test.The median parasite density by qPCR was 292 p/μL of blood [IQR (49.7–1137)]. Using qPCR as the reference diagnostic test, the sensitivities of microscopy, RDT and uRDT were respectively [55.7% (95% CI 47.6–63.6)], [81.7% (95%CI 74.7–87.3)] and [88% (95% CI 81.9–92.6)]. The specificities of the tests were calculated at 98.5% (95% CI 96.6–99.5), 95.2% (95% CI 92.5–97.2) and 94.4% (95% CI 91.4–96.6) for microscopy, RDT and uRDT, respectively. The agreement between qPCR and uRDT was almost perfect (Kappa = 0.82). For parasite density (qPCR) below 100 p/µL, the sensitivity of RDT was 62% (95% CI 47.1–75.3) compared to 68% (95% CI 53.3–80.4) for uRDT. Between 100 and 200 p/µL, the sensitivity of RDT was higher, but still lower compared to uRDT: 89.4% (95% CI 66.8–98.7) for RDT versus 100% (95% CI 82.3–100) for uRDT. In both cases, microscopy was lower, with 20% (95% CI 10–33.7) and 47.3% (95% CI 24.4–71.1) respectively.uRDT has the potential to improve malaria management in pregnant women as it has been found to be slightly more sensitive than RDT in the detection of malaria in pregnant women but the difference was not significant. Microscopy has a more limited value for the diagnosis of malaria during the pregnancy, because of its lower sensitivity. Plasmodium parasites, is a major cause of morbidity and mortality among pregnant women and their offspring in Africa, including in the Democratic Republic of the Congo (DRC) , when compared to microscopy [55.7% (95% CI 47.6–63.6)] (p < 0.001), and a comparable sensitivity to RDT [81.7% (95% CI 74.7–87.3)]  during the screening and substantial Kappa = 0.69 (95% CI 0.55–0.83) during the follow-up. The agreement between RDT and qPCR showed a substantial agreement both during the screening (Kappa = 0.76) and follow-up (Kappa = 0.72). There is no significant difference between the performance of the RDT and uRDT (p = 0.061). However the uRDT seems to perform slightly better compared to RDT during screening and RDT seems to perform slightly better during follow-up when qPCR is considered as reference test  compared to RDT at 44.2% at a mean parasite density of 20.7 p/μL . In addial. reported a sensitivity of 52.4% for uRDT and 42.9% for RDT in the afebrile non-pregnant population in Ghana [Aquach et in Ghana . Neverthin Ghana , resultiin Ghana  and thusin Ghana .Using qPCR as a reference for true positive and negative cases, the sensitivity of uRDT was higher than RDT and microscopy during enrollment. In addition, this sensitivity was higher at enrollment than at follow-up. This result was similar to that found by Turnbull et al. in children in Kenya where the sensitivity of uRDT was higher than microscopy .Although more sensitive than RDT, the uRDT is less specific than RDT in the present study. This was also observed in a another study in non-pregnant individuals . The lowThe advantage of uRDT over the other diagnostic options seems especially relevant at low parasite densities. In blood samples with low parasitaemia (< 100 p/µL blood), uRDT detected more malaria infections in the present study than RDT and microscopy. Missing low density infections in pregnant women and especially associated with lack of symptoms, contribute to onward malaria transmission in the community but also may have adverse consequences on the mother and fetus. Improving malaria screening followed by an effective treatment of positive cases can reduce the silent reservoir infections. Although uRDT still missed almost one third of low density infections and thus seemed not to be the ultimate answer for low density infections in pregnant women, this test outperformed the other tests that were evaluated in this study.Pf HRP2 gene. pfHRP2 is a gene that codes for HRP2, the target antigen in these RDTs. Recent studies have shown that HRP2 gene deletions are leading to test failures and that these deletions are spreading [pfHRP2 gene deletions have not been detected in Kinshasa [A limitation of the current study is the fact that samples that were positive in qPCR and negative in RDT or uRDT were not tested on the presence of the preading , 40. HowKinshasa , but a pKinshasa . In futuThis has been the first study investigating uRDT in pregnant women under field conditions. This study showed that uRDT is a sensitive method in detecting malaria in pregnancy. This test could be used at every antenatal care visit for malaria screening . This isP. falciparum. This indicates the potential value of uRDT in the management of malaria during pregnancy.In conclusion, the uRDT was slightly more sensitive than RDT, but far better than microscopy, especially during the screening and in primigravidae, for the detection of a malaria infection. In malaria-endemic areas, the uRDT can provide added value by detecting more malaria infections than the RDT and the microscopy. In addition uRDT detects more cases in low density carriers


