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Methamphetamine use disorder has emerged as a significant public health concern globally. This study endeavors to elucidate the alterations in expression changes of miRNAs in the plasma of methamphetamine use disorder and elucidate the alterations in miRNA expression in the plasma of individuals with methamphetamine use disorder and investigate the relationship between these differentially expressed miRNAs and the disorder itself, cravings for methamphetamine, and associated mental disorders. Furthermore, the study seeks to clarify the expression of downstream target molecules of specific miRNAs in the plasma of methamphetamine use disorder, assess the diagnostic utility of these miRNAs and their target molecules, explore their potential as biomarkers, and identify potential targets for the diagnosis and treatment of methamphetamine use disorder. The research subjects included 112 individuals with methamphetamine use disorder and 112 healthy controls. A questionnaire was utilized to gather baseline information on methamphetamine use disorder, assess craving for methamphetamine using a Visual Analog Scale (VAS), and evaluate anxiety (SAS) and depression (SDS) states. Employing qRT-PCR technology, we measured the expression levels of miR-9-3p and let-7b-3p in the plasma of those with the disorder. Bioinformatics tools were then used to predict downstream target molecules. Western blot analysis was conducted to quantify the levels of these target molecules in the plasma. Receiver operating characteristic (ROC) curves were utilized to evaluate the diagnostic accuracy of miRNAs and their target molecules. Additionally, we analyzed the correlation between the miRNA expression levels and the psychiatric symptoms of methamphetamine use disorder. The qRT-PCR results revealed that the expression levels of miR-9-3p and let-7b-3p were significantly elevated in the plasma of individuals with methamphetamine use disorder compared to healthy controls (P < 0.05). Furthermore, qRT-PCR and Western blot analyses demonstrated that transfection with miR-9-3p mimic led to overexpression of miR-9-3p, while transfection with let-7-3p mimic promoted overexpression of let-7-3p, concurrently inhibiting the protein levels of BDNF and GSK3B in cells (P < 0.05); ROC curve analysis indicated that the AUC for miR-9-3p was 0.782 (95% CI 0.716–0.848) and for let-7b-3p was 0.720 (95% CI 0.650–0.789). However, Spearman correlation analysis showed no significant association between the expression levels of target miRNAs and proteins and the psychiatric symptoms of methamphetamine use disorder. Notably, the combination of miR-9-3p, let-7b-3p, and BDNF exhibited high diagnostic accuracy for methamphetamine use disorder, suggesting their potential as biomarkers for its diagnosis. [ABSTRACT FROM AUTHOR]

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Background: This split-mouth, double-masked, randomized clinical trial aimed at evaluating the impact of different macro geometries and nano topographical modifications on peri-implant bone repair in smokers. Methods: Thirty-two patients who smoked at least ten cigarettes/day, with the need of a single maxillary or mandibular implant bilaterally, received two implants randomly assigned to DA - Dual Acid-Etched implants (n = 32); HCAN – healing chambers and activated nano surface (n = 32). Implant stability quotient (ISQ) was evaluated 07, 30, 60, 90, and 120 days after implant placement. Levels of bone and angiogenic markers were quantified in the peri-implant fluid after 07, 15, 30, 90, and 120 days of implant insertion. HCAN implants have a higher ISQ than DA implants at 60 days (p < 0.05). Results: PLGF levels were lower for HCAN implants than for DA implants at 07-day period (p < 0.05). Besides, HCAN implants presented higher levels of OPG at 30 days and OPN, BMP-9, FGF-1, PLGF, and VEGF at 90 days, compared to DA implants (p < 0.05). The levels of EGF were higher for HCAN implants at 15, 90, and 120 days compared with DA implants (p < 0.05). HCAN implants also showed lower levels of TNF-α at 07 days in comparison to DA implants (p < 0.05) but had higher levels of DKK1 at 30 days, while DA implants presented higher levels of this marker at 90 days (p < 0.05). Conclusion: Macro geometry and nano topographical modifications positively modulated the bone and angiogenic factors, resulting in higher production of these markers during early peri-implant bone healing and having a positive effect on implant stabilization in smokers. Trial Registration: RBR-10gjvcyt; date of registration: 06/12/2023 (Retrospectively registered). [ABSTRACT FROM AUTHOR]

The potential for combining serum neurofilament light chain (sNfL) and glial fibrillary acidic protein (sGFAP) levels to predict worsening disability in multiple sclerosis remains underexplored. We aimed to investigate whether sNfL and sGFAP values identify distinct subgroups of patients according to the risk of disability worsening and their response to disease-modifying treatments (DMTs). This multicentre study, conducted across 13 European hospitals, spanned from 15 July 1994 to 18 August 2022, with follow-up until 26 September 2023. We enrolled patients with multiple sclerosis who had serum samples collected within 12 months from disease onset and before initiating DMTs. Multivariable regression models were used to estimate the risk of relapse-associated worsening (RAW), progression independent of relapse activity (PIRA) and Expanded Disability Status Scale (EDSS) score of 3. Of the 725 patients included, the median age was 34.2 (interquartile range, 27.6–42.4) years, and 509 patients (70.2%) were female. The median follow-up duration was 6.43 (interquartile range, 4.65–9.81) years. Higher sNfL values were associated with an elevated risk of RAW [hazard ratio (HR) of 1.45; 95% confidence interval (CI) 1.19–1.76; P < 0.001], PIRA (HR of 1.43; 95% CI 1.13–1.81; P = 0.003) and reaching an EDSS of 3 (HR of 1.55; 95% CI 1.29–1.85; P < 0.001). Moreover, higher sGFAP levels were linked to a higher risk of achieving an EDSS score of 3 (HR of 1.36; 95% CI 1.06–1.74; P = 0.02) and, in patients with low sNfL values, to PIRA (HR of 1.86; 95% CI 1.01–3.45; P = 0.04). We also examined the combined effect of sNfL and sGFAP levels. Patients with low sNfL and sGFAP values exhibited a low risk of all outcomes and served as a reference. Untreated patients with high sNfL levels showed a higher risk of RAW, PIRA and reaching an EDSS of 3. Injectable or oral DMTs reduced the risk of RAW in these patients but failed to mitigate the risk of PIRA and reaching an EDSS of 3. Conversely, high-efficacy DMTs counteracted the heightened risk of these outcomes, except for the risk of PIRA in patients with high sNfL and sGFAP levels. Patients with low sNfL and high sGFAP values showed an increased risk of PIRA and achieving an EDSS of 3, which remained unchanged with either high-efficacy or other DMTs. In conclusion, evaluating sNfL and sGFAP levels at disease onset in multiple sclerosis might identify distinct phenotypes associated with diverse immunological pathways of disability acquisition and therapeutic response. [ABSTRACT FROM AUTHOR]

DNA-based therapeutics have emerged as a revolutionary approach for addressing the treatment gap in rare inherited conditions by targeting the fundamental genetic causes of disease. Charcot–Marie–Tooth (CMT) disease, a group of inherited neuropathies, represents one of the most prevalent Mendelian disease groups in neurology and is characterized by diverse genetic aetiology. Axonal forms of CMT, known as CMT2, are caused by dominant mutations in >30 different genes that lead to degeneration of lower motor neuron axons. Recent advances in antisense oligonucleotide therapeutics have shown promise in targeting neurodegenerative disorders. Here, we elucidate pathomechanistic changes contributing to variant specific molecular phenotypes in CMT2E, caused by a single nucleotide substitution (p.N98S) in the neurofilament light chain gene (NEFL). We used a patient-derived induced pluripotent stem cell-induced motor neuron model that recapitulates several cellular and biomarker phenotypes associated with CMT2E. Using an antisense oligonucleotide treatment strategy targeting a heterozygous gain-of-function variant, we aimed to resolve molecular phenotypic changes observed in the CMT2E p.N98S subtype. To determine the therapeutic potential of antisense oligonucleotide, we applied our treatment strategy in induced pluripotent stem cell-derived motor neurons and used both established and new biomarkers of peripheral nervous system axonal degeneration. Our findings demonstrated a significant decrease in clinically relevant biomarkers of axonal degeneration, presenting the first clinically viable genetic therapeutic for CMT2E. Similar strategies could be used to develop precision medicine approaches for otherwise untreatable gain-of-function inherited disorders. [ABSTRACT FROM AUTHOR]

