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Context: Excessive hip adduction and internal rotation are abnormal movements that may lead to the onset and progression of patellofemoral pain. Previous studies have reported that lower dynamic frontal plane hip joint stiffness in the gait of women is associated with the magnitude of hip adduction and internal rotation angles. However, the factors contributing to the lack of dynamic frontal plane hip joint stiffness in the gait of young women are unclear. This study aims to investigate the factors affecting dynamic frontal plane hip joint stiffness during the weight-acceptance phase of the gait of healthy young women. Design: Cross-sectional study. Methods: This study included 30 healthy women between the ages of 18 and 30 years. The pelvic width/femur length ratio was calculated by dividing the pelvic width by the femur length. Data on hip kinematics and kinetics and activation of the gluteus maximus and medius, tensor fasciae latae, and adductor longus muscles during gait were collected using a motion capture system, force plates, and surface electromyography. Stepwise multiple regression analysis was conducted to determine the extent to which each independent factor affected dynamic frontal plane hip joint stiffness. Results: In healthy young women, decreased dynamic frontal plane hip joint stiffness was associated with decreased muscle activity of the gluteus maximus during the gait, as well as greater pelvic width/femur length ratio. Conclusions: Women with a relatively great pelvic width relative to femur length may have more difficulty in producing dynamic frontal plane hip joint stiffness. However, increasing the muscle activity of the gluteus maximus may contribute to increased dynamic frontal plane hip joint stiffness. [ABSTRACT FROM AUTHOR]

Aim: To describe the childhood experiences of patients with polio from the acute phase of the disease during post‐war Finland in the 1950s and 1960s. Design: Qualitative empirical study based on self‐reported history of nursing rooted in the past, a history of experiences. Methodology: Interview materials were gathered in the form of themes (45) and written interviews (4) (29 September 2018 to 30 June 2019). Data were analysed by reflexive thematic analysis to highlight hidden and latent experiences. This approach generated the study's main theme, themes and subthemes. Results: The main theme, 'shattered childhood', generated from the study results and was then divided into two themes, both of which were influenced in part by the loss of a familiar childhood, the changed environment, the breakdown of the body and the absence of control. Through their childhood memories, polio survivors described their broken childhoods using the following themes: 'betrayal by their bodies' and 'isolation'. In the narratives, the theme 'betrayal by one's own body' was generated by the following subthemes: 'suddenness of the affliction', 'paralysis' and 'being moved to the hospital'. The 'isolation' theme developed from the subthemes 'isolation from the body and surroundings' and 'emotional and social loneliness'. Conclusion: Polio survivors' experiences during the acute stage of the disease were traumatic and demonstrated children's inferior nursing position in Finland in the 1950s and 1960s. Impact: The study increases our understanding of the history of caring for children and families who were affected and disabled by polio and the importance of their experiences in society and healthcare settings. Patient or Public Contribution: The authors collaborated with the Finnish Polio Association to recruit study participants and plan the study. Patients with polio during childhood underwent interviews, and their experiences formulated the data, which were analysed and the basis of the results. Reporting Method: Consolidated criteria for reporting qualitative research (COREQ), a 32‐item checklist for interviews and focus groups, have been used as a reporting and checklist tool. All authors have agreed on the final version and the use of the COREQ criteria, relationship with participants, theoretical framework, setting, data collection and data analysis and report. [ABSTRACT FROM AUTHOR]

Senescence and epigenetic alterations are two important hallmarks of cellular aging. During aging, cells subjected to stress undergo many cycles of damage and repair before finally entering either apoptosis or senescence, a permanent state of cell cycle arrest. The first biomarkers of senescence to be identified were increased ß‐galactosidase activity and induction of p16INK4a. Another feature of senescent cells is the senescence‐associated secretory phenotype (SASP), a complex secretome containing more than 80 pro‐inflammatory factors including metalloproteinases, growth factors, chemokines and cytokines. The secretome is regulated through a dynamic process involving a self‐amplifying autocrine feedback loop and activation of the immune system. Senescent cells play positive and negative roles depending on the composition of their SASP and may participate in various processes including wound healing and tumour suppression, as well as cell regeneration, embryogenesis, tumorigenesis, inflammation and finally aging. The SASP is also a biomarker of age, biological aging and age‐related diseases. Recent advances in anti‐age research have shown that senescence can be now prevented or delayed by clearing the senescent cells or mitigating the effects of SASP factors, which can be achieved by a healthy lifestyle (exercise and diet), and senolytics and senomorphics, respectively. An alternative is tissue rejuvenation, which can be achieved by stimulating aged stem cells and reprogramming deprogrammed aged cells. These non‐clinical findings will open up new avenues of clinical research into the development of treatments capable of preventing or treating age‐related pathologies in humans. [ABSTRACT FROM AUTHOR]

Introduction: The prevalence of cranial deformities, including nonsynostotic plagiocephaly, has been increasing, especially since the “Back to Sleep” campaign. Treatment of these deformities can use a cranial remolding orthosis or helmet. However, inconsistencies in results of studies of cranial remolding orthoses have made it increasingly more difficult for providers to accurately make recommendations for individuals with nonsynostotic plagiocephaly. Therefore, the purpose of this study was to assess the effectiveness of cranial remolding orthoses effective in treating nonsynostotic plagiocephaly by reducing cranial vault asymmetry (CVA) and to assess whether age and severity impact length and success of treatment. Materials and Methods: A retrospective analysis of patient files from September 2019–September 2020 was conducted. Paired samples of initial average and discharge average CVA measures and severity ratings were compared. Regression analyses were used to assess the relationship between all factors and severity rating at discharge. Results: A total of 106 infants (73 male, 33 female) were included in final analyses. Results indicated a significant difference between initial and discharge CVA and severity rating as a result of cranial remolding orthosis treatment. It was found that CVA at initial evaluation significantly predicted CVA at discharge (β = 0.73, P = 0.000) and severity at discharge (β = 0.52, P = 0.000), but all other variables were not significant predictors. Conclusions: The cranial remolding orthosis is an effective treatment in the correction of nonsynostotic plagiocephaly when used by a certified practitioner. In addition, this study found that treatment led to significant improvement regardless of age or initial severity. [ABSTRACT FROM AUTHOR]

Background: Autism has been considered a 'male‐dominant' condition. However, recent research suggests that autistic females are underdiagnosed, misdiagnosed, and later diagnosed. Females may also have different and more nuanced behavioral profiles. To examine diagnosis rates of females, we used 20 years of state‐wide data to characterize historical trends in the diagnosis of autism in females to determine whether the proportion of females diagnosed with autism has changed over time. Methods: Data were drawn from 10,247 participants (males = 8,319, females = 1928) who received an autism diagnosis between 2000 and 2021 from state‐wide autism centers associated with the University of North Carolina TEACCH Autism Program. Results: The rates of females diagnosed with autism increased at a greater rate compared with males. Age of diagnosis remained consistently higher for females. Late diagnosis (defined as 13+) increased over time across both males and females, however, was more commonly associated with females, particularly those with co‐occurring intellectual disability. Conclusions: Our results indicate that the proportion of females diagnosed with autism has increased steadily over a 20‐year period, which likely reflects greater societal knowledge of how autism may manifest differentially in females. [ABSTRACT FROM AUTHOR]

Simple Summary: Ovarian cancer has been the most fatal female-specific cancer, and in particular, old patients have worse survival compared to young patients. In this study, we test whether the current oncology practice has been able to improve survival, compared to age group-specific past survival. We were able to show that survival in old patients remains poor, and in all patients, the time after year 1 is a critical period for survival. Although survival in ovarian cancer has improved in the Nordic countries over the past 50 years, age-related disparities have remained, or even increased. Survival has not increased for patients older than 60 years after one year of survival. This study calls for more focus on elderly ovarian cancer patients, to aim for early diagnosis and to explore more active therapeutic intervention for which age should not be considered limiting but rather the physical condition. Background: Despite treatment having improved through intensive surgical procedures and chemotherapy—and more recently, targeted therapies—ovarian cancer is the most fatal female cancer. As such, we wanted to analyze age-specific survival trends for ovarian cancer in Denmark, Finland, Norway and Sweden over the past 50 years, with a special aim of comparing survival development between the age groups. Methods: We modelled survival data from the NORDCAN database for 1-, 5- and conditional 5/1-year relative (between years 1 and 5) survival for ovarian cancer from 1972 to 2021. Results: Young patients had a 70% 5-year survival while the survival was only 30% for the oldest patients. Conditional survival showed that survival between years 1 and 5 did not improve for patients older than 60 years throughout the 50-year period, during which time the gaps between the youngest and the oldest patients widened. Conclusions: Improvement in 1-year survival was so large that it masked the modest development between years 1 and 5, resulting in a widening age disparity in 5-year survival. The current treatment practices, which appear increasingly effective for younger patients, have not helped remedy the large age differences in ovarian cancer survival. Early detection methods and therapeutic innovations are urgently needed, and aged patients need a special focus. [ABSTRACT FROM AUTHOR]