This analysis is to present the burden and trends of morbidity and mortality due to lower respiratory infections (LRIs), their contributing risk factors, and the disparity across administrative regions and cities from 1990 to 2019.This analysis used Global Burden of Disease 2019 framework to estimate morbidity and mortality outcomes of LRI and its contributing risk factors. The Global Burden of Disease study uses all available data sources and Cause of Death Ensemble model to estimate deaths from LRI and a meta-regression disease modelling technique to estimate LRI non-fatal outcomes with 95% uncertainty intervals (UI).The study includes nine region states and two chartered cities of Ethiopia.We calculated incidence, death and years of life lost (YLLs) due to LRIs and contributing risk factors using all accessible data sources. We calculated 95% UIs for the point estimates.In 2019, LRIs incidence, death and YLLs among all age groups were 8313.7 (95% UI 7757.6–8918), 59.4 (95% UI 49.8–71.4) and 2404.5 (95% UI 2059.4–2833.3) per 100 000 people, respectively. From 1990, the corresponding decline rates were 39%, 61% and 76%, respectively. Children under the age of 5 years account for 20% of episodes, 42% of mortalities and 70% of the YLL of the total burden of LRIs in 2019. The mortality rate was significantly higher in predominantly pastoralist regions—Benishangul-Gumuz 101.8 (95% UI 84.0–121.7) and Afar 103.7 (95% UI 86.6–122.6). The Somali region showed the least decline in mortality rates. More than three-fourths of under-5 child deaths due to LRIs were attributed to malnutrition. Household air pollution from solid fuel attributed to nearly half of the risk factors for all age mortalities due to LRIs in the country.In Ethiopia, LRIs have reduced significantly across the regions over the years (except in elders), however, are still the third-leading cause of mortality, disproportionately affecting children younger than 5 years old and predominantly pastoralist regions. Interventions need to consider leading risk factors, targeted age groups and pastoralist and cross-border communities. The analysis has considered political, government and administrative changes of regional states and cities over the years to map available data and populations.The analysis used all available data identified through an extensive collaboration effort and involving more than 700 leading researchers and policy-makers from Ethiopia.When data were not available for a particular regional states or city, the modelling process used data from other locations borrowing strength from geographical locations and time, and use predictive covariates.However, limited quality data availability and accessibility for the analysis resulted in wider 95% uncertainty intervals which largely affect policy debates, prioritisation and health decisions.Lower respiratory infections (LRIs) have been a predominant health problem worldwide, causing more than 2.3 million deaths in 2016 alone, amounting to a mortality rate of 32.2 per 100 000 people.2Streptococcus pneumoniae contributed to more deaths than the other LRIs aetiologies combined.7Ethiopia ranked in the top three African countries in the number of under-5 child deaths from LRIs.Morbidity and mortality from LRIs are attributable to multiple underlying factors. Malnutrition is one of the main underlying risk factors.13The flagship Ethiopian Health Extension Programme (HEP) has been the backbone of the country’s health system strategies to reduce the burden of LRIs and other diseases through preventive and health promotion activities at the community level. The HEP has also improved broader access to healthcare, availability of essential antibiotics and immunisation mainly to the rural population since 2004.15Currently, Ethiopia is implementing its Health Sector