Increasing evidence shows that neuroinflammation is a possible modulator of tau spread effects on cognitive impairment in Alzheimer's disease. In this context, plasma levels of the glial fibrillary acidic protein (GFAP) have been suggested to have a robust association with Alzheimer's disease pathophysiology. This study aims to assess the correlation between plasma GFAP and Alzheimer's disease pathology, and their synergistic effect on cognitive performance and decline. A cohort of 122 memory clinic subjects with amyloid and tau PET, MRI scans, plasma GFAP and Mini-Mental State Examination (MMSE) was included in the study. A subsample of 94 subjects had a follow-up MMSE score at ≥1 year after baseline. Regional and voxel-based correlations between Alzheimer's disease biomarkers and plasma GFAP were assessed. Mediation analyses were performed to evaluate the effects of plasma GFAP on the association between amyloid and tau PET and between tau PET and cognitive impairment and decline. GFAP was associated with increased tau PET ligand uptake in the lateral temporal and inferior temporal lobes in a strong left-sided pattern independently of age, sex, education, amyloid and APOE status (β = 0.001, P < 0.01). The annual rate of MMSE change was significantly and independently correlated with both GFAP (β = 0.006, P < 0.01) and global tau standardized uptake value ratio (β = 4.33, P < 0.01), but not with amyloid burden. Partial mediation effects of GFAP were found on the association between amyloid and tau pathology (13.7%) and between tau pathology and cognitive decline (17.4%), but not on global cognition at baseline. Neuroinflammation measured by circulating GFAP is independently associated with tau Alzheimer's disease pathology and with cognitive decline, suggesting neuroinflammation as a potential target for future disease-modifying trials targeting tau pathology. [ABSTRACT FROM AUTHOR]

Background: The aim of this study was to analyze the prevalence of prefrailty and frailty syndrome (FS) in patients with coronary artery disease (CAD), and the clinical and biological characteristics of frail patients undergoing elective percutaneous coronary intervention (PCI). Material and Methods: The study included 78 patients with CAD who were admitted to the clinic to undergo PCI. To detect prefrailty and FS in patients, we used a short physical performance test battery (10–12 points—no FS, 8–9 points—prefrailty, 7 or fewer points—FS). We used the RayBio® Human ELISA Kit (Norcross, GA, USA), a highly sensitive and highly specific enzyme-linked immunosorbent assay, to determine the concentration of biological markers of inflammation (IL-6, IL-10, IL-13, IL-15, TNF-α) and bone, muscle, and fat remodeling (leptin, calcitonin, osteoprotegerin, osteocalcin, myostatin) in the serum of patients with coronary artery disease before planned PCI. Results: Taking into account the test battery score, the prevalence of FS in patients with CAD before elective PCI was 24.4%, the prevalence of prefrailty was 33.3%. According to the results of the study, older women with type 2 diabetes in their history were significantly more likely to be frail. Studying a wide range of biological markers of inflammation and musculoskeletal and fat remodeling, we noted lower levels of calcitonin (2.60 [1.50; 5.85] pg/mL, p = 0.018) and osteoprotegerin (0.80 [0.60; 1.20] ng/mL, p = 0.025) in the serum of frail patients with CAD. Later we confirmed the results by correlation analysis. Moreover, we found an association between FS and higher serum leptin levels in patients with CAD before elective PCI. Conclusion: The results of the study confirm the high prevalence of prefrailty (33.3%) and FS (24.4%) in patients with CAD. Older women with type 2 diabetes in their history were significantly more likely to be frail. At the same time, the presence of FS is associated with lower levels of calcitonin and osteoprotegerin, and higher levels of leptin in the serum of frail patients before elective PCI. [ABSTRACT FROM AUTHOR]

The drug's activity at the target tissue could help to define the minimal effective dose to promote cancer preventive therapy. Here we present exemestane and sex hormone concentrations within breast tissue from a presurgical study of alternative exemestane schedules. Postmenopausal women candidates for breast surgery for estrogen receptor-positive breast cancer were randomly assigned to exemestane 25 mg once daily (QD), 25 mg 3 times/week (TIW), or 25 mg per week (QW) for 4-6 weeks before surgery. Drug and sex hormones were analyzed from homogenized frozen tissue using a QTRAP 6500+ LC-MS/MS System. Tissue drug concentrations were detectable only in the QD arm with higher concentrations in nonmalignant tissue. Estradiol was nearly suppressed in all groups in the nonmalignant tissue (QD vs TIW P  = .364 and QD vs QW P  = .693). In contrast, a dose-response trend was observed in cancer tissue. Based on estradiol suppression in nonmalignant tissue, lower exemestane schedules should be explored for breast cancer preventive therapy. Trial Registration : Clinical Trials.gov NCT02598557 and EudraCT 2015-005063-1 [ABSTRACT FROM AUTHOR]

Hemolysis is a contributor to CS-AKI. Biochemistry analyzers provide a hemolysis index to quantify in vitro hemolysis, a condition that can, for example, affect the accuracy of potassium concentration measurements. We aimed to assess whether the postoperative plasma level of the hemolysis index (HI postoperative) could aid the early recognition of patients at risk for cardiac surgery–associated acute kidney injury (CS-AKI) and also to evaluate other hemolysis indicators: plasma carboxyhemoglobin (COHb postoperative) and methemoglobin (MetHb postoperative). One-year retrospective study. University hospital. Patients undergoing elective cardiac surgery. None. In 1090 patients, the median HI postoperative was higher in patients who developed CS-AKI compared to patients who did not (11 mg/dL [interquartile range (IQR), 5-38 mg/dL] v 7 mg/dL [IQR, 3-16 mg/dL]; p < 0.001). HI postoperative refined the early recognition of CS-AKI: the area under the precision–recall curve (AUPRC) for HI postoperative was 37% (95% confidence interval [CI], 31%-42%), whereas the AUPRC associated with no discriminative power, equal to the prevalence of CS-AKI in the whole population, was 21%. Among the 611 patients with measurements for all 3 biomarkers, the AUPRC of HI postoperative was higher than that of COHb postoperative or MetHb postoperative (+6.6% and +7.4% respectively; p < 0.0001 for both). Unlike COHb postoperative or MetHb postoperative , the incorporation of HI postoperative into a model (trained on a sample then validated in another sample) of CS-AKI early recognition significantly enhanced its performance, with a +1.9% (95% CI, 1.6%-2.1%) increase in AUPRC (p < 0.0001). Elevated HI postoperative represents an early alert signal for the development of CS-AKI. Our findings support the incorporation of HI postoperative , a readily available biomarker, into predictive scores of CS-AKI. [ABSTRACT FROM AUTHOR]

Background Metabolomic scores based on age (MetaboAge) and mortality (MetaboHealth) are considered indicators of overall health, but their association with cognition in the general population is unknown. Therefore, the association between MetaboAge/MetaboHealth and level and decline in cognition was studied, as were differences between men and women. Methods Data of 2821 participants (50% women, age range 45–75) from the Doetinchem Cohort Study was used. MetaboAge and MetaboHealth were calculated from 1H-NMR metabolomics data at baseline. Cognitive domain scores (memory, flexibility and processing speed) and global cognitive functioning were available over a 10-year period. The association between MetaboAge/MetaboHealth and level of cognitive functioning was studied using linear regressions while for the association between MetaboAge/MetaboHealth and cognitive decline longitudinal linear mixed models were used. Analyses were adjusted for demographics and lifestyle factors. Results Higher MetaboAge, indicating poorer metabolomic ageing, was only associated with lower levels of processing speed in men. Higher MetaboHealth, indicating poorer immune-metabolic health, was associated with lower levels of cognitive functioning for all three domains and global cognitive functioning in both men and women. Only in men, MetaboHealth was also associated with 10-year decline in flexibility, processing speed and global cognition. Metabolites that contributed to the observed associations were in men mainly markers of protein metabolism, and in women mainly markers of lipid metabolism and inflammatory metabolites. Conclusions MetaboHealth, not MetaboAge, was associated with cognitive functioning independent of conventional risk factors. Individual metabolites affect cognitive functioning differently in men and women, suggesting sex-specific pathophysiological pathways underlying cognitive functioning. [ABSTRACT FROM AUTHOR]

Objective Patients with chronic kidney disease (CKD) show features of premature ageing. We aimed to evaluate the association between biological ageing and adverse outcomes, including end-stage kidney disease (ESKD), cardiovascular diseases (CVD) and all-cause mortality, in patients with CKD. Methods 23 435 participants with CKD and free of related adverse outcomes at baseline from the UK Biobank were included. Leukocyte telomere length (LTL) was measured by quantitative polymerase chain reaction assay. Clinical biomarker–based biological ages were quantified using Klemera–Doubal method biological age (KDM-BA) and PhenoAge algorithms. Results During a median follow-up of 12 years, 3417 incident CVD, 383 incident ESKD and 3195 all-cause mortality were recorded. Per SD increment of KDM-BA acceleration was associated with a 56% [95% confidence interval (CI): 41%–73%], 26% (95% CI: 21%–31%) and 39% (95% CI: 34%–44%) increase in the risk of incident ESKD, incident CVD and all-cause mortality, respectively. Similar results were found for PhenoAge acceleration. LTL (per SD increment) was inversely associated with the risk of incident CVD [hazard ratio (HR): 0.96, 95% CI: 0.92–0.99] and all-cause mortality (HR: 0.94, 95% CI: 0.91–0.98) and was not significantly associated with the risk of incident ESKD (HR: 0.96, 95% CI: 0.86–1.06). Adding KDM-BA acceleration or PhenoAge acceleration, but not LTL, to the traditional validated clinical prediction models significantly improved the predictive performance for incident ESKD, all-cause mortality and CVD. Conclusion In patients with CKD, both KDM-BA acceleration and PhenoAge acceleration were associated with an increased risk of ESKD, CVD and all-cause mortality, and KDM-BA or PhenoAge may be a better predictor on adverse outcomes than LTL. [ABSTRACT FROM AUTHOR]