Wasteosomes (or corpora amylacea) are polyglucosan bodies that appear in the human brain with aging and in some neurodegenerative diseases, and have been suggested to have a potential role in a nervous system cleaning mechanism. Despite previous studies in several neurodegenerative disorders, their status in frontotemporal lobar degeneration (FTLD) remains unexplored. Our study aims to characterize wasteosomes in the three primary FTLD proteinopathies, assessing frequency, distribution, protein detection, and association with aging or disease duration. Wasteosome scores were obtained in various brain regions from 124 post-mortem diagnosed sporadic FTLD patients, including 75 participants with tau (FTLD-tau), 42 with TAR DNA-binding protein 43 (FTLD-TDP), and 7 with Fused in Sarcoma (FTLD-FUS) proteinopathies, along with 29 control subjects. The wasteosome amount in each brain region for the different FLTD patients was assessed with a permutation test with age at death and sex as covariables, and multiple regressions explored associations with age at death and disease duration. Double immunofluorescence studies examined altered proteins linked to FTLD in wasteosomes. FTLD patients showed a higher accumulation of wasteosomes than control subjects, especially those with FTLD-FUS. Unlike FTLD-TDP and control subjects, wasteosome accumulation did not increase with age in FTLD-tau and FTLD-FUS. Cases with shorter disease duration in FTLD-tau and FTLD-FUS seemed to exhibit higher wasteosome quantities, whereas FTLD-TDP appeared to show an increase with disease progression. Immunofluorescence studies revealed the presence of tau and phosphorylated-TDP-43 in the periphery of isolated wasteosomes in some patients with FTLD-tau and FTLD-TDP, respectively. Central inclusions of FUS were observed in a higher number of wasteosomes in FTLD-FUS patients. These findings suggest a role of wasteosomes in FTLD, especially in the more aggressive forms of FLTD-FUS. Detecting these proteins, particularly FUS, in wasteosomes from cerebrospinal fluid could be a potential biomarker for FTLD. [ABSTRACT FROM AUTHOR]

Aging represents a key risk factor for a plethora of diseases. Targeting detrimental processes which occur during aging, especially before onset of age-related disease, could provide drastic improvements in healthspan. There is increasing evidence that dietary restriction (DR), including caloric restriction, fasting, or fasting-mimicking diets, extend both lifespan and healthspan. This has sparked interest in the use of dietary regimens as a non-pharmacological means to slow aging and prevent disease. Here, we review the current evidence on the molecular mechanisms underlying DR-induced health improvements, including removal of senescent cells, metabolic reprogramming, and epigenetic rejuvenation. [ABSTRACT FROM AUTHOR]

Differentiated high-grade thyroid carcinoma (DHGTC) is a new subset within the spectrum of thyroid malignancies. This review aims to provide a comprehensive overview of DHGTC, focusing on its historical perspective, diagnosis, clinical characteristics, molecular profiles, management, and prognosis. DHGTC demonstrates an intermediate prognosis that falls between well-differentiated thyroid carcinoma and anaplastic thyroid carcinoma. Previously unenumerated, this entity is now recognized for its significant impact. Patients with DHGTC often present at an older age with advanced disease and exhibit aggressive clinical behavior. Molecularly, DHGTC shares similarities with other thyroid malignancies, harboring driver mutations such as BRAFV600E and RAS, along with additional late mutations. The unique behavior and histologic features of DHGTC underscore the necessity of precise classification for prognostication and treatment selection. This highlights the critical importance of accurate diagnosis and recognition by pathologists to enrich future research on this entity further. [ABSTRACT FROM AUTHOR]

Introduction: Women and those with younger onset Parkinson's Disease (YOPD) are typically diagnosed later and face unique situations and challenges. This essay aims to raise awareness of the difficulties in diagnosing YOPD and the need for a personalised approach to care for women with YOPD. Methods: Two professional women with YOPD (academic physiotherapist and practicing dentist) and a female neurologist (clinician academic) came together to write a narrative essay on their personal experience and perspectives in relation to women and YOPD. Results: The essay outlines how the experience of diagnosis is likened to a complex puzzle box with many interlocking components that are hidden and difficult to solve. The concerns of the women about their identity, work, family and the future, with most supports targeting those that are older and retired are outlined. Conclusion: It is concluded that YOPD is a complex puzzle to solve, but can be done by understanding all the intricate interlocking components of the puzzle and combined with greater awareness could lead to earlier diagnosis and the delivery of successful person‐centred care. Patient or Public Contribution: People with lived experience were involved in the essay conception and writing. [ABSTRACT FROM AUTHOR]

Introduction: Advanced therapies offer unprecedented opportunities for treating rare neurological disorders (RNDs) in children. However, health literacy, perceptions and understanding of novel therapies need elucidation across the RND community. This study explored healthcare professionals' and carers' perspectives of advanced therapies in childhood‐onset RNDs. Methods: In this mixed‐methodology cross‐sectional study, 20 healthcare professionals (clinicians, genetic counsellors and scientists) and 20 carers completed qualitative semistructured interviews and custom‐designed surveys. Carers undertook validated psychosocial questionnaires. Thematic and quantitative data analysis followed. Results: Participants described high positive interest in advanced therapies, but low knowledge of, and access to, reliable information. The substantial 'therapeutic gap' and 'therapeutic odyssey' common to RNDs were recognised in five key themes: (i) unmet need and urgency for access; (ii) seeking information; (iii) access, equity and sustainability; (iv) a multidisciplinary and integrated approach to care and support and (v) difficult decision‐making. Participants were motivated to intensify RND clinical trial activity and access to advanced therapies; however, concerns around informed consent, first‐in‐human trials and clinical trial procedures were evident. There was high‐risk tolerance despite substantial uncertainties and knowledge gaps. RNDs with high mortality, increased functional burdens and no alternative therapies were consistently prioritised for the development of advanced therapies. However, little consensus existed on prioritisation to treatment access. Conclusions: This study highlights the need to increase clinician and health system readiness for the clinical translation of advanced therapeutics for RNDs. Co‐development and use of educational and psychosocial resources to support clinical decision‐making, set therapeutic expectations and promotion of equitable, effective and safe delivery of advanced therapies are essential. Patient or Public Contribution: Participant insights into the psychosocial burden and information need to enhance the delivery of care in this formative study are informing ongoing partnerships with families, including co‐production and dissemination of psychoeducational resources featuring their voices hosted on the Sydney Children's Hospitals Network website SCHN Brain-Aid Resources. [ABSTRACT FROM AUTHOR]

Age is a significant contributing factor to the occurrence and progression of cardiovascular disease (CVD). Pharmacological treatment can effectively alleviate CVD symptoms caused by aging. However, 90% of the drugs have failed in clinics because of the loss of drug effects or the occurrence of the side effects. One of the reasons is the disparity between animal models used and the actual physiological levels in humans. Therefore, we integrated multiple datasets from single‐cell and bulk‐seq RNA‐sequencing data in rats, monkeys, and humans to identify genes and pathways with consistent/differential expression patterns across these three species. An approach called "Cross‐species signaling pathway analysis" was developed to select suitable animal models for drug screening. The effectiveness of this method was validated through the analysis of the pharmacological predictions of four known anti‐vascular aging drugs used in animal/clinical experiments. The effectiveness of drugs was consistently observed between the models and clinics when they targeted pathways with the same trend in our analysis. However, drugs might have exhibited adverse effects if they targeted pathways with opposite trends between the models and the clinics. Additionally, through our approach, we discovered four targets for anti‐vascular aging drugs, which were consistent with their pharmaceutical effects in literatures, showing the value of this approach. In the end, software was established to facilitate the use of "Cross‐species signaling pathway analysis." In sum, our study suggests utilizing bioinformatics analysis based on disease characteristics can help in choosing more appropriate animal models. [ABSTRACT FROM AUTHOR]

Psychiatric illnesses can affect the social transitions of adolescence and young adulthood, such as completing education and entering working life and relationships. However, associations between earlier onset age and long-term outcomes among those with early-onset psychoses (EOP) are unclear, as are the long-term outcomes of EOP compared to non-psychotic disorders. We used national register data of the Northern Finland Birth Cohort 1986 to detect persons with EOP and other early-onset psychiatric disorders. The long-term clinical and work-family outcomes of persons with onset age before 18 years (n = 41 psychoses, n = 495 non-psychoses) or between 18–22 years (n = 61 psychoses, n = 377 non-psychoses) were compared. Individuals with the onset of psychosis between 18–22 years had significantly more unfavourable long-term outcomes when compared to those with psychosis onset before 18 years. Persons with psychosis onset before the age of 18 years had similar outcomes to those with non-psychotic psychiatric disorder onset before 18 years regarding educational level, marital status, having children, and substance use disorders. Individuals with EOP were more often on a disability pension compared to those with other early-onset mental disorders. Adjusting for sex, educational level and substance use only slightly diluted these results. Unexpectedly, later onset age of EOP was associated with worse outcomes. Those with psychosis onset between 18–22 years of age are in a critical period, which underlines the importance of investing on interventions in this age group. Further studies on the effect of the onset age on later outcomes in EOP are needed. [ABSTRACT FROM AUTHOR]

