Midlife sensory and motor functions improve prediction of blood-based measures of neurodegeneration and Alzheimer's disease in late middle-age.

INTRODUCTION: We assessed whether midlife sensory and motor functions added to prediction models using the Cardiovascular Risk Factors, Aging, and Incidence of Dementia Score (CAIDE) and Framingham Risk Score (FRS) improve risk predictions of 10-year changes in biomarkers of neurodegeneration and Alzheimer's disease. METHODS: Longitudinal data of N = 1529 (mean age 49years) Beaver Dam Offspring Study participants from baseline, 5-year, and 10-year follow-up were included. We tested whether including baseline sensory (hearing, vision, olfactory) impairment and motor function measures improves CAIDE or FRS risk predictions of 10-year incidence of biomarker positivity of serum-based neurofilament light chain (NfL) and amyloid beta (Aß)42/Aß40 using logistic regression. RESULTS: Adding sensory and motor measures to CAIDE-only and FRS-only models significantly improved NfL and Aß42/Aß40 positivity predictions in adults above the age of 55. DISCUSSION: Including midlife sensory and motor function improved long-term biomarker positivity predictions. Non-invasive sensory and motor assessments could contribute to cost-effective screening tools that identify individuals at risk for neurodegeneration early to target interventions and preventions. Highlights: Sensory and motor measures improve risk prediction models of neurodegenerative biomarkersSensory and motor measures improve risk prediction models of AD biomarkersPrediction improvements were strongest in late midlife (adults >55 years of age)Sensory and motor assessments may help identify high-risk individuals early.

Prognostic impact of pretreatment cell-free DNA concentration in newly diagnosed peripheral T-cell lymphomas.

Peripheral T-cell lymphomas (PTCLs) have a poor prognosis and, to date, there are no reliable predictive biomarkers of response. In this work we explored the prognostic impact of cell-free DNA (cfDNA) concentration in 75 newly diagnosed patients enrolled in a prospective multicenter study. Pre-treatment cfDNA was strongly associated with clinical risk factors and was identified as a superior predictor for shorter progression-free survival in multivariable analysis, outweighing canonical risk parameters. Furthermore, we identified a cfDNA value above which survival worsens. In conclusion, pre-treatment cfDNA concentration represents an easily usable predictive biomarker that is highly associated with survival of PTCL patients.

Midlife sensory and motor functions improve long-term predictions of cognitive decline and incidence of cognitive impairment.

INTRODUCTION: We aimed to assess whether midlife sensory and motor functions improve risk prediction of 10-year cognitive decline and impairment when added to risk prediction models using the Cardiovascular Risk Factors, Aging, and Incidence of Dementia Score (CAIDE) and Framingham Risk Score (FRS). METHODS: Longitudinal data of N = 1529 (mean age 49 years; 54% women) Beaver Dam Offspring Study (BOSS) participants from baseline, 5 and 10-year follow-up were included. We tested whether including baseline sensory (hearing, vision, olfactory) impairment and motor function improves CAIDE or FRS risk predictions of 10-year cognitive decline or cognitive impairment incidence using logistic regressions. RESULTS: Adding sensory and motor measures to CAIDE-only and FRS-only models significantly improved areas under the curve for cognitive decline and impairment models. DISCUSSION: Including midlife sensory and motor function improved risk predictions of long-term cognitive decline and impairment in middle-aged to older adults. Sensory and motor assessments could contribute to cost-effective and non-invasive screening tools that identify high-risk individuals earlier to target intervention and prevention strategies. Highlights: Sensory and motor measures improve risk prediction models of cognitive decline.Sensory and motor measures improve risk prediction models of cognitive impairment.Prediction improvements were strongest in midlife (adults < 55 years of age).Sensory and motor changes may help identify high-risk individuals early.

Radioimmunotherapy versus autologous hematopoietic stem cell transplantation in relapsed/refractory follicular lymphoma: a Fondazione Italiana Linfomi multicenter, randomized, phase III trial.