Blood biomarkers are an emerging diagnostic and prognostic tool that reflect a range of neuropathological processes following traumatic brain injury (TBI). Their effectiveness in identifying long-term neuropathological processes after TBI is unclear. Studying biomarkers in the chronic phase is vital because elevated levels in TBI might result from distinct neuropathological mechanisms during acute and chronic phases. Here, we examine plasma biomarkers in the chronic period following TBI and their association with amyloid and tau PET, white matter microarchitecture, brain age and cognition. We recruited participants ≥40 years of age who had suffered a single moderate–severe TBI ≥10 years previously between January 2018 and March 2021. We measured plasma biomarkers using single molecule array technology [ubiquitin C-terminal hydrolase L1 (UCH-L1), neurofilament light (NfL), tau, glial fibrillary acidic protein (GFAP) and phosphorylated tau (P-tau181)]; PET tracers to measure amyloid-β (18F-NAV4694) and tau neurofibrillary tangles (18F-MK6240); MRI to assess white matter microstructure and brain age; and the Rey Auditory Verbal Learning Test to measure verbal-episodic memory. A total of 90 post-TBI participants (73% male; mean = 58.2 years) were recruited on average 22 years (range = 10–33 years) post-injury, and 32 non-TBI control participants (66% male; mean = 57.9 years) were recruited. Plasma UCH-L1 levels were 67% higher {exp(b) = 1.67, P = 0.018, adjusted P = 0.044, 95% confidence interval (CI) [10% to 155%], area under the curve = 0.616} and P-tau181 were 27% higher {exp(b) = 1.24, P = 0.011, adjusted P = 0.044, 95% CI [5% to 46%], area under the curve = 0.632} in TBI participants compared with controls. Amyloid and tau PET were not elevated in TBI participants. Higher concentrations of plasma P-tau181, UCH-L1, GFAP and NfL were significantly associated with worse white matter microstructure but not brain age in TBI participants. For TBI participants, poorer verbal-episodic memory was associated with higher concentration of P-tau181 {short delay: b = −2.17, SE = 1.06, P = 0.043, 95% CI [−4.28, −0.07]; long delay: b P-tau = −2.56, SE = 1.08, P = 0.020, 95% CI [−4.71, −0.41]}, tau {immediate memory: b Tau = −6.22, SE = 2.47, P = 0.014, 95% CI [−11.14, −1.30]} and UCH-L1 {immediate memory: b UCH-L1 = −2.14, SE = 1.07, P = 0.048, 95% CI [−4.26, −0.01]}, but was not associated with functional outcome. Elevated plasma markers related to neuronal damage and accumulation of phosphorylated tau suggest the presence of ongoing neuropathology in the chronic phase following a single moderate–severe TBI. Plasma biomarkers were associated with measures of microstructural brain disruption on MRI and disordered cognition, further highlighting their utility as potential objective tools to monitor evolving neuropathology post-TBI. [ABSTRACT FROM AUTHOR]

It is debated whether CNS involvement begins during acute human immunodeficiency virus (HIV) infection in persons without meningitis/encephalitis and whether specific antiretroviral drugs or combinations would be beneficial. Neurologically asymptomatic participants enrolled in a randomized and controlled study comparing three combination antiretroviral regimens (tenofovir alafenamide/emtricitabine plus dolutegravir; darunavir; or both) during primary HIV infection were enrolled. Serum and CSF were collected at baseline and at 12 and 48 (serum only) weeks after treatment initiation. Single molecule array was used to measure neurofilament light chain (NFL), total tau protein (Tau), brain-derived neurotrophic factor, glial fibrillary acidic protein (GFAP) and ubiquitin C-terminal hydrolase. We assessed the longitudinal change in biomarkers over time, in addition to the change in the prevalence of serum NFL concentrations above previously published age-adjusted cut-offs (7 pg/ml if 5–18 years, 10 pg/ml if 18–51 years, 15 pg/ml if 51–61 years, 20 pg/ml if 61–70 years and 35 pg/ml if >70 years). Serum was available from 47 participants at all time points, and CSF was available from 13 participants at baseline and 7 at Week 12. We observed a significant direct serum-to-CSF correlation for NFL (ρ = 0.692, P = 0.009), GFAP (ρ = 0.659, P = 0.014) and brain-derived neurotrophic factor (ρ = 0.587, P = 0.045). Serum (ρ = 0.560, P = 0.046) and CSF NFL (ρ = 0.582, P = 0.037) concentrations were directly associated with CSF HIV RNA levels. We observed a significant decrease over time in serum NFL (P = 0.006) and GFAP (P = 0.006) but not in the other biomarkers. No significant difference was observed among the treatment arms. At baseline, serum and CSF age-adjusted NFL levels were above age-adjusted cut-offs in 23 (48.9%) and four participants (30.8%), respectively; considering serum NFL, this proportion was lower at Weeks 12 (31.9%, P = 0.057) and 48 (27.7%, P = 0.13). A relevant proportion of neurologically asymptomatic participants had abnormal CSF and serum NFL levels during primary HIV infection. NFL and GFAP decreased in serum following combination antiretroviral therapy without significant differences among the treatment arms. [ABSTRACT FROM AUTHOR]

The clinical manifestation of Parkinson's disease exhibits significant heterogeneity in the prevalence of non-motor symptoms and the rate of progression of motor symptoms, suggesting that Parkinson's disease can be classified into distinct subtypes. In this study, we aimed to explore this heterogeneity by identifying a set of subtypes with distinct patterns of spatiotemporal trajectories of neurodegeneration. We applied Subtype and Stage Inference (SuStaIn), an unsupervised machine learning algorithm that combined disease progression modelling with clustering methods, to cortical and subcortical neurodegeneration visible on 3 T structural MRI of a large cross-sectional sample of 504 patients and 279 healthy controls. Serial longitudinal data were available for a subset of 178 patients at the 2-year follow-up and for 140 patients at the 4-year follow-up. In a subset of 210 patients, concomitant Alzheimer's disease pathology was assessed by evaluating amyloid-β concentrations in the CSF or via the amyloid-specific radiotracer 18F-flutemetamol with PET. The SuStaIn analysis revealed three distinct subtypes, each characterized by unique patterns of spatiotemporal evolution of brain atrophy: neocortical, limbic and brainstem. In the neocortical subtype, a reduction in brain volume occurred in the frontal and parietal cortices in the earliest disease stage and progressed across the entire neocortex during the early stage, although with relative sparing of the striatum, pallidum, accumbens area and brainstem. The limbic subtype represented comparative regional vulnerability, which was characterized by early volume loss in the amygdala, accumbens area, striatum and temporal cortex, subsequently spreading to the parietal and frontal cortices across disease stage. The brainstem subtype showed gradual rostral progression from the brainstem extending to the amygdala and hippocampus, followed by the temporal and other cortices. Longitudinal MRI data confirmed that 77.8% of participants at the 2-year follow-up and 84.0% at the 4-year follow-up were assigned to subtypes consistent with estimates from the cross-sectional data. This three-subtype model aligned with empirically proposed subtypes based on age at onset, because the neocortical subtype demonstrated characteristics similar to those found in the old-onset phenotype, including older onset and cognitive decline symptoms (P < 0.05). Moreover, the subtypes correspond to the three categories of the neuropathological consensus criteria for symptomatic patients with Lewy pathology, proposing neocortex-, limbic- and brainstem-predominant patterns as different subgroups of α-synuclein distributions. Among the subtypes, the prevalence of biomarker evidence of amyloid-β pathology was comparable. Upon validation, the subtype model might be applied to individual cases, potentially serving as a biomarker to track disease progression and predict temporal evolution. [ABSTRACT FROM AUTHOR]