Aim: Biallelic mutations in the PTRH2 gene have been associated with infantile multisystem neurological, endocrine, and pancreatic disease (IMNEPD), a rare autosomal recessive disorder of variable expressivity characterized by global developmental delay, intellectual disability or borderline IQ level, sensorineural hearing loss, ataxia, and pancreatic insufficiency. Various additional features may be included, such as peripheral neuropathy, facial dysmorphism, hypothyroidism, hepatic fibrosis, postnatal microcephaly, cerebellar atrophy, and epilepsy. Here, we report the first Italian family presenting only predominant neurological features. Methods: Extensive neurological and neurophysiological evaluations have been conducted on the two affected brothers and their healthy mother since 1996. The diagnosis of peripheral neuropathy of probable hereditary origin was confirmed through a sural nerve biopsy. Exome sequencing was performed after the analysis of major neuropathy‐associated genes yielded negative results. Results: Whole‐exome sequencing analysis identified the homozygous substitution c.256C>T (p.Gln86Ter) in the PTRH2 gene in the two siblings. According to American College of Medical Genetics and Genomics (ACMG) guidelines, the variant has been classified as pathogenic. At 48 years old, the proband's reevaluation confirmed a demyelinating sensorimotor polyneuropathy with bilateral sensorineural hearing loss that had been noted since he was 13. Additionally, drug‐resistant epileptic seizures occurred when he was 32 years old. No hepatic or endocrinological signs developed. The younger affected brother, 47 years old, has an overlapping clinical presentation without epilepsy. Interpretation: Our findings expand the clinical phenotype and further demonstrate the clinical heterogeneity related to PTRH2 variants. We thereby hope to better define IMNEPD and facilitate the identification and diagnosis of this novel disease entity. [ABSTRACT FROM AUTHOR]

Background and Aims: This study aimed to report nine Charcot–Marie–Tooth disease (CMT) families with six novel IGHMBP2 mutations in our CMT2 cohort and to summarize the genetic and clinical features of all AR‐CMT2S patients reported worldwide. Methods: General information, clinical and neurophysiological data of 275 axonal CMT families were collected. Genetic screening was performed by inherited peripheral neuropathy related genes panel or whole exome sequencing. The published papers reporting AR‐CMT2S from 2014 to 2023 were searched in Pubmed and Wanfang databases. Results: In our CMT2 cohort, we detected 17 AR‐CMT2S families carrying IGHMBP2 mutations and eight were published previously. Among these, c.743 T > A (p.Val248Glu), c.884A > G (p.Asp295Gly), c.1256C > A (p.Ser419*), c.2598_2599delGA (p.Lys868Sfs*16), c.1694_1696delATG (p.Asp565del) and c.2509A > T (p.Arg837*) were firstly reported. These patients prominently presented with early‐onset typical axonal neuropathy and without respiratory dysfunction. So far, 56 AR‐CMT2S patients and 57 different mutations coming from 43 families have been reported in the world. Twenty‐nine of 32 missense mutations were clustered in helicase domain and ATPase region. The age at onset ranged from 0.11to 20 years (Mean ± SD: 3.43 ± 3.88 years) and the majority was infantile‐onset (<2 years). The initial symptoms included weakness of limbs (19, 29.7%), delayed milestones (12, 18.8%), gait disturbance (11, 17.2%), feet deformity (8, 12.5%), feet drop (8, 12.5%), etc. Interpretation: AR‐CMT2S accounted for 6.2% in our CMT2 cohort. We firstly reported six novel IGHMBP2 mutations which expanded the genotypic spectrum of AR‐CMT2S. Furthermore, 17 AR‐CMT2S families could provide more resources for natural history study, drug research and development. [ABSTRACT FROM AUTHOR]

Objective Whether metformin and its adenosine 5'monophosphate-activated protein kinase (AMPK) activation protect from psoriasis risk is unconcluded. We investigated the effect of AMPK, a pharmacological target of metformin, on the risk of psoriasis and its comorbidities and mortality among participants in the UK Biobank (UKB). Methods To avoid immortal time biases in pharmacoepidemiologic studies, Mendelian randomization was used to infer the AMPK pathway-dependent effects. The cut-off age for distinguishing early-onset/late-onset psoriasis (EOP/LOP) was set at 60 years, based on the incident psoriasis peak in UKB. A genetic instrument comprising 44 single-nucleotide polymorphisms associated with glycated haemoglobin (HbA1c), serving as a proxy for AMPK genetic risk score (negatively associated with AMPK activation), was employed as previously reported in the literature. Log-binomial models were used to estimate the effect size of AMPK regarding relative risk (RR) and 95% CI. Results A total of 407 159 participants were analysed, including 9126 EOP and 3324 LOP. The AMPK genetic risk score was associated with a 12.4% increase in the risk of LOP in men (RR = 1.124, 95% CI: 1.022–1.236). This association was not significant for EOP or women. AMPK genetic risk score exhibited an elevated risk of ischemic heart disease (RR = 1.217, 95% CI 1.062–1.395) in male psoriasis patients. Conclusions AMPK activation may protect against LOPs and associated ischemic heart disease in men. A sex-specific, comorbidity-targeted intervention for psoriasis is needed. [ABSTRACT FROM AUTHOR]

A recently published concept considers a significant proportion of the occurrence and persistence of functional movement disorders (FMD) to be explained by increased/incorrect weighting of the expected movement (feedforward signal) in the presence of decreased/altered actual feedback of the movement. In the context of aging and age-associated diseases, there is an increased likelihood that these prerequisites will occur, also in combination. For example, the feedforward signal can be enhanced by accumulation of a wealth of experience but can for example become prone to error due to changes in attention and (fear of) falling. Conversely, the actual feedback is subject to age-related changes, such as reduction of sensory functions. This could explain why FMDs also occur in old age and offer treatment approaches for this so far poorly studied disorder. It follows that a specific focus on (the correction of) feedforward signals and strengthening as well as training of the actual feedback are potentially promising therapeutic approaches for older people with FMD. [ABSTRACT FROM AUTHOR]

Objective The aim of the study is to analyze the risk factors for neonatal acute respiratory distress syndrome (NARDS) development based on the Montreux definition among near- and full-term neonates with sepsis and received meropenem. Study Design This was a single-center, case–control, retrospective trial from January 2019 to June 2020. Newborns of gestational ages (GAs) ≥35 weeks, diagnosed with sepsis and received meropenem were included. Patients who developed NARDS subsequently were defined as the study group (NARDS group), while the others without NARDS were enrolled in the control group (non-NARDS group). Results Out of 213 eligible neonates, NARDS occurred in 52 (24.4%) cases. In univariate analysis, infants with NARDS had a lower GA and birth weight, but a higher rate of premature birth (p <0.05). The median onset times of sepsis were earlier among neonates with NARDS compared with those without NARDS (1 [1,1] vs. 6 [1,15] days, p <0.001). Neonates with NARDS were more likely to suffer from early-onset sepsis (EOS), persistent pulmonary hypertension of newborns, pulmonary hemorrhage, septic shock, and patent ductus arteriosus (p <0.05). During labor, women whose neonates experienced NARDS were more likely to have a cesarean delivery (67.3 vs. 46.6%, p = 0.009) and likely to receive at least one dose of corticosteroids (21.2 vs. 5.0%, p = 0.001). In multivariable analyses, factors remaining independently associated with NARDS were premature birth, cesarean delivery, EOS, and septic shock. Compared with conventional inflammatory markers for NARDS, procalcitonin (PCT) was correlated with septic neonates who developed NARDS (p = 0.012) but had a low diagnostic value (area under the curve [AUC] = 0.609). C-reactive protein, white blood cells, and PLT did not correlate with morbidity of NARDS (AUC <0.05 and p >0.05). Conclusion Premature birth, cesarean delivery, EOS, and septic shock were independently associated with NARDS among near- and full-term septic neonates. PCT showed limited predictive value for NARDS. Key Points NARDS is serious and sepsis is proved as a cause for it. But rare study suggests the risk factors of NARDS based on the Montreux definition. This study may first found the independent risk factors associated with NARDS in septic neonates. [ABSTRACT FROM AUTHOR]

Epigenetics plays an important role in the aging process, but it is unclear whether epigenetic factors also influence frailty, an age‐related state of physiological decline. In this study, we performed a meta‐analysis of epigenome‐wide association studies in four samples drawn from the Swedish Adoption/Twin Study of Aging (SATSA) and the Longitudinal Study of Aging Danish Twins (LSADT) to explore the association between DNA methylation and frailty. Frailty was defined using the frailty index (FI), and DNA methylation levels were measured in whole blood using Illumina's Infinium HumanMethylation450K and MethylationEPIC arrays. In the meta‐analysis consisting of a total of 829 participants, we identified 589 CpG sites that were statistically significantly associated with either the continuous or categorical FI (false discovery rate <0.05). Many of these CpGs have previously been associated with age and age‐related diseases. The identified sites were also largely directionally consistent in a longitudinal analysis using mixed‐effects models in SATSA, where the participants were followed up to a maximum of 20 years. Moreover, we identified three differentially methylated regions within the MGRN1, MIR596, and TAPBP genes that have been linked to neuronal aging, tumor growth, and immune functions. Furthermore, our meta‐analysis results replicated 34 of the 77 previously reported frailty‐associated CpGs at p < 0.05. In conclusion, our findings demonstrate robust associations between frailty and DNA methylation levels in 589 novel CpGs, previously unidentified for frailty, and strengthen the role of neuronal/brain pathways in frailty. [ABSTRACT FROM AUTHOR]