Transformation Plan-2 (HSTP-2) which is adapted from the Sustainable Development Goals. Some of the aims include increasing the proportion of under-5 children with pneumonia who received antibiotics from 48% to 69% and improving full vaccination coverage from 44% to 69% between 2020 and 2025.17As Ethiopia is a country of stark contrasts in socioeconomic, epidemiological and geographical variations, estimating disease burden at the regional level could provide valid and reliable information to inform policy decisions, including efficient resource allocation to match the burden in the subnational states. Hence, this article presents the 2019 Global Burden of Diseases, Injuries and Risk Factors study (GBD) results on the burden, trends and regional variations of LRIs in Ethiopia from 1990 to 2019.Ethiopia is the second-most populous country in Africa next to Nigeria, with an estimated population of 112 million in 2019.The healthcare system of the country is a three-tiered system consisting of primary, secondary and tertiary levels of healthcare delivery units with 21 154 functioning health facilities and 159 545 health workforce in 2019.16http://ghdx.healthdata.org/gbd-2019/data-input-sources). This study outputs predates the COVID-19 and civil war occurred in the northern and other parts of the country and does not include the impact of COVID-19 or civil war.The analysis and findings of LRIs presented in this analysis were produced by the Ethiopia Subnational Burden of Disease Initiative, a collaborative endeavour between the National Data Management Center for Health (NDMC) at the Ethiopian Public Health Institute (EPHI) and the Institute for Health Metrics and Evaluation (IHME), as part of GBD. The details of the methodology were described elsewhere.The GBD details are reported elsewhere.22 28We present the burden of LRIs in Ethiopia and its regional states using incidence, deaths and YLLs categorised by sex, age groups and year. We used numbers, rates and per cent change for the quantification of the burden. We also estimated the risk factors contributing to LRIs in Ethiopia and the per cent change between 1990 and 2019. We reported GBD causes and risk factors using level 3 classifications, with 95% UIs. Additional tables and figures are attached in 10.1136/bmjopen-2022-068498.supp1Supplementary dataPatients and the public were not involved in the design of the study.In 2019, an estimated 6 628 673.6 (95% UI 6 108 786.2–7 230 986.3) new cases of LRIs occurred in Ethiopia resulting in an age-standardised incidence rate of 8313.7 per 100 000 people (95% UI 7757.6–8918). Out of the total LRI episodes, 22% (1 448 680.0 new cases (95% UI 1 150 089.8–1 799 704.4)) of new cases occurred among children younger than 5 years, yielding an annual incidence rate of 8685.0 per 100 000 children (95% UI 6895.1–10 789.8). In adults older than 70 years, there were 725 273.3 (95% UI 640 315.4–837 746.3) new cases of LRIs with an annual incidence of 38 394.4 per 100 000 people (95% UI 33 896.9–44 348.5) .Compared with national estimates, a significantly lower age-standardised incidence rate of LRIs per 100 000 people was observed in the chartered cities (6788.1 (95% UI 6285.1–7339.1) in Addis Ababa, 7148.8 (95% UI 6634.6–7750.7) in Dire Dawa) and in Harari region (7190.5 (95% UI 6684.1–7718.6)). The highest rates of age-standardised incidence per 100 000 people were observed in Afar (9350.2 (95% UI 8648.8–10 157.4)), Somali (9220.0 (95% UI 8515.9–10 046.4)) and Benishangul-Gumuz (9054.6 (95% UI 8394.2–9766.0)) although not significant compared with the national estimate .In children younger than 5 years, the lowest incidence rates were observed in Addis Ababa (4927.2 (95% UI 3812.5–6231.8)), Harari (6821.6 (95% UI 5373.5–8607.3)) and Gambella (6791.1 (95% UI 5370.4–8460.1)) per 100 000 people, substantially below the national estimate. The highest incidence of LRIs per 100 000 children were recorded in Benishangul-Gumuz (10 481.8 (95% UI 8269.5–13 219.0)), Somali (10 062.7 (95% UI 7949.6–12 802.8)), Afar (9365.5 (95% UI 7421.7–11 714.7)) and Oromia (9039.4 (95% UI 7080.5–11 277.7)).The age-standardised decline rate between 1990 and 2019 was 39% for both sexes, and it was 56% in under-5 children and 13% in adults older than 70. The lowest decline in age-standardised incidence rate was in Somali (19%); while it was between 