Single-value scores reflecting the deviation from (FADE score) or similarity with (SAME score) prototypical novelty-related and memory-related functional MRI activation patterns in young adults have been proposed as imaging biomarkers of healthy neurocognitive ageing. Here, we tested the utility of these scores as potential diagnostic and prognostic markers in Alzheimer's disease (AD) and risk states like mild cognitive impairment (MCI) or subjective cognitive decline (SCD). To this end, we analysed subsequent memory functional MRI data from individuals with SCD, MCI and AD dementia as well as healthy controls and first-degree relatives of AD dementia patients (AD-rel) who participated in the multi-centre DELCODE study (n = 468). Based on the individual participants' whole-brain functional MRI novelty and subsequent memory responses, we calculated the FADE and SAME scores and assessed their association with AD risk stage, neuropsychological test scores, CSF amyloid positivity and APOE genotype. Memory-based FADE and SAME scores showed a considerably larger deviation from a reference sample of young adults in the MCI and AD dementia groups compared to healthy controls, SCD and AD-rel. In addition, novelty-based scores significantly differed between the MCI and AD dementia groups. Across the entire sample, single-value scores correlated with neuropsychological test performance. The novelty-based SAME score further differed between Aβ-positive and Aβ-negative individuals in SCD and AD-rel, and between ApoE ɛ4 carriers and non-carriers in AD-rel. Hence, FADE and SAME scores are associated with both cognitive performance and individual risk factors for AD. Their potential utility as diagnostic and prognostic biomarkers warrants further exploration, particularly in individuals with SCD and healthy relatives of AD dementia patients. [ABSTRACT FROM AUTHOR]

Objectives We sought to assess the expression of human leukocyte antigen (HLA) proteins and β2-microglobulin (B2M) in tumor cells and the relationship with immune microenvironment and outcome in colorectal cancer (CRC). Methods A total of 953 CRC cases were evaluated by immunohistochemistry for HLA class I, HLA class II, and B2M. The expression level of these biomarkers was correlated with clinicopathologic information, BRAF V600E and mismatch repair (MMR) proteins, and the quantitated expression levels of immune cells (CD8 and CD163) and immune regulatory proteins (FoxP3, programmed cell death 1 ligand 1 [PD-L1], and LAG3). Results We found that B2M-low tumors were statistically correlated with aggressive histologic features, including higher stage, higher grade, extramural venous invasion, perineural invasion, and distant metastasis. Expression of B2M was positively correlated (R 2 = 0.3) and significantly associated with MMR-deficient tumors (P <.001); B2M-low tumors were also associated with an "immune cold"' microenvironment, including a reduced number of immune cells (CD8 and CD163), reduced expression of immune regulatory proteins by immune cells (PD-L1, FoxP3, and LAG3), and reduced tumor cell expression of PD-L1. These B2M-low tumors correlated with lower disease-specific survival (P =.018), a finding that maintained significance only for the proficient MMR cohort (P =.037). Conclusions Our findings suggest that B2M expression may support predictive models for both outcome and checkpoint inhibitor therapy treatment response for colorectal adenocarcinoma. [ABSTRACT FROM AUTHOR]

Background Distinguishing between different types of pleural effusions (PEs) is crucial for clinical diagnosis and treatment. This study evaluates the diagnostic value of carcinoembryonic antigen (CEA) and interferon-gamma (IFN-γ) levels in PE and serum, as well as the PE/serum ratios of these markers, in classifying PE. Methods We retrospectively analyzed 99 patients with PE, categorizing them into malignant pleural effusion (MPE), tuberculous pleural effusion (TPE), and benign PE groups. Levels of CEA and IFN-γ in PE and serum were quantified and their ratios were calculated. Diagnostic performance was assessed using receiver operating characteristic analysis, focusing on the area under the curve (AUC) to determine the efficacy of these biomarkers. Results Significantly elevated levels of CEA in PE and serum were observed in the MPE group compared to the benign and TPE groups, with the PE/serum CEA ratio offering substantial diagnostic value (AUCs: PE = 0.843, serum = 0.744). Conversely, IFN-γ levels in PE and serum were markedly higher in the TPE group, demonstrating notable diagnostic accuracy (AUCs: PE = 0.970, serum = 0.917). Conclusion Both CEA and IFN-γ demonstrate high clinical utility in differentiating between MPE and TPE. The PE/serum ratio of these biomarkers enhances diagnostic accuracy, potentially facilitating earlier and more accurate therapeutic interventions. [ABSTRACT FROM AUTHOR]

Abstract Background This split-mouth, double-masked, randomized clinical trial aimed at evaluating the impact of different macro geometries and nano topographical modifications on peri-implant bone repair in smokers. Methods Thirty-two patients who smoked at least ten cigarettes/day, with the need of a single maxillary or mandibular implant bilaterally, received two implants randomly assigned to DA - Dual Acid-Etched implants (n = 32); HCAN – healing chambers and activated nano surface (n = 32). Implant stability quotient (ISQ) was evaluated 07, 30, 60, 90, and 120 days after implant placement. Levels of bone and angiogenic markers were quantified in the peri-implant fluid after 07, 15, 30, 90, and 120 days of implant insertion. HCAN implants have a higher ISQ than DA implants at 60 days (p

Abstract Background Understanding the potential risk factors of heart diseases is key to effectively managing cardiac diseases. The present study quantifies the association of identified risk factors. In addition, the study has compared the association of mortality with hypertension, uncontrolled diabetes, and uncontrolled hyperlipidemia using Grey Relational Approach (GRA) for stroke, lung diseases, smoking, stress, obesity, and lack of exercise. Method Data on risk factors of heart failure were collected from the Global Burden of Disease (GBD) study (2001–2017). From the GBD database, variables have selected the top leading risk factors responsible for mortality from cardiac diseases. Data on risk factors was analyzed using the GRA procedure (utilizing Grey [8.0] software). In the GRA method, the correlation was categorized into three components: GRA – Deng (assesses the effect of one variable specified by data on the other variables), GRA- absolute (assesses the association between variables measured), and GRA-SS (assessed the overall association between the variables measured). Stroke, lung diseases, smoking, stress, obesity, and lack of exercise were taken as dependent variables and their impact was assessed. Hypertension (high grade) uncontrolled diabetes, and uncontrolled hyperlipidemia were considered as independent variables. The relationship between dependent and independent variables was assessed. Results Overall correlational analysis showed that type 2 diabetes (T2DM) is the risk factor that has a strong relationship with causing heart failure and thereby increases morbidity and mortality among Chinese patients. After T2DM, the second highest risk factor associated was severe dyslipidemia which is responsible for causing heart failure. High-grade hypertension is one-third most common risk factor in causing heart failure. GRA – Deng analysis showed that T2DM is the top risk factor associated with heart failure, followed by high-grade hypertension and severe dyslipidemia (uncontrolled). GRA-absolute analysis showed that severe dyslipidemia is the top risk factor associated with heart failure, followed by high-grade hypertension and T2DM (uncontrolled). GRA-SS analysis showed that high-grade hypertension is the top risk factor associated with heart failure, followed by severe dyslipidemia and T2DM (uncontrolled). Conclusions The study reported that T2DM, severe dyslipidemia, and high-grade hypertension as strongly correlated with the development of heart failure after considering other several key risk factors (stroke, lung diseases, smoking, stress, obesity, and lack of exercise). Level of evidence IV. Technical efficacy Stage 5.

Background Cognitive decline, a common process of brain ageing, has been associated with telomere length (TL). Delving into the identification of reliable biomarkers of brain ageing is essential to prevent accelerated cognitive impairment. Methods We selected 317 non-smoking 'Prevención con Dieta Mediterránea-Plus' (PREDIMED-Plus) participants (mean age, 65.8 ± 5.0 years) with metabolic syndrome from two trial centres who were following a lifestyle intervention. We measured TL and cognitive function at baseline and after 3 and 4 years of follow-up, respectively. Associations between baseline or 3-year changes in TL and baseline or 4-year changes in cognitive function were analysed using multivariable regression models. Results Baseline TL was not associated with baseline cognitive performance. Nevertheless, longer baseline TL was associated with improved 4-year changes in the Executive Function domain (β: 0.29; 95%CI: 0.12 to 0.44; P < 0.001) and the Global Cognitive Function domain (β: 0.19; 95%CI: 0.05 to 0.34; P = 0.010). Besides, a positive association was found between longer baseline TL and improved 4-year changes in the animal version of the Verbal Fluency Test (β: 0.33; 95%CI: 0.12 to 0.52; P =  0.002). By contrast, 3-year changes in TL were not associated with changes in cognitive function after 4 years. Conclusions Longer baseline TL could protect from cognitive decline and be used as a useful biomarker of brain ageing function in an older Mediterranean population at risk of cardiovascular disease and cognitive impairment. [ABSTRACT FROM AUTHOR]