While Brugada syndrome (BrS) is well described in adults and older children, presentation of BrS within the first 12 months of life is rare and therefore poorly characterized. We report a 7‐year‐old male with a malignant BrS phenotype with onset at 8 months of age, leading to multiple ventricular tachycardia (VT) and ventricular fibrillation (VF) related cardiac arrests and ultimately his death. The report is supplemented by a comprehensive review of existing literature on infantile‐onset BrS and unique features in this population are discussed. [ABSTRACT FROM AUTHOR]

A wealth of evidence has emerged that there is an association between aging, senescence and tumorigenesis. Senescence, a biological process by which cells cease to divide and enter a status of permanent cell cycle arrest, contributes to aging and aging-related diseases, including cancer. Aging populations have the higher incidence of cancer due to a lifetime of exposure to cancer-causing agents, reduction of repairing DNA damage, accumulated genetic mutations, and decreased immune system efficiency. Cancer patients undergoing cytotoxic therapies, such as chemotherapy and radiotherapy, accelerate aging. There is growing evidence that p53/MDM2 (murine double minute 2) axis is critically involved in regulation of aging, senescence and oncogenesis. Therefore, in this review, we describe the functions and mechanisms of p53/MDM2-mediated senescence, aging and carcinogenesis. Moreover, we highlight the small molecular inhibitors, natural compounds and PROTACs (proteolysis targeting chimeras) that target p53/MDM2 pathway to influence aging and cancer. Modification of p53/MDM2 could be a potential strategy for treatment of aging, senescence and tumorigenesis. [ABSTRACT FROM AUTHOR]

Simple Summary: A family history of lung cancer has been reported to increase the risk of lung cancer development. Since a family history of lung cancer is generally regarded as an unmodifiable factor, understanding the relationship between a family history of lung cancer and the development of lung cancer is essential for establishing lung cancer screening strategies. However, previous studies on this issue did not consider various characteristics of study participants, such as age, sex, and smoking status, and there is an ongoing debate regarding which subgroups exhibit a higher genetic predisposition to lung cancer. Furthermore, no data are available on the impact of a family history of lung cancer on lung cancer risk in the general Korean population. Therefore, we aimed to investigate the association between a family history of lung cancer in first-degree relatives and lung cancer development through a comprehensive analysis of a large population-based cohort in Korea. Comprehensive analyses of the association between a family history of lung cancer and lung cancer risk are limited, especially in the Korean population. We used baseline data from the Korean Genome and Epidemiology Study, conducted between 2001 and 2013. This study enrolled 198,980 individuals. Lung cancer diagnoses and family histories were determined using questionnaires. Multivariable logistic regression analysis was performed to evaluate the effect of family history on the risk of lung cancer. Of 198,980 individuals, 6296 (3.2%) and 140 (0.1%) had a family history of lung cancer and lung cancer, respectively. Individuals with a family history of lung cancer in first-degree relatives (FDRs) had a higher risk of lung cancer development than those without (adjusted odds ratio [aOR] = 2.28, 95% confidence interval [CI] = 1.11–4.66). This was more pronounced in young individuals (<60 years) who had affected relatives diagnosed with lung cancer before the age of 60 years (aOR = 3.77, 95% CI = 1.19–11.88). In subgroup analyses, this association was more evident in women, never smokers, and young individuals. A family history of lung cancer, especially in FDRs, is a significant risk factor for lung cancer development in Korea. [ABSTRACT FROM AUTHOR]

Simple Summary: Over the last decade, early-onset colorectal cancer incidence has continued to increase. The disparities in outcomes and overall survival (OS) between early-onset colorectal cancer and average-onset colorectal cancer remain controversial. The aim of our study was to compare survival rates and identify potential influential factors affecting outcomes between these two groups. Our results show better overall survival and cancer specific survival in patients with early-onset colorectal cancer which could be contributed to better general health, fewer comorbidities and higher likelihood of receiving aggressive cancer treatments. Background: Early-onset colorectal cancer (EO-CRC) is defined as colorectal cancer diagnosed before the age of 50 years, and its incidence has been increasing over the last decade, now accounting for 10% of all new CRC diagnoses. Average-onset colorectal cancer (AO-CRC) has shown a steady decline in its incidence and related mortality over the past 20 years. The disparities in outcomes and overall survival (OS) between EO-CRC and AO-CRC are controversial. Our study compared OS and cause-specific survival (CSS) between metastatic EO-CRC (mEO-CRC) and metastatic AO-CRC (mAO-CRC) and identified the associated factors. Methods: Data on patient characteristics, tumor characteristics, incidence, and mortality were obtained from the SEER database from 2010 to 2020. We identified 23,278 individuals aged > 18 years with a confirmed diagnosis of all histological subtypes of metastatic CRC (M1 on TNM stage) using ICD-O-3 site codes. mEO-CRC and mAO-CRC were compared. OS distributions and CCS were analyzed using the Kaplan–Meier method and log-rank test to assess differences. A Cox regression model was used to assess the associations between variables. Results: mEO-CRC constituted 17.79% of the cases, whereas 82.21% had mAO-CRC. Most patients with mEO-CRC were 45–49 years old (47.66%), male (52.16%) and White (72.57%) and had adenocarcinoma histology (87.30%). Left colon tumors were most prevalent in both groups (40.26%) but were more prevalent in mEO-CRC patients than in mAO-CRC patients (49.63% vs. 38.23%, p < 0.001). Patients with mEO-CRC had higher OS (p < 0.001) and CSS (p < 0.001) than those with mAO-CRC. Patients with mEO-CRC also had significantly better median overall survival (30 months vs. 18 months, p < 0.001). The factors associated with worse OS included mAO-CRC (p < 0.001), mucinous adenocarcinoma (p < 0.001), male sex (p = 0.003), and a lack of surgical intervention (p < 0.001). Conclusions: Most patients with mEO-CRC fall within the range of 45 to 49 years of age. Patients with mEO-CRC were more likely to receive cancer-directed therapy (including chemotherapy and radiotherapy) and had better OS and CSS than those with mAO-CRC. This is likely attributable to the better performance status, fewer comorbidities, and better tolerance to cancer-directed therapy in mEO-CRC patients. The factors associated with worse OS and CSS were age > 50 years, mucinous adenocarcinoma, male sex, and no surgical treatment. [ABSTRACT FROM AUTHOR]

Simple Summary: This is the first report portraying the situation of childhood acute lymphoblastic leukemia (ALL) in Kosovo over the past 15 years. We examine treatment protocols, remission and relapse rates, and 2-year and 5-year event-free survival (EFS) and overall survival (OS) rates. In our study cohort, 55% of patients achieved 2-year EFS, 40% achieved 5-year EFS, 61% achieved 2-year OS, and 46% achieved 5-year OS, which are lower rates compared to most other studies. These findings emphasize the importance of genotyping for common polymorphisms and therapeutic drug monitoring, which have not been utilized to date, as foundational methods among healthcare providers treating childhood ALL in Kosovo. Advances in research, including novel biomarker identification and patient stratification, have significantly improved the therapy for childhood acute lymphoblastic leukemia (ALL), though access to improved healthcare services varies across geographical regions. In an effort to evaluate the advances in therapeutic approaches, we performed a retrospective analysis of childhood ALL in Kosovo. Our retrospective analysis included 225 cases diagnosed between 2008 and 2023, representing 52% of 429 diagnosed childhood cancers. The average annual incidence was 14, with a median age diagnosis of seven years, and a male predominance (59.54%). Patients were categorized into risk groups, with the majority (43%) in the standard-risk category. We identified five different treatment protocols for this study period. Over 61% of patients achieved remission after the first chemotherapy cycle and we observed a 20% mortality rate. Survival analysis showed that 55% and 40% of patients achieved 2-year and 5-year event-free survival (EFS), respectively, with significant differences across risk groups. Treatment advancements significantly correlated with improved survival rates, achieving a 5-year overall survival (OS) of 88% in the currently used standardized AIEOP-BFM-2009 protocol. Our study emphasizes the need for continued research and customized care strategies to enhance clinical outcomes. [ABSTRACT FROM AUTHOR]

Background: Type 2 diabetes exposes the body to a state of high blood sugar for a long time and causes varying degrees of hardening of the arteries, making it more prone to cardiovascular emergencies. Objective: The aim of the study was to explore the risk factors of early arterial stiffness in patients with type 2 diabetes mellitus (T2DM). Methods: A retrospective study was conducted on 316 T2DM patients without macroangiopathy in The First Hospital of Qinhuangdao. Early arterial stiffness was evaluated by brachial-ankle pulse wave velocity (baPWV). Results: Ninety patients (28.5%) had baPWV≥1800cm/s. baPWV showed positive correlation with systolic blood pressure (r=0.456, p<0.001), diastolic blood pressure (r=0.133, p=0.018), urine albumin-creatinine ratio (UACR) (r=0.232, p<0.001), neutrophil lymphocyte ratio (NLR) (r=0.185, p=0.001), and visceral fat area (r=0.139, p=0.014). In multiple linear regression analysis, systolic blood pressure (β=6.240, p<0.001), UACR (β=3.805, p=0.019), NLR (β=43.722, p=0.013), and visceral fat area (β=0.778, p=0.030) were significant independent predictors for baPWV. Conclusion: The decline of arterial elasticity was common in T2DM patients without macroangiopathy. Elevated blood pressure, microangiopathy, chronic inflammation, and visceral fat accumulation were the risk factors of early arterial stiffness in patients with T2DM. [ABSTRACT FROM AUTHOR]