38% and 44% for the remaining regions .In children younger than 5, the incidence rates increased slightly between 1990 and 1995, except in Addis Ababa and Amhara region. The highest decline rates were found between the years 2005 and 2015 across all regions .In 2019, LRIs caused 46 300.7 (95% UI 39 515–54 642) deaths in Ethiopia, giving the age-standardised mortality rate of 86.4 (75.3–97.6) per 100 000 people. Under-5 mortality accounted for 42% (19 591.8 (95% UI 14 018.4–26 899.0)) of all deaths due to LRIs which resulted in a mortality rate of 117.4 (84.0–161.2) per 100 000 children. Of the under-5 deaths, 71% (13 919.0 (95% UI 9946.0–18 860.0)) occurred in the first year of life. In adults older than 70 years, LRIs caused 14 627.6 (95% UI 12 393.7–16 892.8) deaths, which was a mortality rate of 774.3 (95% UI 656–894.2) deaths per 100 000 adults .In 2019, a number of deaths in all age groups by region were highest in Oromia (18 206 (95% UI 15 193–21 745)), Amhara (9525 (95% UI 7530–11 872)), SNNP (9494 (95% UI 7713–11 649)) and Somali (3907.5 (95% UI 3007.4–4959.4)), followed by Tigray (2551.4 (95% UI 2090.3–3028.6)), Afar (706.2 (95% UI 567.7–869.6)), Benishangul-Gumuz (619 (95% UI 470.7–803.0)), Dire Dawa (154.6 (95% UI 120.6–193.8)) and Gambella (123.2 (95% UI 98.2–151.9)). Harari (93.1 (95% UI 73.8–116.0) had the lowest number of deaths .Between 1990 and 2019, the age-standardised mortality rate declined by 61%, and the decline in under-5 children and adults over 70 years was 86% and 30%, respectively .In Ethiopia, the age-standardised mortality rate was higher among males (100.6 (95% UI 84.1–121.4)) than females (71.8 (95% UI 60.2–82.9)) .In 1990, the age-standardised mortality rate per 100 000 people was the highest in Benishangul-Gumuz (284.1 (95% UI 221.8–358.1)), Afar (244.8 (95% UI 186.5–316.9)) and SNNP (243.7 (95% UI 196.4–296.9)), although it is not significantly different from the national estimate. On the other hand, the lowest age standardised mortality rate was exhibited in Somali (147.6 (95% UI 113.8–192.6)). Although the value was not significantly different from the national value in 1990, Addis Ababa showed the second lowest age-standardised mortality rate (163.4 (95% UI 134.6–206.9)) .In 2019, the age-standardised mortality rate per 100 000 people was significantly lower in Addis Ababa (59.4 (95% UI 49.8–71.4)) when compared with other regions, although not significantly lower than Gambella and other urban areas (Harari and Dire Dawa). Dire Dawa showed a significantly lower age-standardised mortality rate when compared with Benishangul-Gumuz, Afar and SNNP. Compared with the national estimate, the regions of Afar (103.7 (95% UI 86.6–122.6)) and Benishangul-Gumuz (101.8 (95% UI 84.0–121.7)) recorded the highest age-standardised mortality rates per 100 000 people, although the difference is not statistically significant . CompareAmong children below the age of 5, the mortality rate per 100 000 people was significantly lower in Addis Ababa (23.4 ((95% UI 14.1–36.4)) than other regions, although it was not significantly less than Gambella in 2019. The mortality rate was the highest in Benishangul-Gumuz (215.1 (95% UI 141.4–311.0)), Somali (197.3 (95% UI 135.2–279.8)) and Oromia (122.3 (95% UI 84.8–171.0)) despite being not significantly higher than the national estimate . Dire DaThe mortality rate in adults older than 70 was the lowest in Addis Ababa (503.6 (95% UI 410.5–633.7)). Other regions and cities have not shown a statistically significant difference from the national estimate. The decline in mortality rates between 1990 and 2019 is below 50% across all regions . The morIn 2019, premature death due to LRIs was 2 445 093.7 (95% UI 1 934 420.8–3 119 838.6) YLLs, yielding an age-standardised rate of 2404.5 per 100 000 people (95% UI 2059.4–2833.3). Compared with 1990, the age-standardised YLL rate declined by 76% in 2019. In parallel, 70% of all premature mortality occurred in children younger than 5, which accounted for 1 721 122.3 (95% UI 1 231 032.1–2 362 958.7) YLLs. The YLL rate of 72 055.4 (95% UI 55 718.5–92 064) per 100 000 under-5 children in 2019 declined by 86% compared with the YLL rate in 1990. Adults over 70 years contributed 8% of all YLLs due to LRIs (194 756.2 (95% UI 165 462.0–225 502.1)), yielding a rate of 10 309.9 (95% UI 8759.2–11 937.6) YLLs per 