Background Studying long-term treatment outcomes of TB is time-consuming and impractical. Early and reliable biomarkers reflecting treatment response and capable of predicting long-term outcomes are urgently needed. Objectives To develop a pharmacometric multistate model to evaluate the link between potential predictors and long-term outcomes. Methods Data were obtained from two Phase II clinical trials (TMC207-C208 and TMC207-C209) with bedaquiline on top of a multidrug background regimen. Patients were typically followed throughout a 24 week investigational treatment period plus a 96 week follow-up period. A five-state multistate model (active TB, converted, recurrent TB, dropout, and death) was developed to describe observed transitions. Evaluated predictors included patient characteristics, baseline TB disease severity and on-treatment biomarkers. Results A fast bacterial clearance in the first 2 weeks and low TB bacterial burden at baseline increased probability to achieve conversion, whereas patients with XDR-TB were less likely to reach conversion. Higher estimated mycobacterial load at the end of 24 week treatment increased the probability of recurrence. At 120 weeks, the model predicted 55% (95% prediction interval, 50%–60%), 6.5% (4.2%–9.0%) and 7.5% (5.2%–10%) of patients in converted, recurrent TB and death states, respectively. Simulations predicted a substantial increase of recurrence after 24 weeks in patients with slow bacterial clearance regardless of baseline bacterial burden. Conclusions The developed multistate model successfully described TB treatment outcomes. The multistate modelling framework enables prediction of several outcomes simultaneously, and allows mechanistically sound investigation of novel promising predictors. This may help support future biomarker evaluation, clinical trial design and analysis. [ABSTRACT FROM AUTHOR]

Human hair cortisol concentration (HCC) has previously been found to be highly stable for a 1‐year interval (r = 0.73) in terms of a product–moment correlation. The present study aimed to replicate this finding and compare HCC stability regarding 1‐year and 2‐year test–retest intervals. Female university students (N = 39) provided hair strands twice (t1 and t2) at intervals of 1 (n = 21) or 2 years (n = 18). Multiple regression analysis predicting HCC at t2 revealed a significant interaction term (HCC at t1 × time interval condition). It was determined that HCCs were substantially related for the 1‐year interval but unrelated for the 2‐year interval. The findings were not attributable to potential influences, such as hair treatment. The product–moment correlation showed nearly identical consistency with previous research regarding the 1‐year test–retest interval. There was no significant product–moment correlation for the 2‐year interval. Overall, these findings indicate that within a temporal framework of 1 year, HCCs may be stable predictors in correlational studies where the focus is on the rank orders of measured values. [ABSTRACT FROM AUTHOR]

Concomitant Alzheimer's disease (AD) pathology is a frequent event in the context of Lewy body disease (LBD), occurring in approximately half of all cases. Evidence shows that LBD patients with AD copathology show an accelerated disease course, a greater risk of cognitive decline and an overall poorer prognosis. However, LBD-AD cases may show heterogeneous motor and non-motor phenotypes with a higher risk of dementia and, consequently, be not rarely misdiagnosed. In this review, we summarize the current understanding of LBD-AD by discussing the synergistic effects of AD neuropathological changes and Lewy pathology and their clinical relevance. Furthermore, we provide an extensive overview of neuroimaging and fluid biomarkers under assessment for use in LBD-AD and their possible diagnostic and prognostic values. AD pathology can be predicted in vivo by means of CSF, MRI and PET markers, whereas the most promising technique to date for identifying Lewy pathology in different biological tissues is the α-synuclein seed amplification assay. Pathological imaging and CSF AD biomarkers are associated with a higher likelihood of cognitive decline in LBD but do not always mirror the neuropathological severity as in pure AD. Implementing the use of blood-based AD biomarkers might allow faster screening of LBD patients for AD copathology, thus improving the overall diagnostic sensitivity for LBD-AD. Finally, we discuss the literature on novel candidate biomarkers being exploited in LBD-AD to investigate other aspects of neurodegeneration, such as neuroaxonal injury, glial activation and synaptic dysfunction. The thorough characterization of AD copathology in LBD should be taken into account when considering differential diagnoses of dementia syndromes, to allow prognostic evaluation on an individual level, and to guide symptomatic and disease-modifying therapies. [ABSTRACT FROM AUTHOR]

Positive effects of new anti-amyloid-β (Aβ) monoclonal antibodies in Alzheimer's disease (AD) have been attributed to brain amyloid reduction. However, most anti-Aβ antibodies also increase the CSF levels of the 42-amino acid isoform (Aβ42). We evaluated the associations of changes in CSF Aβ42 and brain Aβ-PET with cognitive and clinical end points in randomized trials of anti-Aβ drugs that lowered (β- and γ-secretase inhibitors) or increased CSF Aβ42 levels (anti-Aβ monoclonal antibodies) to test the hypothesis that post-treatment increases in CSF Aβ42 levels are independently associated with cognitive and clinical outcomes. From long-term (≥12 months) randomized placebo-controlled clinical trials of anti-Aβ drugs published until November 2023, we calculated the post-treatment versus baseline difference in ADAS-Cog (cognitive subscale of the Alzheimer's Disease Assessment Scale) and CDR-SB (Clinical Dementia Rate-Sum of Boxes) and z -standardized changes in CSF Aβ42 and Aβ-PET Centiloids (CL). We estimated the effect size [regression coefficients (RCs) and confidence intervals (CIs)] and the heterogeneity (I2) of the associations between AD biomarkers and cognitive and clinical end points using random-effects meta-regression models. We included 25 966 subjects with AD from 24 trials. In random-effects analysis, increases in CSF Aβ42 were associated with slower decline in ADAS-Cog (RC: −0.55; 95% CI: −0.89, −0.21, P = 0.003, I2 = 61.4%) and CDR-SB (RC: −0.16; 95% CI: −0.26, −0.06, P = 0.002, I2 = 34.5%). Similarly, decreases in Aβ–PET were associated with slower decline in ADAS-Cog (RC: 0.69; 95% CI: 0.48, 0.89, P < 0.001, I2 = 0%) and CDR-SB (RC: 0.26; 95% CI: 0.18, 0.33, P < 0.001, I2 = 0%). Sensitivity analyses yielded similar results. Higher CSF Aβ42 levels after exposure to anti-Aβ drugs are independently associated with slowing cognitive impairment and clinical decline. Increases in Aβ42 may represent a mechanism of potential benefit of anti-Aβ monoclonal antibodies in AD. [ABSTRACT FROM AUTHOR]

Cerebral adrenoleukodystrophy (CALD) is an X-linked rapidly progressive demyelinating disease leading to death usually within a few years. The standard of care is haematopoietic stem cell transplantation (HSCT), but many men are not eligible due to age, absence of a matched donor or lesions of the corticospinal tracts (CST). Based on the ADVANCE study showing that leriglitazone decreases the occurrence of CALD, we treated 13 adult CALD patients (19–67 years of age) either not eligible for HSCT (n = 8) or awaiting HSCT (n = 5). Patients were monitored every 3 months with standardized neurological scores, plasma biomarkers and brain MRI comprising lesion volumetrics and diffusion tensor imaging. The disease stabilized clinically and radiologically in 10 patients with up to 2 years of follow-up. Five patients presented with gadolinium enhancing CST lesions that all turned gadolinium negative and, remarkably, regressed in four patients. Plasma neurofilament light chain levels stabilized in all 10 patients and correlated with lesion load. The two patients who continued to deteriorate were over 60 years of age with prominent cognitive impairment. One patient died rapidly from coronavirus disease 2019. These results suggest that leriglitazone can arrest disease progression in adults with early-stage CALD and may be an alternative treatment to HSCT. [ABSTRACT FROM AUTHOR]

Introduction Cigarette smoking greatly promotes the progression and poor prognosis of colorectal cancer (CRC) patients, with the molecular mechanism still not fully clear. Methods In this study, CRC cells were exposed to tobacco-specific nitrosamine 4‑(methylnitrosamino)‑1‑(3‑pyridyl)-1‑butanone (NNK), and the differentially expressed smoking-related genes were identified based on both NNK-induced CRC cells and a total of 763 CRC tissues from The Cancer Genome Atlas cohort. Cox regression analysis, receiver operating characteristic curve and Kaplan–Meier plot were used to establish the risk score model for CRC prognosis. Moreover, quantitative real-time–PCR, western blotting, colony formation, migration, and invasion assays were performed to verify the core differentially expressed smoking-related gene and its molecular function in NNK-induced CRC progression. Results Results indicated NNK significantly enhanced CRC cell proliferation, migration and invasion. Moreover, a four-gene signature containing AKR1B10, CALB2, PLAC1, and GNA15 was established as a CRC prognosis marker. Among these four genes, AKR1B10 was further validated as the core gene, and its expression was significantly inhibited after NNK exposure in CRC cells. Results of gene enrichment analysis and western blotting suggested AKR1B10 might reduce the malignant progression of NNK-induced CRC cells by inhibiting the Wnt signaling pathway by promoting E-Cadherin expression and inhibiting the expression of N-Cadherin, β-Catenin, Vimentin, and Snail. Conclusions In conclusion, new four smoking-related genes can be jointly used as prognostic markers for CRC. AKR1B10 served as a tumor suppressor, and can be used as a potential target to inhibit NNK-induced CRC malignant progression by regulating the Wnt signaling pathway. Implications This study demonstrates that tobacco-derived NNK dependence would promote the malignant progression of colorectal cancer by regulating the expressions of the AKR1B10/Wnt signaling pathway. A novel four-gene signature is established for the prognosis prediction of smoking CRC patients. These findings have important translational implications given the continued use of tobacco and the difficulty in smoking cessation worldwide, which can be applied to alleviate the adverse effects induced by tobacco dependence on colorectal cancer patients. [ABSTRACT FROM AUTHOR]