Osteoporosis is a disease characterized by loss of bone mass, where bones become fragile and more likely to fracture. Bone density begins to decrease at age 50, and a state of osteoporosis is defined by loss of more than 25%. Cellular senescence is a permanent arrest of normal cell cycle, while maintaining cell viability. The number of senescent cells increase with age. Since osteoporosis is an aging disease, it is natural to consider the question to what extend senescent cells induce bone density loss and osteoporosis. In this paper we use a mathematical model to address this question. We determine the percent of bone loss for men and women during age 50 to 100 years, and the results depend on the rate η of net formation of senescent cell, with η = 1 being the average rate. In the case η = 1, the model simulations are in agreement with empirical data. We also consider senolytic drugs, like fisetin and quercetin, that selectively eliminate senescent cells, and assess their efficacy in terms of reducing bone loss. For example, at η = 1, with estrogen hormonal therapy and early treatment with fisetin, bone density loss for women by age 75 is 23.4% (below osteoporosis), while with no treatment with fisetin it is 25.8% (osteoporosis); without even a treatment with estrogen hormonal therapy, bone loss of 25.3% occurs already at age 65. [ABSTRACT FROM AUTHOR]

Mitochondria reside at the crossroads of catabolic and anabolic metabolism—the essence of life. How their structure and function are dynamically tuned in response to tissue-specific needs for energy, growth repair, and renewal is being increasingly understood. Mitochondria respond to intrinsic and extrinsic stresses and can alter cell and organismal function by inducing metabolic signaling within cells and to distal cells and tissues. Here, we review how the centrality of mitochondrial functions manifests in health and a broad spectrum of diseases and aging. Mitochondria, central to metabolic processes, adapt their structure and function to meet cellular energy and repair demands. Understanding of their role in responding to stresses and signaling for cellular and systemic health, disease, and aging is expanding. [ABSTRACT FROM AUTHOR]

Adverse neonatal outcomes are a prevailing risk factor for both short- and long-term mortality and morbidity in infants. Given the importance of these outcomes, refining their assessment is paramount for improving prevention and care. Here we aim to enhance the assessment of these often correlated and multifaceted neonatal outcomes. To achieve this, we employ factor analysis to identify common and unique effects and further confirm these effects using criterion-related validity testing. This validation leverages methylome-wide profiles from neonatal blood. Specifically, we investigate nine neonatal health risk variables, including gestational age, Apgar score, three indicators of body size, jaundice, birth diagnosis, maternal preeclampsia, and maternal age. The methylomic profiles used for this research capture data from nearly all 28 million methylation sites in human blood, derived from the blood spot collected from 333 neonates, within 72 h post-birth. Our factor analysis revealed two common factors, size factor, that captured the shared effects of weight, head size, height, and gestational age and disease factor capturing the orthogonal shared effects of gestational age, combined with jaundice and birth diagnosis. To minimize false positives in the validation studies, validation was limited to variables with significant cumulative association as estimated through an in-sample replication procedure. This screening resulted in that the two common factors and the unique effects for gestational age, jaundice and Apgar were further investigated with full-scale cell-type specific methylome-wide association analyses. Highly significant, cell-type specific, associations were detected for both common effect factors and for Apgar. Gene Ontology analyses revealed multiple significant biologically relevant terms for the five fully investigated neonatal health risk variables. Given the established links between adverse neonatal outcomes and both immediate and long-term health, the distinct factor effects (representing the common and unique effects of the risk variables) and their biological profiles confirmed in our work, suggest their potential role as clinical biomarkers for assessing health risks and enhancing personalized care. [ABSTRACT FROM AUTHOR]

Background: Sepsis is one of the main causes of death in newborns worldwide. Vitamin D levels during fetal and neonatal periods have a significant role in the development of the immunological system. The study aims to evaluate the association between vitamin D levels and the risk of early-onset neonatal sepsis in full-term neonates in a developing country. Methods: This case–control study was conducted at the Neonatal Intensive Care Units (NICUs) of Kasr Alainy Hospital, Cairo, Egypt. The study was composed of two groups; the sepsis group involved full-term neonates appropriate for gestational age with sepsis-related clinical signs. The control group included newborns with no signs of clinical/laboratory infection within 72 h of life. Blood samples were collected on admission during the first three days of life in both groups for the measurement of 25-hydroxyvitamin D levels, Complete Blood Count (CBC), C reactive protein (CRP), and blood culture. Results: Forty-five newborns with clinical and laboratory findings of early-onset neonatal sepsis within 72 h of life were enrolled, and the control group included forty-five newborns with no evidence of sepsis. Vitamin D levels in the sepsis group were significantly lower than in the control group. Apgar score at the first minute was significantly lower in the sepsis group. 57.8% of neonates with sepsis had positive blood cultures. There was a statistical difference between deficient, insufficient, and sufficient vitamin D levels regarding the duration of the NICU stay, which was longer in neonates with deficient vitamin D levels. CRP was significantly higher in neonates with deficient vitamin D levels. The area under the receiver operating characteristic curve for serum vitamin D in the prediction of neonatal sepsis was 0.76 at a cutoff < 19.7(ng/ml). Conclusion: In the current study, full-term newborns with EOS had considerably lower vitamin D levels than healthy controls. Through appropriate vitamin supplementation of the mothers during pregnancy, it could be possible to ensure adequate vitamin D levels for newborns. This may contribute to the reduction of the risk of EOS, together with the other well-known preventive measures (i.e. breastfeeding and intrapartum antibiotic prophylaxis). [ABSTRACT FROM AUTHOR]

Aging affects all cell types in the CNS and plays an important role in CNS diseases. However, the underlying molecular mechanisms driving these age-associated changes and their contribution to diseases are only poorly understood. The white matter in the aging brain as well as in diseases, such as Multiple sclerosis is characterized by subtle abnormalities in myelin sheaths and paranodes, suggesting that oligodendrocytes, the myelin-maintaining cells of the CNS, lose the capacity to preserve a proper myelin structure and potentially function in age and certain diseases. Here, we made use of directly converted oligodendrocytes (dchiOL) from young, adult and old human donors to study age-associated changes. dchiOL from all three age groups differentiated in an comparable manner into O4 + immature oligodendrocytes, but the proportion of MBP + mature dchiOL decreased with increasing donor age. This was associated with an increased ROS production and upregulation of cellular senescence markers such as CDKN1A, CDKN2A in old dchiOL. Comparison of the transcriptomic profiles of dchiOL from adult and old donors revealed 1324 differentially regulated genes with limited overlap with transcriptomic profiles of the donors' fibroblasts or published data sets from directly converted human neurons or primary rodent oligodendroglial lineage cells. Methylome analyses of dchiOL and human white matter tissue samples demonstrate that chronological and epigenetic age correlate in CNS white matter as well as in dchiOL and resulted in the identification of an age-specific epigenetic signature. Furthermore, we observed an accelerated epigenetic aging of the myelinated, normal appearing white matter of multiple sclerosis (MS) patients compared to healthy individuals. Impaired differentiation and upregulation of cellular senescence markers could be induced in young dchiOL in vitro using supernatants from pro-inflammatory microglia. In summary, our data suggest that physiological aging as well as inflammation-induced cellular senescence contribute to oligodendroglial pathology in inflammatory demyelinating diseases such as MS. [ABSTRACT FROM AUTHOR]

Background: This study aimed to assess the anthropometric measures and pubertal growth of children and adolescents with Type 1 diabetes mellitus (T1DM) and to detect risk determinants affecting these measures and their link to glycemic control. Patients and methods: Two hundred children and adolescents were assessed using anthropometric measurements. Those with short stature were further evaluated using insulin-like growth factor 1 (IGF-1), bone age, and thyroid profile, while those with delayed puberty were evaluated using sex hormones and pituitary gonadotropins assay. Results: We found that 12.5% of our patients were short (height SDS < -2) and IGF-1 was less than -2 SD in 72% of them. Patients with short stature had earlier age of onset of diabetes, longer duration of diabetes, higher HbA1C and urinary albumin/creatinine ratio compared to those with normal stature (p < 0.05). Additionally, patients with delayed puberty had higher HbA1c and dyslipidemia compared to those with normal puberty (p < 0.05). The regression analysis revealed that factors associated with short stature were; age at diagnosis, HbA1C > 8.2, and albumin/creatinine ratio > 8 (p < 0.05). Conclusion: Children with uncontrolled T1DM are at risk of short stature and delayed puberty. Diabetes duration and control seem to be independent risk factors for short stature. [ABSTRACT FROM AUTHOR]

Objectives: The lesion distribution of juvenile-onset recurrent respiratory papillomatosis (JORRP) during first-time surgery has been rarely reported. The purpose of this study was to describe the anatomical distribution of papilloma across 25 Derkay sites during initial surgery and to assess the impact of the lesion distribution on disease severity. Methods: Surgical videos and medical records of 106 patients with JORRP (27 aggressive and 79 nonaggressive cases) were retrospectively reviewed. Lesion locations were recorded using Derkay anatomical sites. Logistic regression was used to analyze the effect of the lesion distribution on disease severity. Results: Among the 106 patients, the true vocal cords (90.6% left, 84.0% right) were the most frequently involved site, followed by the false vocal cords (39.6% left, 35.8% right) and the anterior commissure (26.4%). Two patients (1.9%) had tracheal involvement. Patients with false vocal cord involvement (odds ratio [OR] = 3.425, 95% confidence interval [CI] [1.285, 9.132], P =.014) and a younger age at diagnosis (OR =.698, 95% CI [.539,.905], P =.007) were more likely to require more than 4 procedures in the year following first-time surgery. Conclusions: Lesions were most common on the true vocal cords. False vocal cord involvement and a younger age at diagnosis were risk factors for disease severity. [ABSTRACT FROM AUTHOR]