BACKGROUND: Optimal consolidation for young patilents with relapsed/refractory (R/R) follicular lymphoma (FL) remains uncertain in the rituximab era, with an unclear benefit of autologous stem cell transplantation (ASCT). The multicenter, randomized, phase III FLAZ12 (NCT01827605) trial compared anti-CD20 radioimmunotherapy (RIT) with ASCT as consolidation after chemoimmunotherapy, both followed by rituximab maintenance. PATIENTS AND METHODS: Patients (age 18-65 years) with R/R FL and without significant comorbidities were enrolled and treated with three courses of conventional, investigator-chosen chemoimmunotherapies. Those experiencing at least a partial response were randomized 1 : 1 to ASCT or RIT before CD34+ collection, and all received postconsolidation rituximab maintenance. Progression-free survival (PFS) was the primary endpoint. The target sample size was 210 (105/group). RESULTS: Between August 2012 and September 2019, of 164 screened patients, 159 were enrolled [median age 57 (interquartile range 49-62) years, 55% male, 57% stage IV, 20% bulky disease]. The study was closed prematurely because of low accrual. Data were analyzed on 8 June 2023, on an intention-to-treat basis, with a 77-month median follow-up from enrollment. Of the 141 patients (89%), 70 were randomized to ASCT and 71 to RIT. The estimated 3-year PFS in both groups was 62% (hazard ratio 1.11, 95% confidence interval 0.69-1.80, P = 0.6662). The 3-year overall survival also was similar between the two groups. Rates of grade ≥3 hematological toxicity were 94% with ASCT versus 46% with RIT (P < 0.001), and grade ≥3 neutropenia occurred in 94% versus 41%, respectively (P < 0.001). Second cancers occurred in nine patients after ASCT and three after radioimmunotherapy (P = 0.189). CONCLUSIONS: Even if prematurely discontinued, our study did not demonstrate the superiority of ASCT versus RIT. ASCT was more toxic and demanding for patients and health services. Both strategies yielded similar, favorable long-term outcomes, suggesting that consolidation programs milder than ASCT require further investigation in R/R FL.

Phylogenetic diversity and structure in moist and dry upland forests in the semi-arid region of Brazil.

Understanding the factors influencing variation in the diversity and structure of rich biological communities (e.g., Neotropical upland forests) is essential in the context of climate change. In this study, we examine how environmental filters (temperature, precipitation, and elevation) and distinct habitats (moist upland forests - MUF and dry upland forests - DHF) influence the phylogenetic diversity and structure of 54 tree communities (28 MHF and 26 DHF). We used the standardized effect size (ses) of the metrics phylogenetic diversity (ses.PD), mean pairwise distance (ses.MPD), and mean nearest neighbor distance (ses.MNTD) to quantify changes in tree community diversity and structure. Then, we assessed the relationships of the phylogenetic metrics with the environmental filters as predictors using generalized linear models (GLMs). Our results indicate that increasing temperature negatively affects the phylogenetic indices analyzed, leading to less diverse and more clustered communities. In contrast, increasing precipitation and elevation showed a significant positive relationship with the analyzed indices, directing communities towards greater phylogenetic diversity and random or overdispersed structure. Our findings also reveal that phylogenetic diversity and structure vary with habitat type. For example, while MUFs exhibit higher phylogenetic diversity and random structure, DUFs display lower phylogenetic diversity and clustered structure. In conclusion, our results suggest that the phylogenetic patterns exhibited by upland communities in the semiarid region are strongly related to climatic conditions and the habitat in which they are found. Therefore, if the predicted temperature increases and precipitation decreases in climate change scenarios for the semi-arid region materialize, these communities may face significant biodiversity loss.

Odontogenic tumours in a Chilean population: a retrospective study of 544 cases based on 2022 WHO classification.

BACKGROUND: Odontogenic tumours are infrequent lesions. Studies on the frequency of odontogenic tumours from Latin America are scarce. This work aimed to determine the relative frequency of odontogenic tumours in a Chilean population using the 2022 World Health Organization classification. MATERIAL AND METHODS: This is a case series retrospective study. We reviewed 35,530 samples from 1975 to 2022 from the Oral Pathology Referral Institute and the Pathological Anatomy Service, Faculty of Dentistry, University of Chile. We utilized the 2022 World Health Organization classification for histological typification. RESULTS: According to 2022 World Health Organization classification, 544 odontogenic tumours were confirmed. The most frequent odontogenic tumours were: odontoma (n=241; 44.3%), ameloblastoma (n=109; 20.0%) and cemento-ossifying fibroma (n=71; 13.1%). Benign odontogenic tumours corresponded to 538 cases (98.9%) and malignant tumours were only six cases (1.1%). CONCLUSIONS: In our population, odontoma was the most frequent odontogenic tumour followed by ameloblastoma and cemento-ossifying fibroma. Malignant odontogenic tumours were very rare. The results of this study are similar to reports from America, but there are some differences concerning the data from Africa and Asia.