Background Clinical utility data on pulmonary nodule (PN) risk stratification biomarkers are lacking. We aimed to determine the incremental predictive value and clinical utility of using an artificial intelligence (AI) radiomics-based computer-aided diagnosis (CAD) tool in addition to routine clinical information to risk stratify PNs among real-world patients. Methods We performed a retrospective cohort study of patients with PNs who underwent lung biopsy. We collected clinical data and used a commercially available AI radiomics-based CAD tool to calculate a Lung Cancer Prediction (LCP) score. We developed logistic regression models to evaluate a well-validated clinical risk prediction model (the Mayo Clinic model) with and without the LCP score (Mayo vs Mayo + LCP) using area under the curve (AUC), risk stratification table, and standardized net benefit analyses. Results Among the 134 patients undergoing PN biopsy, cancer prevalence was 61%. Addition of the radiomics-based LCP score to the Mayo model was associated with increased predictive accuracy (likelihood ratio test, P  =  .012). The AUCs for the Mayo and Mayo + LCP models were 0.58 (95% CI = 0.48 to 0.69) and 0.65 (95% CI = 0.56 to 0.75), respectively. At the 65% risk threshold, the Mayo + LCP model was associated with increased sensitivity (56% vs 38%; P  =  .019), similar false positive rate (33% vs 35%; P  =  .8), and increased standardized net benefit (18% vs -3.3%) compared with the Mayo model. Conclusions Use of a commercially available AI radiomics-based CAD tool as a supplement to clinical information improved PN cancer risk prediction and may result in clinically meaningful changes in risk stratification. [ABSTRACT FROM AUTHOR]

Background Lung cancer screening programs concern smokers at risk for cardiovascular diseases (CVDs) and chronic obstructive pulmonary disease (COPD). The LUMASCAN (LUng Cancer Screening, MArkers and low-dose computed tomography SCANner) study aimed to evaluate the acceptability and feasibility of screening for these 3 diseases in a community population with centralized organization and to determine low-dose computed tomography (CT) markers associated with each disease. Methods This cohort enrolled participants meeting National Comprehensive Cancer Network criteria (v1.2014) in an organized lung cancer–screening program including low-dose CT scans; spirometry; evaluations of coronary artery calcifications (CACs); and a smoking cessation plan at inclusion, 1, and 2 years; then telephone follow-up. Outcomes were the participation rate and the proportion of participants affected by lung cancer, obstructive lung disease, or CVD events. Logistic-regression models were used to identify radiological factors associated with each disease. Results Between 2016 and 2019, a total of 302 participants were enrolled: 61% men; median age 58.8 years; 77% active smoker; 11% diabetes; 38% hypertension; and 27% taking lipid-lowering agents. Inclusion, 1-year, and 2-year participation rates were 99%, 81%, 79%, respectively. After a median follow-up of 5.81 years, screenings detected 12 (4%) lung cancer, 9 of 12 via low-dose CT (78% localized) and 3 of 12 during follow-up (all stage IV), 83 (27%) unknown obstructive lung disease, and 131 (43.4%) moderate to severe CACs warranting a cardiology consultation. Preexisting COPD and moderate to severe CACs were associated with major CVD events with odds ratios of 1.98 (95% confident interval [CI] = 1.00 to 3.88) and 3.27 (95% CI = 1.72 to 6.43), respectively. Conclusion The LUMASCAN study demonstrated the feasibility of combined screening for lung cancer, COPD, and CVD in a community population. Its centralized organization enabled high participation and coordination of healthcare practitioners. [ABSTRACT FROM AUTHOR]

Purpose We evaluated whether plasma Alzheimer disease (AD)–related biomarkers were associated with cancer-related cognitive decline among older breast cancer survivors. Methods We included survivors aged 60-90 years with primary stage 0-III breast cancers (n = 236) and frequency-matched noncancer control paricipant (n = 154) who passed a cognitive screen and had banked plasma specimens. Participants were assessed at baseline (presystemic therapy) and annually for up to 60 months. Cognition was measured using tests of attention, processing speed, and executive function and learning and memory; perceived cognition was measured by the Functional Assessment of Cancer Therapy-Cognitive Function v3 Perceived Cognitive Impairments. Baseline plasma neurofilament light, glial fibrillary acidic protein, β-amyloid 42 and 40 and phosphorylated tau 181 were assayed using single molecule arrays. Mixed models tested associations between cognition and baseline AD biomarkers, time, group (survivor vs control participant), and their 2- and 3-way interactions, controlling for age, race, Wide Range 4 Achievement Test Word Reading score, comorbidity, and body mass index; 2-sided P values of.05 were considered statistically significant. Results There were no group differences in baseline AD-related biomarkers except survivors had higher baseline neurofilament light levels than control participants (P  = .013). Survivors had lower adjusted longitudinal attention, processing speed, and executive function than control participants starting from baseline and continuing over time (P  ≤ .002). However, baseline AD-related biomarker levels were not independently associated with adjusted cognition over time, except control participants had lower attention, processing speed, and executive function scores with higher glial fibrillary acidic protein levels (P  = .008). Conclusion The results do not support a relationship between baseline AD-related biomarkers and cancer-related cognitive decline. Further investigation is warranted to confirm the findings, test effects of longitudinal changes in AD-related biomarkers, and examine other mechanisms and factors affecting cognition presystemic therapy. [ABSTRACT FROM AUTHOR]

Background Camonsertib is a selective oral inhibitor of ataxia telangiectasia and Rad3-related (ATR) kinase with demonstrated efficacy in tumors with DNA damage response gene deficiencies. On-target anemia is the main drug-related toxicity typically manifesting after the period of dose-limiting toxicity evaluation. Thus, dose and schedule optimization requires extended follow-up to assess prolonged treatment effects. Methods Long-term safety, tolerability, and antitumor efficacy of 3 camonsertib monotherapy dosing regimens were assessed in the TRESR study dose-optimization phase: 160 mg once daily (QD) 3 days on, 4 days off (160 3/4; the preliminary recommended Phase II dose [RP2D]) and two step-down groups of 120 mg QD 3/4 (120 3/4) and 160 mg QD 3/4, 2 weeks on, 1 week off (160 3/4, 2/1w). Safety endpoints included incidence of treatment-related adverse events (TRAEs), dose modifications, and transfusions. Efficacy endpoints included overall response rate, clinical benefit rate, progression-free survival, and circulating tumor DNA (ctDNA)-based molecular response rate. Results The analysis included 119 patients: 160 3/4 (n = 67), 120 3/4 (n = 25), and 160 3/4, 2/1w (n = 27) treated up to 117.1 weeks as of the data cutoff. The risk of developing grade 3 anemia was significantly lower in the 160 3/4, 2/1w group compared with the preliminary RP2D group (hazard ratio = 0.23, 2-sided P  = .02), translating to reduced transfusion and dose reduction requirements. The intermittent weekly schedule did not compromise antitumor activity. Conclusion The 160 3/4, 2/1w dose was established as an optimized regimen for future camonsertib monotherapy studies offering a substantial reduction in the incidence of anemia without any compromise to efficacy. Clinical Trial ID NCT04497116. [ABSTRACT FROM AUTHOR]

Background Serum level of microRNA-122 (miR-122) has been reported as a sensitive diagnostic biomarker for detecting liver injury, comparable to the aminotransferases. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities are increased in other conditions, such as acute skeletal muscle injury (ASMI). We determined whether miR-122 is nonspecifically increased in patients suffering from ASMI. Methods We measured ALT, AST, creatine kinase (CK), and miR-122 in 3 groups: healthy controls (n = 24), patients with ASMI (total n = 29, 11 with recreational drug use and 18 without recreational drug use), and patients with acute liver injury (ALI; n = 14). Results Levels of ALT, AST, and CK increased 83%, 97%, and 100% for patients with ASMI and 100% for all 3 enzymes in ALI patients. In contrast, miR-122 increased in 34% of patients with ASMI (44.4% with recreational drug use and 18.2% without recreational drug use) and 100% of ALI patients. In 2 drug-induced liver injury cases, miR-122 increased about 12-24 hours before ALT and AST. Conclusion Recreational drug misuse is associated with both rhabdomyolysis and drug-induced liver injury (DILI). The traditional liver function markers AST and ALT were nonspecifically increased in the majority of patients with ASMI. miR-122 is only increased in patients at risk for DILI and demonstrates superior specificity for liver injury. [ABSTRACT FROM AUTHOR]