OBJECTIVES: This study simulated the potential multiyear health and economic benefits of participation in 4 cardiometabolic virtual-first care (V1C) programs: prevention, hypertension, diabetes, and diabetes plus hypertension. STUDY DESIGN: Using nationally available data and existing clinical and demographic information from members participating in cardiometabolic V1C programs, a microsimulation approach was used to estimate potential reduction in onset of disease sequelae and associated gross savings (ie, excluding the cost of V1C programs) in health care costs. METHODS: Members of each program were propensity matched to similar records in the combined 2012-2020 National Health and Nutrition Examination Survey files based on age, sex, race/ethnicity, body mass index, and diagnosis status of diabetes and/or hypertension. V1C program-attributed changes in clinical outcomes combined with baseline biometric levels and other risk factors were used as inputs to model disease onset and related gross health care costs. RESULTS: Across the V1C programs, sustained improvements in weight loss, hemoglobin A1c, and blood pressure levels were estimated to reduce incidence of modeled disease sequelae by 2% to 10% over the 5 years following enrollment. As a result of sustained improvement in biometrics and reduced disease onset, the estimated gross savings in medical expenditures across the programs would be $892 to $1342 after 1 year, and cumulative estimated gross medical savings would be $2963 to $4346 after 3 years and $5221 to $7756 after 5 years. In addition, high program engagement was associated with greater health and economic benefits. CONCLUSIONS: V1C programs for prevention and management of cardiometabolic chronic conditions have potential long-term health and financial implications. [ABSTRACT FROM AUTHOR]

Objective: Warthin's tumours are the second most common benign parotid tumours in the UK. The World Health Organization states that 5–14 per cent of patients have bilateral Warthin's tumours. This study aimed to: assess the presence of contralateral Warthin's tumours in patients who underwent surgery over the past 16 years at a head and neck unit in England, and perform the first systematic literature review on bilateral Warthin's tumours. Methods: A retrospective analysis was conducted on patients diagnosed with Warthin's tumour based on histology between 2005 and 2020. Additionally, a systematic review (International Prospective Register of Systematic Reviews ('PROSPERO') registration number: CRD42022326846) was performed using PubMed and the Cochrane Library. Results: Among 290 patients diagnosed with Warthin's tumours based on histology following surgery, 24.5 per cent had bilateral Warthin's tumours. The systematic review identified 157 papers, with 14 meeting the inclusion criteria. Conclusion: This study revealed that 24.5 per cent of patients had bilateral Warthin's tumours, deviating from the suggested range. These findings are of interest to surgeons discussing the disease with patients. [ABSTRACT FROM AUTHOR]

Objectives We evaluated the association between anti-ribosomal P antibody (anti-RibP) titres and disease activity in Japanese SLE patients. Methods Eighty patients admitted and treated in Niigata University Hospital for new-onset or flare-up of SLE were included in this retrospective cross-sectional study. Clinical data were obtained from medical records at admission. The anti-RibP index, and cytokine and tryptophan metabolite levels were determined by ELISA. Results Of the 80 SLE patients, 30 had anti-RibP. Anti-RibP presence was associated with a greater prevalence of skin rash and more severe inflammatory responses, demonstrated by higher inflammatory cytokine levels, hypocomplementemia, and accelerated tryptophan metabolism, in younger patients. The serum anti-RibP index was correlated with age at diagnosis, clinical indicators, initial prednisolone dose, and cytokines and tryptophan metabolite levels in univariate analysis. Multivariate analysis showed that the anti-RibP index was independently associated with the initial prednisolone dose and the prevalence of skin rash. The anti-RibP IgGs were mainly the IgG2 and IgG3 subclasses, and anti-RibP IgG3 was associated with hypocomplementemia, higher DAS, accelerated kynurenine pathway activity, and higher proinflammatory cytokine production. The coexistence of anti-dsDNA IgG and anti-RibP IgG2 or IgG3 accompanied higher IL-10 and IFN-α2 levels; furthermore, anti-RibP IgG3 coexistence with anti-dsDNA antibody contributed to the requirement for higher initial prednisolone doses and accelerated kynurenine pathway activity. Conclusion Anti-RibP was associated with clinical manifestations and parameters in SLE, and its index might be a useful indicator of disease severity. Anti-RibP IgG3 was the IgG subclass most strongly associated with the pathogenesis of SLE. [ABSTRACT FROM AUTHOR]

Objectives: Cerebral Small Vessel Disease (CSVD) is a chronic, progressive vascular disorder that confers increased vulnerability to psychiatric syndromes, including late‐life mood disorders. In this study, we investigated the impact of CSVD on electroconvulsive therapy (ECT) outcomes in patients with late‐onset bipolar disorder (BD). Methods: A sample of 54 non‐demented elderly patients (≥60 years) with late‐onset BD and treatment‐resistant major depression, mixed state, or catatonia who underwent bilateral ECT were included in this naturalistic observational study. A diagnosis of CSVD was established based on brain neuroimaging performed before ECT. All patients were evaluated before and after ECT using the Brief Psychiatric Rating Scale (BPRS), the Hamilton Rating Scale for Depression (HAM‐D), and the Clinical Global Impression scale (CGI). Results: Of the total sample, 19 patients were diagnosed with CSVD (35.2%). No significant differences were observed at baseline between patients with and without CSVD. Overall, a response was obtained in 66%–68.5% of patients, with remission in 56.2%. No significant differences in ECT outcomes were found between those with and without CSVD, and both groups exhibited substantial improvements in symptom severity following ECT. Conclusions: The outcome of ECT in late‐onset BD was not influenced by the presence of CSVD. This finding aligns with previous research on unipolar depression. Accordingly, ECT should be considered for elderly patients with late‐onset BD, regardless of the presence of CSVD. Key points: CSVD was found in 19 out of 54 (35.2%) elderly with late‐onset BD referred to ECT.Response to ECT was achieved in about two‐thirds of patients with late‐onset BD.ECT was equally effective in patients with and without CSVD. [ABSTRACT FROM AUTHOR]

The extraocular muscles (EOMs) possess unique characteristics that set them apart from other skeletal muscles. These muscles, responsible for eye movements, exhibit remarkable resistance to various muscular dystrophies and aging, presenting a significant contrast to the vulnerability of skeletal muscles to these conditions. In this review, we delve into the cellular and molecular underpinnings of the distinct properties of EOMs. We explore their structural complexity, highlighting differences in fiber types, innervation patterns, and developmental origins. Notably, EOM fibers express a diverse array of myosin heavy-chain isoforms, retaining embryonic forms into adulthood. Moreover, their motor innervation is characterized by a high ratio of nerve fibers to muscle fibers and the presence of unique neuromuscular junctions. These features contribute to the specialized functions of EOMs, including rapid and precise eye movements. Understanding the mechanisms behind the resilience of EOMs to disease and aging may offer insights into potential therapeutic strategies for treating muscular dystrophies and myopathies affecting other skeletal muscles. [ABSTRACT FROM AUTHOR]

Dynamic changes in genomic DNA methylation patterns govern the epigenetic developmental programs and accompany the organism's aging. Epigenetic clock (eAge) algorithms utilize DNA methylation to estimate the age and risk factors for diseases as well as analyze the impact of various interventions. High-throughput bisulfite sequencing methods, such as reduced-representation bisulfite sequencing (RRBS) or whole genome bisulfite sequencing (WGBS), provide an opportunity to identify the genomic regions of disordered or heterogeneous DNA methylation, which might be associated with cell-type heterogeneity, DNA methylation erosion, and allele-specific methylation. We systematically evaluated the applicability of five scores assessing the variability of methylation patterns by evaluating within-sample heterogeneity (WSH) to construct human blood epigenetic clock models using RRBS data. The best performance was demonstrated by the model based on a metric designed to assess DNA methylation erosion with an MAE of 3.686 years. We also trained a prediction model that uses the average methylation level over genomic regions. Although this region-based model was relatively more efficient than the WSH-based model, the latter required the analysis of just a few short genomic regions and, therefore, could be a useful tool to design a reduced epigenetic clock that is analyzed by targeted next-generation sequencing. [ABSTRACT FROM AUTHOR]

Aging and age-related diseases are associated with a decline in the capacity of protein turnover. Intrinsically disordered proteins, as well as proteins misfolded and oxidatively damaged, prone to aggregation, are preferentially digested by the ubiquitin-independent proteasome system (UIPS), a major component of which is the 20S proteasome. Therefore, boosting 20S activity constitutes a promising strategy to counteract a decrease in total proteasome activity during aging. One way to enhance the proteolytic removal of unwanted proteins appears to be the use of peptide-based activators of the 20S. In this study, we synthesized a series of peptides and peptidomimetics based on the C-terminus of the Rpt5 subunit of the 19S regulatory particle. Some of them efficiently stimulated human 20S proteasome activity. The attachment of the cell-penetrating peptide TAT allowed them to penetrate the cell membrane and stimulate proteasome activity in HEK293T cells, which was demonstrated using a cell-permeable substrate of the proteasome, TAS3. Furthermore, the best activator enhanced the degradation of aggregation-prone α-synuclein and Tau-441. The obtained compounds may therefore have the potential to compensate for the unbalanced proteostasis found in aging and age-related diseases. [ABSTRACT FROM AUTHOR]