Effect of Neurotoxin Exposure on Blood Biomarkers of Neurodegeneration and Alzheimer Disease.

AIM: To determine whether exposure to neurotoxins in midlife is associated with changes in blood-based biomarkers of neurodegeneration and Alzheimer disease pathology. METHODS: Blood cadmium, lead, neurofilament light (NfL) chain, total tau (TTau), and amyloid beta (Aß) 40 and Aß42 concentrations were measured in 1516 participants in the Beaver Dam Offspring Study. Linear mixed-effect models were used to determine associations between baseline cadmium and lead levels and baseline NfL, TTau, and Aß42/Aß40, and 10-year change in concentrations using repeated measures of these biomarkers as the outcome. RESULTS: In women, higher cadmium and lead levels were associated with higher baseline TTau concentrations. A higher baseline cadmium level was associated with lower baseline Aß42/Aß40 in both men and women. In age-sex-adjusted models, a doubling in baseline cadmium level was associated with a 0.2% (95% CI: 0.0, 0.3) higher increase per year in NfL concentrations. In men, a doubling of baseline lead level was associated with a 0.9% (95% CI: 0.1, 1.7) higher increase per year in TTau concentration. CONCLUSIONS: Participants with relatively higher levels of cadmium and lead had blood biomarker concentrations consistent with more neuronal damage and Alzheimer disease pathology. Environmental exposure to neurotoxins may contribute to neurodegeneration.

Associations of Midlife Lifestyle and Health Factors with Long-Term Changes in Blood-Based Biomarkers of Alzheimer's Disease and Neurodegeneration.

BACKGROUND: Pathological biomarkers of Alzheimer's disease (AD) and other dementias can change decades before clinical symptoms. Lifestyle and health factors might be relevant modifiable risk factors for dementia. Many previous studies have been focusing on associations of lifestyle and health-related factors with clinical outcomes later in life. OBJECTIVE: We aimed to determine to what extent midlife factors of lifestyle, inflammation, vascular, and metabolic health were associated with long-term changes in blood-based biomarkers of AD (amyloid beta (Aß)) and neurodegeneration (neurofilament light chain (NfL); total tau(TTau)). METHODS: In 1,529 Beaver Dam Offspring Study (BOSS) participants (mean age 49 years, standard deviation (SD) = 9; 54% were women), we applied mixed-effects models with baseline risk factors as determinants and 10-year serum biomarker change as outcomes. RESULTS: We found that education and inflammatory markers were associated with levels and/or change over time across all three markers of AD and neurodegeneration in the blood. There were baseline associations of measures of cardiovascular health with lower Aß42/Aß40. TTau changed little over time and was higher in individuals with diabetes. Individuals with lower risk in a number of cardiovascular and metabolic risk factors, including diabetes, hypertension, and atherosclerosis had slower accumulation of neurodegeneration over time, as determined by NfL levels. CONCLUSION: Various lifestyle and health factors, including education and inflammation, were associated with longitudinal changes of neurodegenerative and AD biomarker levels in midlife. If confirmed, these findings could have important implications for developing early lifestyle and health interventions that could potentially slow processes of neurodegeneration and AD.

The Sapienza count-down for a healthy and sustainable diet.

Abstract: The prevalence of obesity and of other non-communicable diseases related to overnutrition is significantly increasing in the past few years. Policy makers are called to counteract this pandemic, orienting consumers towards a healthier and more sustainable diet. Most of the proposed initiatives are dedicated to the content of nutrients with "unfavourable" effects but, in fact, focusing the attention only or mainly on single foods or nutrients is not effective in decreasing the incidence/prevalence of non-communicable diseases. Whole dietary patterns play by far a more important role than specific dietary components in promoting health and modulating survival; and the adherence to eating patterns like the Mediterranean diet reduces the risk of non-communicable diseases. The challenge is therefore to be able to transmit information relating to a healthy eating pattern through positive messages in a few simple indications which in turn represent the nutritional, but also the socio-cultural, environmental and economic characteristics of a healthy and sustainable dietary model. The Mediterranean Diet is normally proposed through a graphic depiction that represents a pyramid which is a simple and effective representation but not of immediate impact. For this reason, we are proposing to adopt the "Sapienza Count-down for a Healthy and Sustainable Diet" that will integrate the pyramid with a more immediate approach.