Non–small cell lung cancer (NSCLC) has been found to have recurrent genetic abnormalities, and novel therapies targeting these aberrations have improved patient survival. In this study, specimens from benign tissue, primary tumors, and brain metastases were obtained at autopsy from a 55-year-old White female patient diagnosed with NSCLC and were examined using next-generation sequencing (NGS) and chromosomal microarray assay (CMA). No genetic aberrations were noted in the benign tissue; however, NGS identified a mutation in the KRAS proto-oncogene, GTPase (KRAS): KRAS exon 2 p.G12D in primary and metastatic tumor specimens. We observed 7 DNA copy number aberrations (CNAs) in primary and metastatic tumor specimens; an additional 7 CNAs were exclusively detected in the metastatic tumor specimens. These DNA alterations may be genetic drivers in the pathogenesis of the tumor specimen from our patient and may serve as biomarkers for the classification and prognosis of NSCLC. [ABSTRACT FROM AUTHOR]

Lupus nephritis (LN) is one of the most severe clinical manifestations of systemic lupus erythematosus (SLE). Notably, the clinical manifestations of LN are not always consistent with the histopathological findings. Therefore, the diagnosis and activity monitoring of this disease are challenging and largely depend on invasive renal biopsy. Renal biopsy has side effects and is associated with the risk of bleeding and infection. There is a growing interest in the development of novel noninvasive biomarkers for LN. In this review, we summarize most of the LN biomarkers discovered so far by correlating current knowledge with future perspectives. These biomarkers fundamentally reflect the biological processes of kidney damage and repair during disease. Furthermore, this review highlights the role of urinary cell phenotype detection in the diagnosis, monitoring, and treatment of LN and summarizes the limitations and countermeasures of this test. [ABSTRACT FROM AUTHOR]

Background Cardiac injury caused by iron overload is the leading cause of mortality and morbidity in patients with beta-thalassemia, owing to frequent blood transfusion, increased iron overload, and blood hemolysis. Objective This research aimed to assess several novel cardiac biomarkers in the blood samples of children and adult patients with beta-thalassemia major (βTM), along with their respective control groups. These biomarkers included endothelin 1 (ET-1), N-terminal pro-brain natriuretic peptide (NT-proBNP), atrial natriuretic peptide (ANP), growth differentiation factor-15 (GDF-15), and renalase (RNLS). Methods This case-control study was done on 46 patients with βTM (23 children <18 years, and 23 adults ≥18 years) from the Genetic Hematology Center in Thi-Qar province, Iraq, and 42 comparable controls in 2 groups (21 for each group) in the period from February to April 2023. Results Levels of ET-1, NT-proBNP, ANP, GDF-15, RNLS, and ferritin were higher in the children and adults with βTM than in the control subjects. Conclusion Elevations of the novel cardiac biomarkers ET-1, NT-proBNP, ANP, GDF-15, and RNLS in the sera of children and adult patients with βTM when compared with comparable control subjects confirm that the majority of patients with βTM are at risk of cardiac and cardiovascular complications even when there are no obvious symptoms, especially in children, which gives suitable predictive biomarkers. [ABSTRACT FROM AUTHOR]

Apilimod dimesylate is a first-in-class phosphoinositide kinase, FYVE-type zinc finger-containing (PIKfyve) inhibitor with a favourable clinical safety profile and has demonstrated activity in preclinical C9orf72 and TDP-43 amyotrophic lateral sclerosis (ALS) models. In this ALS clinical trial, the safety, tolerability, CNS penetrance and modulation of pharmacodynamic target engagement biomarkers were evaluated. This phase 2a, randomized, double-blind, placebo-controlled, biomarker-end-point clinical trial was conducted in four US centres (ClinicalTrials.gov NCT05163886). Participants with C9orf72 repeat expansions were randomly assigned (2:1) to receive twice-daily oral treatment with 125 mg apilimod dimesylate capsules or matching placebo for 12 weeks, followed by a 12-week open-label extension. Safety was measured as the occurrence of treatment-emergent or serious adverse events attributable to the study drug and tolerability at trial completion or treatment over 12 weeks. Changes from baseline in plasma and CSF and concentrations of apilimod dimesylate and its active metabolites and of pharmacodynamic biomarkers of PIKfyve inhibition [soluble glycoprotein nonmetastatic melanoma protein B (sGPNMB) upregulation] and disease-specific CNS target engagement [poly(GP)] were measured. Between 16 December 2021 and 7 July 2022, 15 eligible participants were enrolled. There were no drug-related serious adverse events reported in the trial. Fourteen (93%) participants completed the double-blind period with 99% dose compliance [ n = 9 (90%) apilimod dimesylate; n = 5 (100%) placebo]. At Week 12, apilimod dimesylate was measurable in CSF at 1.63 ng/ml [standard deviation (SD): 0.937]. At Week 12, apilimod dimesylate increased plasma sGPNMB by >2.5-fold (P < 0.001), indicating PIKfyve inhibition, and lowered CSF poly(GP) protein levels by 73% (P < 0.001), indicating CNS tissue-level proof of mechanism. Apilimod dimesylate met prespecified key safety and biomarker end-points in this phase 2a trial and demonstrated CNS penetrance and pharmacodynamic target engagement. Apilimod dimesylate was observed to result in the greatest reduction in CSF poly(GP) levels observed to date in C9orf72 clinical trials. [ABSTRACT FROM AUTHOR]

Objectives To determine the role of keratin 17 (K17) as a predictive biomarker for response to chemotherapy by defining thresholds of K17 expression based on immunohistochemical tests that could be used to optimize therapeutic intervention for patients with pancreatic ductal adenocarcinoma (PDAC). Methods We profiled K17 expression, a hallmark of the basal molecular subtype of PDAC, by immunohistochemistry in 2 cohorts of formalin-fixed, paraffin-embedded PDACs (n = 305). We determined a K17 threshold of expression to optimize prognostic stratification according to the lowest Akaike information criterion and explored the potential relationship between K17 and chemoresistance by multivariate predictive analyses. Results Patients with advanced-stage, low K17 PDACs treated using 5-fluorouracil (5-FU)–based chemotherapeutic regimens had 3-fold longer survival than corresponding cases treated with gemcitabine-based chemotherapy. By contrast, PDACs with high K17 did not respond to either regimen. The predictive value of K17 was independent of tumor mutation status and other clinicopathologic variables. Conclusions The detection of K17 in 10% or greater of PDAC cells identified patients with shortest survival. Among patients with low K17 PDACs, 5-FU–based treatment was more likely than gemcitabine-based therapies to extend survival. [ABSTRACT FROM AUTHOR]

Introduction Multimodal monitoring is the use of data from multiple physiological sensors combined in a way to provide individualized patient management. It is becoming commonplace in the civilian care of traumatic brain-injured patients. We hypothesized we could bring the technology to the battlefield using a noninvasive sensor suite and an artificial intelligence-based patient management guidance system. Methods Working with military medical personnel, we gathered requirements for a hand-held system that would adapt to the rapidly evolving field of neurocritical care. To select the optimal sensors, we developed a method to evaluate both the value of the sensor's measurement in managing brain injury and the burden to deploy that sensor in the battlefield. We called this the Value-Burden Analysis which resulted in a score weighted by the Role of Care. The Value was assessed using 7 criteria, 1 of which was the clinical value as assessed by a consensus of clinicians. The Burden was assessed using 16 factors such as size, weight, and ease of use. We evaluated and scored 17 sensors to test the assessment methodology. In addition, we developed a design for the guidance system, built a prototype, and tested the feasibility. Results The resulting architecture of the system was modular, requiring the development of an interoperable description of each component including sensors, guideline steps, medications, analytics, resources, and the context of care. A Knowledge Base was created to describe the interactions of the modules. A prototype test set-up demonstrated the feasibility of the system in that simulated physiological inputs would mimic the guidance provided by the current Clinical Practice Guidelines for Traumatic Brain Injury in Prolonged Care (CPG ID:63). The Value-Burden analysis yielded a ranking of sensors as well as sensor metadata useful in the Knowledge Base. Conclusion We developed a design and tested the feasibility of a system that would allow the use of physiological biomarkers as a management tool in forward care. A key feature is the modular design that allows the system to adapt to changes in sensors, resources, and context as well as to updates in guidelines as they are developed. Continued work consists of further validation of the concept with simulated scenarios. [ABSTRACT FROM AUTHOR]