100 000 people .Compared with 1990, the number of YLLs has decreased by 70% in all age groups and by 76% in children younger than 5 in 2019. However, the number of YLLs has increased by 45% in adults older than 70 .The age-standardised YLL rate was significantly lower in Addis Ababa (1285.6 (95% UI 1065–1561.8)) in 2019 compared with the national average. The highest age standardised YLL rate were in Benishangul-Gumuz (3571.1 (95% UI 2772.4–4510.7)), Somali (3236.4 (95% UI 2537.4–4006)) and Afar (2824.6 (95% UI 2323–3414)), although not statistically significant compared with the national estimate .In children younger than 5 years, Addis Ababa (2069 (95% UI 1253–3217.5)) had a significantly lower YLL rate than the national estimate. The YLL rate was observed to be the lowest in Gambella (5031.8 (95% UI 2867.2–7885.7)), although not significantly lower than the national estimate .The age-standardised premature mortality rate between 1990 and 2019 showed a continuous decline in all regions, except Somali. Benishangul-Gumuz showed the highest burden between 1990 and 2019 .The change in premature mortality in children younger than 5 was significant throughout the years. However, the reduction in premature mortality among adults older than 70 was not as significant .Across all population groups, about half (48%) of the mortalities (measured in rates) due to LRIs in Ethiopia were attributed to household air pollution from solid fuel. In addition, lack of access to a hand-washing facility (23%), childhood wasting (23%), low birth weight (9%), short gestation period (7%) and ambient particulate matter pollution (6%) were also risk factors for mortality due to LRIs. The contribution of the risk factors to death due to LRIs in all regions was similar to the national estimate, except in Addis Ababa, where lack of access to hand-washing facilities, ambient particulate matter pollution, and low temperature were the main contributing factors. Ambient particulate matter pollution was also relatively higher in Dire Dawa, Harari and Tigray regions .In children younger than 5, more than three-fourths of deaths due to LRIs were attributed to childhood wasting (54%) stunting (12%) and child underweight (10%) in Ethiopia. In addition, 50% of the LRIs mortalities were attributed to household air pollution from solid fuel. Lack of access to hand-washing facilities (23%), low birth weight (23%), short gestation period (17%), high (4%) or low temperature (4%), absence of exclusive breast feeding (4%) were also the risk factors with evident contribution. The distribution of risk factors varied among the regions. Child wasting, low birth weight and preterm birth were the contributing factors of mortality in Addis Ababa. In Harari and Dire Dawa, child wasting, lack of access to hand-washing facilities, preterm birth and household air pollution from solid fuels contributed more to the death from LRIs than the other risk factors in 2019. All the risk factors except for ambient particulate air matter and low temperature were the highest in Somali and Benishangul-Gumuz . When weThe findings from this study indicate that although the burden of LRIs, measured in incidence or mortality rates, has shown a significant decline, they are still the third-leading cause of death after neonatal disorders and diarrheal diseases in 2019 in Ethiopia. Cities and predominantly urban areas had lower mortality rates than predominantly pastoralist regions of the country. The rate of decline in mortality between 1990 and 2019 varied slightly across regions and chartered cities. The mortality rate decreased by more than three-fourths among children under the age of 5 and only by one-third among adults older than 70 between 1990 and 2019. Half of LRIs mortalities are attributed to household air pollution from solid fuels in all age groups. About three-fourths of LRIs in children were attributed to malnutrition.S. pneumoniae, which is responsible for about half of the LRIs mortality in African countries, with the PCV 10 vaccine since 2011 helped reduce the burden of LRIs.29The mortality rate of LRIs among children below the age of 5 has declined by 86% between 1990 and 2019. This decline could be attributed to improvements in living conditions, access to healthcare and immunisation. The national health delivery infrastructure has grown from 2600 health