Lithium levels and lifestyle in patients with bipolar disorder: a new tool for self-management.

BACKGROUND: Patients should get actively involved in the management of their illness. The aim of this study was to assess the influence of lifestyle factors, including sleep, diet, and physical activity, on lithium levels in patients with bipolar disorder. METHODS: A multicenter study was performed. In total, 157 lithium measurements were done biweekly in a sample of 65 patients (35 women) over 6 weeks. Lifestyle, based on total sleep hours and physical activity, was assessed by actigraphy. Diet was evaluated using the Mediterranean Lifestyle Index (Medlife). RESULTS: 35.4% of patients had a normal weight. The mean Medlife score was 14.5 (± 2.5) (moderate-good adherence to Mediterranean diet). BMI, daily dose of lithium and intensity of physical activity had a combined effect on lithium levels, after adjustment for other variables. Patients who practiced intense physical exercise, who took lower doses and had a higher BMI exhibited lower levels of lithium. CONCLUSIONS: Higher physical activity and BMI contribute to lower lithium levels. Patients should be made aware of these relationships to improve their perception of control and self-management. Lifestyle-based interventions contribute to establishing a more personalized medicine.

Quantitative MRI evaluation of bone marrow in sickle cell disease: relationship with haemolysis and clinical severity.

AIM: To evaluate bone marrow fat fraction using the Dixon technique (FFDix) of magnetic resonance imaging (MRI) as a potential biomarker of haemolysis and clinical severity in the overall assessment and follow-up of sickle cell disease (SCD) patients. MATERIAL AND METHODS: The present study was a cross-sectional study in which healthy individuals and SCD patients (matched for age, sex, and weight) were subjected to MRI of the lumbar spine and pelvis to quantify FFDix in the bone marrow using the Dixon technique. SCD severity was analysed by clinical and laboratory data, and an online calculator. A high degree of haemolysis was defined using the cut-off values haemoglobin (Hb) ≤10 g/dl, lactate dehydrogenase (LDH) ≥325 U/l, reticulocytes ≥3% and total bilirubin (TB) ≥1.2 mg/dl. Pearson's correlation, receiver operating characteristic (ROC) curve and binary logistic regression analysis were performed. RESULTS: Forty-eight SCD patients (26 homozygous: HbSS and 22 compound heterozygous: HbSC) and 48 healthy individuals participated in the study. FFDix was lower in SCD patients than in the control group, showing even lower values in the HbSS subtype and patients with a higher degree of haemolysis. HbSC patients with a higher degree of haemolysis using hydroxyurea (medium dosage 9.8 mg/kg/day) had lower FFDix. ROC curves and odds ratios for detecting patients with a higher degree of haemolysis at the different FFDix measurement sites demonstrated excellent performance: iliac bones (cut-off ≤16.75%, AUC = 0.824, p<0.001), femoral heads (cut-off ≤46.7%, AUC = 0.775, p=0.001), lumbar vertebrae (cut-off ≤7.8%, AUC = 0.755, p=0.002). CONCLUSION: Decreased FFDix is indicative of higher degree of haemolysis and SCD severity with great potential as a non-invasive biomarker contributing to the overall assessment and follow-up of SCD patients.

Relationship between cognition and age at onset of first-episode psychosis: comparative study between adolescents, young adults, and adults.