The older population is increasing worldwide, and life expectancy is continuously rising, predominantly thanks to medical and technological progress. Healthspan refers to the number of years an individual can live in good health. From a gerontological viewpoint, the mission is to extend the life spent in good health, promoting well‐being and minimizing the impact of aging‐related diseases to slow the aging process. Biologically, aging is a malleable process characterized by an intra‐ and inter‐individual heterogeneous and dynamic balance between accumulating damage and repair mechanisms. Cellular senescence is a key component of this process, with senescent cells accumulating in different tissues and organs, leading to aging and age‐related disease susceptibility over time. Removing senescent cells from the body or slowing down the burden rate has been proposed as an efficient way to reduce age‐dependent deterioration. In animal models, senotherapeutic molecules can extend life expectancy and lifespan by either senolytic or senomorphic activity. Much research shows that dietary and physical activity‐driven lifestyle interventions protect against senescence. This narrative review aims to summarize the current knowledge on targeting senescent cells to reduce the risk of age‐related disease in animal models and their translational potential for humans. We focused on studies that have examined the potential role of senotherapeutics in slowing the aging process and modifying age‐related disease burdens. The review concludes with a general discussion of the mechanisms underlying this unique trajectory and its implications for future research. [ABSTRACT FROM AUTHOR]

This systematic review aimed to (1) synthesize average means and prevalence rates of adverse childhood experiences (ACEs) measured by the Adverse Childhood Experiences International Questionnaire (ACE‐IQ) in clinical and at‐risk samples; (2) discuss the ACE‐IQ prevalence and means according to participants' gender, age (both adults and <18 years old), and geographic area; (3) map relationships between ACE‐IQ scores and other outcomes; (4) detect methodological issues in studies. PRISMA guidelines were followed, searching studies in seven academic databases, including retrieval of grey literature. After screening, 23 studies were included. Results revealed the following: (1) several clinical (e.g., mood disorders and substance abuse) and at‐risk (e.g., criminal and low‐income) conditions were studied, with an average 4.93 mean and 81.74% prevalence of total ACEs; (2) there is a lack of data on males, with the prevalence of domestic violence and physical neglect being especially marked in minors, and no studies involving European and North‐American at‐risk samples; (3) ACE‐IQ scores were mostly related to substance abuse and risk‐taking behaviours; (4) major methodological issues were not‐randomized/convenience sampling techniques and a lack of methodological information on sample and procedure. In conclusion, the ACE‐IQ seems a promising tool in clinical/at‐risk samples, but more studies are needed to answer all research questions. [ABSTRACT FROM AUTHOR]

The phenomenon of an aging population is advancing at a precipitous rate. Alzheimer's disease (AD) and Parkinson's disease (PD) are two of the most common age-associated neurodegenerative diseases, both of which are primarily characterized by the accumulation of toxic proteins and the progressive demise of neuronal structures. Recent discoveries about the brain lymphatic drainage system have precipitated a growing body of investigations substantiating its novel roles, including the clearance of macromolecular waste and the trafficking of immune cells. Notably, aquaporin 4-mediated glymphatic transport, crucial for maintaining neural homeostasis, becomes disrupted during the aging process and is further compromised in the pathogenesis of AD and PD. Functional meningeal lymphatic vessels, which facilitate the drainage of cerebrospinal fluid into the deep cervical lymph nodes, are integral in bridging the central nervous system with peripheral immune responses. Dysfunction in these meningeal lymphatic vessels exacerbates pathological trajectory of the age-related neurodegenerative disease. This review explores modulatory influence of the glymphatic system and meningeal lymphatic vessels on the aging brain and its associated neurodegenerative disorders. It also encapsulates the insights of potential mechanisms and prospects of the targeted non-pharmacological interventions. [ABSTRACT FROM AUTHOR]

Background: Young‐onset dementia (YOD) community care requires personalised approaches. Yet, the specific details of YOD consultations are unclear. This study explored how initial consultations correlate with client profiles. Methods: Data from regional YOD helplines were used to analyze the main characteristics of people living with YOD or who had concerns about the possibility of YOD (n = 132). Among several categorical variables, the following were used for analysis: age group, sex, type of living arrangement, employment status, presence of dementia, and content of the consultation. To identify groups of items that frequently occur together, strongly connected rules were identified using association rule analysis with the a priori algorithm. To focus on the characteristics of clients, rules related to client characteristics were extracted based on the type of consultation. Results: A total of 51 rules were identified for the consultations. These rules fell into two categories: (1) consultations for medical matters, which mainly involved employed individuals with undiagnosed dementia, and (2) other consultations on daily life or work, which mainly involved individuals diagnosed with dementia and were characterised by the influence of sex. These rules indicate the importance of medical involvement in confirming the diagnosis and specific individualised care following diagnosis for people living with YOD. Conclusion: Clients with or without a dementia diagnosis were consulted differently in the YOD helplines. Before receiving a diagnosis, medical matters were the main theme of consultations, whereas after receiving a diagnosis, adjustments to daily life or work were the main themes. The results of this study suggest that the needs of people living with YOD and the services they require may vary depending on their backgrounds. [ABSTRACT FROM AUTHOR]

Aims: Most evidence on psychosocial factors in recent-onset psychosis comes from high-income countries in Europe, Australia, Canada and the USA, while these factors are likely to differ under varying sociocultural and economic circumstances. In this study, we aimed to investigate associations of self-stigma, religiosity and perceived social support with symptom severity and psychosocial functioning in an Iranian cohort of people with recent-onset psychosis (i.e. illness duration of <2 years). Methods: We used baseline data of 361 participants (N = 286 [74%] male, mean age = 34 years [Standard Deviation = 10.0]) from the Iranian Azeri Recent-onset Acute Phase Psychosis Survey (ARAS). We included assessments of self-stigma (Internalized Stigma of Mental Illness, ISMI), religiosity (based on Stark & Glock), perceived social support (Multidimensional Scale of Perceived Social Support, MSPSS), symptom severity (Positive And Negative Syndrome Scale, PANSS) and psychosocial functioning (clinician-rated Global Assessment of Functioning Scale, GAF, and self-reported World Health Organization Disability Assessment Schedule 2.0, WHODAS 2.0). Descriptive analyses were employed to characterize the study sample. Covariate-adjusted ordinal and multivariable linear regression analyses were performed to investigate cross-sectional associations of baseline ISMI, religiosity and MSPSS with concurrent PANSS, GAF and WHODAS 2.0. Results: Higher self-stigma was associated with poorer self-reported functioning (B = 0.375 [95% Confidence Interval (CI): 0.186, 0.564]) and more severe concurrent symptoms (B = 0.436 [95% CI: 0.275, 0.597]). Being more religious was associated with poorer clinician-rated functioning (OR = 0.967 [95% CI: 0.944, 0.991]), but with less severe symptoms (B = −0.258 [95% CI: −0.427, −0.088]). Stronger social support was associated with poorer clinician-rated (OR = 0.956 [95% CI: 0.935, 0.978]) and self-reported functioning (B = 0.337 [95% CI: 0.168, 0.507]). Conclusion: This study shows that self-stigma, religiosity and perceived social support were associated with symptom severity and clinician-rated as well as self-reported psychosocial functioning in an Iranian cohort of people with recent-onset psychosis. The findings extend previous evidence on these psychosocial factors to one of the largest countries in the Middle East, and suggest that it may be worthwhile to develop strategies aimed at tackling stigma around psychosis and integrate the role of religiosity and social support in mental ill-health prevention and therapy. [ABSTRACT FROM AUTHOR]

We aimed to evaluate differences in dietary factors between young-onset (diagnosed at ages <50) and older-onset colorectal cancer (CRC). CRC patients diagnosed from 1998 to 2018 reported to the Puget Sound Surveillance, Epidemiology, and End Results registry were recruited using mail and telephone. Consented patients completed questionnaires assessing demographics, medical history, and CRC risk factors, including dietary factors. We used multi-variable logistic regression to calculate adjusted odds ratios (ORs) and 95% confidence intervals (CIs) comparing dietary intake in young-onset vs. older-onset CRC. Analyses included 1,087 young- and 2,554 older-onset CRC patients. Compared to older-onset CRC, young-onset CRC patients had lower intake of vegetables (OR for highest intake vs. lowest = 0.59 CI: 0.55, 0.64) and fruit (OR for highest intake vs. lowest = 0.94 CI: 0.88, 0.99) and higher intake of processed meat (OR for highest intake vs. lowest = 1.82 CI: 1.11, 2.99) and spicy food (OR for highest intake vs. lowest = 1.69 CI: 1.09, 2.61). There was no statistically significant difference between young- and older-onset CRC patients for red meat consumption. Dietary patterns differed between young- and older-onset CRC; young-onset CRC patients had lower intake of vegetables and fruit and higher intakes of processed meat and spicy food. [ABSTRACT FROM AUTHOR]