facilities in 1997–21 154 facilities, including 314 hospitals, 3678 health centres, and 17 162 health posts and private health facilities in 2019. As a result, the health workforce has increased from 46 000 in 2007 to 159 545 in 2019.Despite the achievements reached in improving child health outcomes in Ethiopia, children are still disproportionately affected by LRIs. Out of the total burden of LRIs, 42% of all the deaths were among children younger than 5. In that regard, this study has shown that 1 out of 10 child deaths are due to LRIs. However, another study estimated that pneumonia alone shared about 17% of all deaths in children younger than 5 years.31Urban areas of the country, mainly Addis Ababa and Dire Dawa, had significantly lower mortality rates than pastoralist areas such as Benishangul-Gumuz and Somali. These regional variations could be attributed to gaps in availability and access to healthcare and socioeconomic status differences among the subnational states. A previously conducted study indicated that disease burden is high among people in the poorest wealth quintile and people located mainly in Afar, Somali, Oromia, SNNP and Benishangul-Gumuz and also have the lowest level of health service utilisation.33In addition to children, LRIs affects people older than 70 years. The number of people dying from LRIs increased over the years in people older than 70 years, partly due to the increase in the ageing population. However, the mortality rate declined by 30% between 1990 and 2019.33Wasting, stunting and underweight were major risk factors contributing to the death of children younger than 5 years due to LRIs.15Ambient particulate matter and household air pollution from solid fuel use were the two essential components of air pollution. Household air pollution from solid fuel use the was the second leading risk factor for LRIs, and ambient particulate matter is the eight leading risk factor among the top ten risk factors for LRIs.3To reduce the burden of LRIs, both national and global efforts are underway. The Global Action Plan for the Prevention and Control of Pneumonia and Diarrhoea (GAPPD), established by the WHO, set goals in 2013 to reduce child LRI mortality rates to below 3 in 1000 live births and to reduce severe LRI incidence by 75% of the 2010 baseline by 2025. To achieve these goals, reaching 90% of children with full-dose vaccine coverage, 90% access to pneumonia treatment, 50% coverage of exclusive breastfeeding in the first 6 months and exclusive breastfeeding promotion were set as prerequisites.30Ethiopia’s major health sector strategic plan, the HSTP-2 for the year 2021–2024, aims to reduce the infant mortality rate to 35, the neonatal mortality rate to 21 and the children under-5 mortality rate to 43 per 1000 live births. Similarly, the 2030 Sustainable Development Goals (SDG) has set targets to reduce childhood mortality significantly. These targets can be achieved if the country implements high-impact priority curative and preventive interventions against LRIs.43This study is not without limitations; limitations in the GBD methods also apply to this study and limitations on Ethiopia subnational burden of disease that includes scarcity of quality data is published elsewhere.Despite the substantial reduction in morbidity and mortality at national and regional states, LRIs still remain one of the leading causes of the burden of disease in Ethiopia. Children and elders are still disproportionately affected by LRIs. The burden of illness and death due to LRIs varies across regional states in Ethiopia, with lower rates in cities and predominantly urban areas while predominantly pastoralist areas of the country have higher rates. Efforts should be made to tackle the major risk factors contributing to death by LRIs. Improving child nutrition, access to immunisation and curative health services, as well as universal electrification to reduce indoor air pollution will be very useful strategies to reduce deaths due to LRIs in Ethiopia. Furthermore, improvement in socioeconomic factors will also help to reduce LRI burden at national and regional levels. To reach the targets set at the national and international level, mobilising resources to health and improving the provision of health services to the community according to the needs of the regions is of paramount importance.