Psychotic disorders typically manifest from late adolescence to early adulthood, and an earlier onset might be associated with greater symptom severity and a worse long-term prognosis. This study aimed to compare the cognitive characteristics of patients with first-episode psychosis (FEP) by their age at onset. We included 298 patients diagnosed with FEP and classified them as having an early onset (EOS), youth onset (YOS), or adult onset (AOS) based on age limits of ≤ 18 years (N = 61), 19-24 years (N = 121), and ≥ 25 years (N = 116), respectively. Socio-demographic and clinical variables included age at baseline, gender, socio-economic status, antipsychotic medication, DSM-IV diagnoses assessed by clinical semi-structured interview, psychotic symptom severity, and age at onset. Neuropsychological assessment included six cognitive domains: premorbid intelligence, working memory, processing speed, verbal memory, sustained attention, and executive functioning. The EOS group had lower scores than the YOS or AOS groups in global cognition, executive functioning, and sustained attention. Although the scores in the YOS group were intermediate to those in the EOS and AOS groups for most cognitive factors, no statistically significant differences were detected between the YOS and AOS groups. Age at onset results in specific patterns of cognitive interference. Of note, impairment appears to be greater with EOS samples than with either YOS or AOS samples. A longitudinal study with a larger sample size is needed to confirm our findings.

Inflammation, metabolic dysregulation and environmental neurotoxins and risk of cognitive decline and impairment in midlife.

BACKGROUND: Age-related declines in cognitive function may begin in midlife. PURPOSE: To determine whether blood-based biomarkers of inflammation, metabolic dysregulation and neurotoxins are associated with risk of cognitive decline and impairment. METHODS: Baseline blood samples from the longitudinal Beaver Dam Offspring Study (2005-2008) were assayed for markers of inflammation, metabolic dysregulation, and environmental neurotoxins. Cognitive function was measured at baseline, 5-year (2010-2013) and 10-year (2015-2017) examinations. Participants without cognitive impairment at baseline and with cognitive data from at least one follow-up were included. Cox proportional hazards models were used to evaluate associations between baseline blood biomarkers and the 10-year cumulative incidence of cognitive impairment. Poisson models were used to estimate the relative risk (RR) of 5-year decline in cognitive function by baseline blood biomarkers. Models were adjusted for age, sex, education, and cardiovascular related risk factors. RESULTS: Participants (N = 2421) were a mean age of 49 years and 55% were women. Soluble vascular cell adhesion molecule-1 (sVCAM-1Tertile(T)3 vs T1-2 hazard ratio (HR) = 1.72, 95% confidence interval (CI) = 1.05,2.82) and hemoglobin A1C (HR = 1.75, 95% CI = 1.18,2.59, per 1% in women) were associated with the 10-year cumulative incidence of cognitive impairment. sVCAM-1 (RRT3 vs T1-2 = 1.45, 95% CI = 1.06,1.99) and white blood cell count (RR = 1.10, 95% CI = 1.02,1.19, per 103/µL) were associated with 5-year cognitive decline. CONCLUSIONS: Biomarkers related to inflammation and metabolic dysregulation were associated with an increased risk of developing cognitive decline and impairment. These results extend previous research in cognitive aging to early markers of cognitive decline in midlife, a time when intervention methods may be more efficacious.

Incidence and Outcomes of Early Cancers After Kidney Transplantation.

Outcomes of early cancers after kidney transplantation are not well-understood. We included recipients of first live and deceased donor kidney transplants who developed de novo cancers in Australia and New Zealand between 1980-2016. We compared the frequency and stage of specific cancer types that developed early (≤12-months) and late (>12-months) post-transplantation. Risk factors for death were evaluated using multivariable Cox regression analyses. Of 2,759 recipients who developed de novo cancer, followed-up for 40,035 person-years, 243 (8.8%) patients were diagnosed with early cancer. Post-transplant lymphoproliferative disease, urinary cancers and melanoma were the most common cancer types (26%, 18%, and 12%) and the majority were either in-situ or locally invasive lesions (55%, 84%, and 86%). Tumors arising early from the gastrointestinal and respiratory systems were uncommon but aggressive, with 40% presenting with metastatic disease at time of diagnosis. Overall, 32% of patients with early cancers died within a median of 4.7 months (IQR:0.6-16) post-diagnosis and 91% were cancer-related deaths. Older recipient and donor age were associated with an increased risk of all-cause death. Early cancers, though infrequent in kidney transplant recipients, are associated with poor outcomes, as nearly 1 in 3 died from cancer-related death; with majority of deaths occurring within 12-months of cancer diagnosis.

Better cognitive function in younger generations - Insights from two cohort studies of middle-aged to older adults in Wisconsin.