Background: There is growing evidence that gray matter atrophy is constrained by normal brain network (or connectome) architecture in neuropsychiatric disorders. However, whether this finding holds true in individuals with depression remains unknown. In this study, we aimed to investigate the association between gray matter atrophy and normal connectome architecture at individual level in depression. Methods: In this study, 297 patients with depression and 256 healthy controls (HCs) from two independent Chinese dataset were included: a discovery dataset (105 never-treated first-episode patients and matched 130 HCs) and a replication dataset (106 patients and matched 126 HCs). For each patient, individualized regional atrophy was assessed using normative model and brain regions whose structural connectome profiles in HCs most resembled the atrophy patterns were identified as putative epicenters using a backfoward stepwise regression analysis. Results: In general, the structural connectome architecture of the identified disease epicenters significantly explained 44% (±16%) variance of gray matter atrophy. While patients with depression demonstrated tremendous interindividual variations in the number and distribution of disease epicenters, several disease epicenters with higher participation coefficient than randomly selected regions, including the hippocampus, thalamus, and medial frontal gyrus were significantly shared by depression. Other brain regions with strong structural connections to the disease epicenters exhibited greater vulnerability. In addition, the association between connectome and gray matter atrophy uncovered two distinct subgroups with different ages of onset. Conclusions: These results suggest that gray matter atrophy is constrained by structural brain connectome and elucidate the possible pathological progression in depression. [ABSTRACT FROM AUTHOR]

Background: Although diagnostic instability in first-episode psychosis (FEP) is of major concern, little is known about its determinants. This very long-term follow-up study aimed to examine the diagnostic stability of FEP diagnoses, the baseline predictors of diagnostic change and the timing of diagnostic change. Methods: This was a longitudinal and naturalistic study of 243 subjects with FEP who were assessed at baseline and reassessed after a mean follow-up of 21 years. The diagnostic stability of DSM-5 psychotic disorders was examined using prospective and retrospective consistencies, logistic regression was used to establish the predictors of diagnostic change, and survival analysis was used to compare time to diagnostic change across diagnostic categories. Results: The overall diagnostic stability was 47.7%. Schizophrenia and bipolar disorder were the most stable diagnoses, with other categories having low stability. Predictors of diagnostic change to schizophrenia included a family history of schizophrenia, obstetric complications, developmental delay, poor premorbid functioning in several domains, long duration of untreated continuous psychosis, spontaneous dyskinesia, lack of psychosocial stressors, longer duration of index admission, and poor early treatment response. Most of these variables also predicted diagnostic change to bipolar disorder but in the opposite direction and with lesser effect sizes. There were no significant differences between specific diagnoses regarding time to diagnostic change. At 10-year follow-up, around 80% of the diagnoses had changed. Conclusions: FEP diagnoses other than schizophrenia or bipolar disorder should be considered as provisional. Considering baseline predictors of diagnostic change may help to enhance diagnostic accuracy and guide therapeutic interventions. [ABSTRACT FROM AUTHOR]

In Denmark, people are expected to take responsibility for their health, not least as their bodies age and they experience signs of physical or mental decline. Drawing on fieldwork among older Danes, I illustrate that an excessive focus on health gives rise to social and structural controversies and disparities, linking ideas of healthy behavior at the individual level with the societal framing of disease and aging. I argue that this emphasis contributes to the unwarranted diagnosis of bodily variations that naturally occur in the aging process, a phenomenon referred to as overdiagnosis, adding to a broader medicalization of old age. [ABSTRACT FROM AUTHOR]

Aims: The aim is to identify people with HNF1A‐MODY among individuals in diabetic cohort solely based on low hs‐CRP serum level and early diabetes onset. Methods: In 3537 participants, we analyzed the hs‐CRP levels. We analyzed the HNF1A gene in 50 participants (1.4% of the cohort) with type 1 or type 2 diabetes who had hs‐CRP ≤0.25 mg/L and were diagnosed with diabetes mellitus (DM) at the age of 8–40 years. We functionally characterized two identified missense variants. Results: Three participants had a rare variant in the HNF1A gene, two of which we classified as likely pathogenic: c.1369_1384dup (p.Val462Aspfs*92) and c.737T>G (p.Val246Gly), and one as likely benign: c.1573A>T (p.Thr525Ser). Our functional studies revealed that p.Val246Gly decreased HNF1α transactivation activity to ~59% and the DNA binding ability to ~16% of the wild‐type, while p.Thr525Ser variant showed no effect on transactivation activity, DNA binding, nor nuclear localization. Based on the two identified HNF1A‐MODY patients among 3537 people with diabetes, we estimate 0.057% as the minimal HNF1A‐MODY prevalence in Slovakia. A positive predictive value of hs‐CRP ≤0.25 mg/L for finding HNF1A‐MODY individuals was 4.0% (95% CI 0.7%, 13.5%). Conclusions: Hs‐CRP value and age of DM onset could be an alternative approach to current diagnostic criteria with a potential to increase the diagnostic rate of HNF1A‐MODY. [ABSTRACT FROM AUTHOR]

Simple Summary: Colorectal cancer is one of the leading causes of cancer-related deaths in the US. Lately, there has been a rise in colorectal cancer in younger patients; however, there is a paucity of data on geographical variations of early-onset colorectal cancer in the US. Thus, our study aimed to evaluate the temporal change in early-onset colorectal cancer incidence rates in different regions in the US and assess these trends by sex and histopathological subtypes. We analyzed data from 2001 to 2020 from the United States Cancer Statistics database, which encompasses nearly 98% of the US population. Our results demonstrated that early-onset colorectal cancer incidence rates and time trends increased in men and women across different regions in the US, with the steepest increase noted in the west and the least in the south. These findings persisted across both main colorectal cancer histopathological subtypes (adenocarcinoma and neuroendocrine tumors) with neuroendocrine tumors showing a more pronounced increase compared to adenocarcinoma, especially in the west and northeast. Our findings hold public health implications prompting healthcare policies and future research to investigate any disproportional exposure to region-specific risk factors over the past two decades in the US, especially in western regions. Background: Colorectal cancer remains the second leading cause of cancer-related death in the US. As early-onset colorectal cancer (EO-CRC) becomes more prevalent in the US, research attention has shifted towards identifying at-risk populations. Previous studies have highlighted the rising rate of early-onset adenocarcinoma (ADC) and neuroendocrine tumors (NET) in the US. However, data on geographical variations of EO-CRC are scarce. Hence, our study aims to analyze time trends in EO-CRC incidence rates across various US regions and to assess these trends by sex and histopathological subtypes (ADC and NET). Methods: We analyze data spanning from 2001 to 2020 from the United States Cancer Statistics (USCS) database, covering nearly 98% of the US population. Using SEER*Stat software version (8.4.2, NCI), we calculated EO-CRC incidence rates among adults aged 20–54 years, adjusting for the age standard 2000 US population. The rates were categorized by sex and US geographical regions into west, midwest, northeast, and south. Time trends, reported as annual percentage change (APC) and average APC (AAPC), were generated via Joinpoint Regression software (v.5.0.2, NCI) utilizing the weighted Bayesian Information Criteria "BIC" method to generate the best-fit trends with a two-sided p-value cutoff at 0.05. The rates were also stratified by histopathology into ADC and NET. Results: Between 2001 and 2020, a total of 514,875 individuals were diagnosed with early-onset CRC in the US, with 54.78% being men. Incidence rates and trends varied across geographical regions. In the western region (comprising 106,685 patients, 54.85% men), incidence rates significantly increased in both women (AAPC = 1.37, p < 0.001) and men (AAPC = 1.34, p < 0.001). Similarly, in the midwestern region (with 110,380 patients, 55.46% men), there were significant increases in incidence rates among women (AAPC = 1.06, p < 0.001) and men (AAPC = 1.35, p < 0.001). The northeastern region (with 94,758 patients, 54.53% men) also witnessed significant increases in incidence rates for both women (AAPC = 0.71, p < 0.001) and men (AAPC = 0.84, p < 0.001). In contrast, the southern region (with 203,052 patients, 54.48% men) experienced slower increases in incidence rates among both women and men (AAPC = 0.25, p < 0.05 in women; AAPC = 0.66, p < 0.05 in men). When stratified by histopathology, incidence rates for adenocarcinomas (ADC) increased in all regions, most notably in the west (AAPC = 1.45, p < 0.05), and least in the south (AAPC = 0.46, p < 0.05). Conversely, for neuroendocrine tumors (NET), while incidence rates increased similarly across all regions, the pace was notably faster compared to ADC, particularly in the west (AAPC = 3.26, p < 0.05) and slower in the south (AAPC = 2.24, p < 0.05) Discussion: Our analysis of nationwide US data spanning two decades and encompassing over half a million early-onset CRC patients, representing nearly 98% of the US population, highlights significant temporal variation in incidence rates across various geographical regions. The most substantial increases in incidence rates were observed in the west, while the least pronounced changes were noted in the south, affecting both men and women. These trends persisted across the main CRC histopathological subtypes, with NET exhibiting a notably swifter pace of increase compared with ADC. These findings hold important implications for public health strategies and underscore the need for targeted interventions to address the rising burden of early-onset CRC across different regions in the US. [ABSTRACT FROM AUTHOR]