BACKGROUND: Understanding generational trends in dementia and cognitive decline is essential to quantify future healthcare needs and may help identify interventions and preventions. We aimed to determine whether individuals from more recent generations showed better neurocognitive function. METHODS: This cross-sectional study combined data from 4439 participants (mean age 64 years (SD = 13); 57% were women) from the Epidemiology of Hearing Loss Study and Beaver Dam Offspring Study. We assessed participants' birth cohort (1901-1924, Greatest Generation; 1925-1945, Silent Generation; 1946-1964, Baby Boom Generation; 1965-1984, Generation X) and neurocognition (Trail-Making Tests A and B, Digit Symbol Substitution Test, Auditory Verbal Learning Test, Verbal Fluency Test). Multivariable linear regression models were utilized. RESULTS: Adjusted for age, sex, education, and known risk factors for cognitive decline, more recent generations showed better processing speed, executive function, attention, and verbal fluency than the Greatest Generation. Largest benefits were found in the Baby Boom Generation. Compared with the Greatest Generation, individuals from the Baby Boom Generation performed better on Trail-Making Tests A (-0.21 ln(time in s); 95% confidence interval (CI) -0.29, -0.13) and B (-0.31 ln(time in s); 95% CI -0.40, -0.22), Digit Symbol Substitution Test (6.07 numbers correct; 95% CI 3.61, 8.52) and Verbal Fluency Test (8.75 numbers correct; 95% CI 5.07, 12.42 in women; 5.28 numbers correct; 95% CI 0.79, 9.78 in men), with effect sizes similar to effects of 11-15 years of less aging. CONCLUSIONS: This indicates that some benefits of younger generations might be related to yet unknown and potentially modifiable environmental, health-related or lifestyle factors and motivates research of such underlying factors to promote healthy cognitive aging.

Mental impact of Covid-19 among Spanish healthcare workers. A large longitudinal survey.

AIMS: Longitudinal data on the mental health impact of the coronavirus disease 2019 (Covid-19) pandemic in healthcare workers is limited. We estimated prevalence, incidence and persistence of probable mental disorders in a cohort of Spanish healthcare workers (Covid-19 waves 1 and 2) -and identified associated risk factors. METHODS: 8996 healthcare workers evaluated on 5 May-7 September 2020 (baseline) were invited to a second web-based survey (October-December 2020). Major depressive disorder (PHQ-8 ≥ 10), generalised anxiety disorder (GAD-7 ≥ 10), panic attacks, post-traumatic stress disorder (PCL-5 ≥ 7), and alcohol use disorder (CAGE-AID ≥ 2) were assessed. Distal (pre-pandemic) and proximal (pandemic) risk factors were included. We estimated the incidence of probable mental disorders (among those without disorders at baseline) and persistence (among those with disorders at baseline). Logistic regression of individual-level [odds ratios (OR)] and population-level (population attributable risk proportions) associations were estimated, adjusting by all distal risk factors, health care centre and time of baseline interview. RESULTS: 4809 healthcare workers participated at four months follow-up (cooperation rate = 65.7%; mean = 120 days s.d. = 22 days from baseline assessment). Follow-up prevalence of any disorder was 41.5%, (v. 45.4% at baseline, p < 0.001); incidence, 19.7% (s.e. = 1.6) and persistence, 67.7% (s.e. = 2.3). Proximal factors showing significant bivariate-adjusted associations with incidence included: work-related factors [prioritising Covid-19 patients (OR = 1.62)], stress factors [personal health-related stress (OR = 1.61)], interpersonal stress (OR = 1.53) and financial factors [significant income loss (OR = 1.37)]. Risk factors associated with persistence were largely similar. CONCLUSIONS: Our study indicates that the prevalence of probable mental disorders among Spanish healthcare workers during the second wave of the Covid-19 pandemic was similarly high to that after the first wave. This was in good part due to the persistence of mental disorders detected at the baseline, but with a relevant incidence of about 1 in 5 of HCWs without mental disorders during the first wave of the Covid-19 pandemic. Health-related factors, work-related factors and interpersonal stress are important risks of persistence of mental disorders and of incidence of mental disorders. Adequately addressing these factors might have prevented a considerable amount of mental health impact of the pandemic among this vulnerable population. Addressing health-related stress, work-related factors and interpersonal stress might reduce the prevalence of these disorders substantially. Study registration number: NCT04556565.