Introduction Achieving simultaneous cerebral blood flow (CBF) and oxygenation measures, specifically for point-of-care injury monitoring in prolonged field care, requires the implementation of appropriate methodologies and advanced medical device design, development, and evaluation. The near-infrared spectroscopy (NIRS) method measures the absorbance of light whose attenuation is related to cerebral blood volume and oxygenation. By contrast, diffuse correlation spectroscopy (DCS) allows continuous noninvasive monitoring of microvascular blood flow by directly measuring the degree of light scattering because of red blood cell (RBC) movement in tissue capillaries. Hence, this study utilizes these two optical approaches (DCS–NIRS) to obtain a more complete hemodynamic monitoring by providing cerebral microvascular blood flow, hemoglobin oxygenation and deoxygenation in hemorrhage, and hypoxia-induced injuries. Materials and Methods Piglet models of hemorrhage and hypoxia-induced brain injury were used with DCS and NIRS sensors placed over the preorbital to temporal skull regions. To induce hemorrhagic shock, up to 70% of the animal's total blood volume was withdrawn through graded hemorrhage serially via a syringe from a femoral artery cannula in 10 mL/kg aliquots over 1 minute every 10 minutes. A second group of animals was subjected to hypoxia for ∼1 hour through graded hypoxia by serial titration from normoxic fraction inspired oxygen of 21% to hypoxic fraction inspired oxygen of 6%. A subset of animals served as sham-controls undergoing anesthesia, instrumentation, and ventilation as the injury groups, yet experiencing no blood loss or hypoxia. Results We first investigated the relationship between hemorrhagic shock and no shock by using measured biomarkers, including blood flow index from DCS associated with CBF and oxygenated (HbO) and de-oxygenated hemoglobin from NIRS. The statistical analysis revealed a significant difference between no shock and hemorrhagic shock (P  < .01). The HbO decreased with each blood loss as expected, yet the de-oxygenated hemoglobin was slightly changed. During hypoxia-induced global hypoxic–ischemic injury tests, the CBF results from graded hypoxia were consistent with the response previously measured during hemorrhagic shock. Moreover, HbO decreased when the animal was hypoxic, as expected. A statistical analysis was also conducted to compare the results with those of the sham controls. Conclusions There is a consistency in blood flow measures in both injury mechanisms (hemorrhagic shock and hypoxia), which is significant as the new prototype system provides similar measures and trends for each brain injury type, suggesting that the optical system can be used in response to different injury mechanisms. Notably, the results support the idea that this optical system can probe the hemodynamic status of local cerebral cortical tissue and provide insight into the underlying changes of cerebral tissue perfusion at the microvascular level. These measurement capabilities can improve shock identification and monitoring of medical management of injuries, particularly hemorrhagic shock, in prolonged field care. [ABSTRACT FROM AUTHOR]

Introduction Asthma is the most common diagnosis in military personnel who endorse chronic dyspnea. Service members have unique occupational risk factors, and there is concern that airborne exposures in the deployed environment as well as other occupational exposures may contribute to the development of asthma or exacerbate pre-existing disease. Asthma phenotyping with clinical biomarkers such as serum immunoglobulin E (IgE) levels and eosinophil (EOS) counts is useful in defining treatment strategies for the management of asthma. This study sought to characterize the phenotype of medically separated military personnel with career-limiting asthma to define potential management strategies and guide future research evaluating the unexplained prevalence of asthma in this population. Materials and Methods A retrospective chart review of active duty service members (ADSM) who underwent fitness for duty evaluation via medical evaluation board between 2005 and 2016 and were separated with a minimum 30% conditional disability rating for asthma was performed. Only ADSM who were diagnosed with asthma by a pulmonologist and had spirometry data available were included in the analysis. Demographics, spirometry data, and laboratory data to include IgE levels, radioallergosorbent panels, and EOS counts were analyzed from the DoD electronic medical record. Results A total of 141 service members were evaluated with a mean age of 42 ± 6.8 years, mean serum EOS count of 300 ± 358 cells/μL, and mean IgE level of 305 ± 363 IU/mL. The patients were further categorized into 4 subgroups based on serum EOS count and IgE level: group A with IgE < 100 IU/mL and EOS < 300 cells/μL (n  = 45; 33%), group B with IgE > 100 IU/mL and EOS < 300 cells/μL (n  = 44; 32%), group C with IgE < 100 IU/mL and EOS > 300 cells/μL (n  = 6; 1%), and group D with IgE > 100 IU/mL, EOS > 300 cells/μL (n  = 46; 34%). Among the cohorts, there were no statistically significant differences in demographics, body mass index, spirometry, smoking history, or disability rating. Conclusion The majority of ADSM with a defined asthma history do not have concordant elevations in serum IgE and blood EOS suggestive of a Th2-high phenotype. Asthma in this population is heterogeneous, and phenotyping using clinical biomarkers may be useful to define optimal treatment strategies. [ABSTRACT FROM AUTHOR]

Purpose: Biomarkers are substances measured at the systemic level to evaluate organic responses in certain situations, establishing diagnoses, disease staging, and prognosis. Blood glucose is a biomarker recognized as a predictor of prognosis in children victims of traumatic brain injury (TBI). The scope of this study was to identify the accuracy of blood glucose as a biomarker of severe brain injury. Methods: A retrospective analytical study was conducted through the consecutive review of medical records of children and teenage victims of TBI who underwent neurological surgery between 2016 and 2023 in a level 1 trauma center. Two groups were compared: children with Glasgow Coma Scale (GCS) score ≤ 8 and children with GCS > 8. We calculated the predictive values to define the accuracy of blood glucose as a biomarker of brain injury. Results: Ninety-two medical records were included for analysis. Hyperglycemia predominated in cases with GCS ≤ 8 (48% vs 3%; p < 0.0001; OR, 30; 95% CI, 5.9902–150.2448). The glycemic measurement considering the cutoff point of 200 mg/dL or 11.1 mmol/L showed a specificity of 97%, a positive predictive value of 86%, an accuracy of 84%, and a likelihood ratio for a positive test of 16. Conclusion: Victims with GCS ≤ 8 are 16 times more likely to develop acute hyperglycemia after TBI when compared to those with GCS > 8. Blood glucose is a biomarker with an accuracy of 84% to predict severe brain injury, considering the cutoff point of 200 mg/dL or 11.1 mmol/L. [ABSTRACT FROM AUTHOR]

Bipolar disorder (BD) is a severe psychiatric disease with high rates of misdiagnosis and underdiagnosis, resulting in a significant disease burden on both individuals and society. Abnormal neural oscillations have garnered significant attention as potential neurobiological markers of BD. However, untangling the mechanisms that subserve these baseline alternations requires measurement of their electrophysiological underpinnings. This systematic review investigates consistent abnormal resting-state EEG power of BD and conducted an initial exploration into how methodological approaches might impact the study outcomes. This review was conducted in Pubmed-Medline and Web-of-Science in March 2024 to summarize the oscillation changes in resting-state EEG (rsEEG) of BD. We focusing on rsEEG to report spectral power in different frequency bands. We identified 10 studies, in which neural oscillations was compared with healthy individuals (HCs). We found that BD patients had abnormal oscillations in delta, theta, beta, and gamma bands, predominantly characterized by increased power, indicating potential widespread neural dysfunction, involving multiple neural networks and cognitive processes. However, the outcomes regarding alpha oscillation in BD were more heterogeneous, which is thought to be potentially influenced by the disease severity and the diversity of samples. Furthermore, we conducted an initial exploration into how demographic and methodological elements might impact the study outcomes, underlining the importance of implementing standardized data collection methods. Key aspects we took into account included gender, age, medication usage, medical history, the method of frequency band segmentation, and situation of eye open/eye close during the recordings. Therefore, in the face of abnormal multiple oscillations in BD, we need to adopt a comprehensive research approach, consider the multidimensional attributes of the disease and the heterogeneity of samples, and pay attention to the standardized experimental design to improve the reliability and reproducibility of the research results. [ABSTRACT FROM AUTHOR]

Background: Understanding the potential risk factors of heart diseases is key to effectively managing cardiac diseases. The present study quantifies the association of identified risk factors. In addition, the study has compared the association of mortality with hypertension, uncontrolled diabetes, and uncontrolled hyperlipidemia using Grey Relational Approach (GRA) for stroke, lung diseases, smoking, stress, obesity, and lack of exercise. Method: Data on risk factors of heart failure were collected from the Global Burden of Disease (GBD) study (2001–2017). From the GBD database, variables have selected the top leading risk factors responsible for mortality from cardiac diseases. Data on risk factors was analyzed using the GRA procedure (utilizing Grey [8.0] software). In the GRA method, the correlation was categorized into three components: GRA – Deng (assesses the effect of one variable specified by data on the other variables), GRA- absolute (assesses the association between variables measured), and GRA-SS (assessed the overall association between the variables measured). Stroke, lung diseases, smoking, stress, obesity, and lack of exercise were taken as dependent variables and their impact was assessed. Hypertension (high grade) uncontrolled diabetes, and uncontrolled hyperlipidemia were considered as independent variables. The relationship between dependent and independent variables was assessed. Results: Overall correlational analysis showed that type 2 diabetes (T2DM) is the risk factor that has a strong relationship with causing heart failure and thereby increases morbidity and mortality among Chinese patients. After T2DM, the second highest risk factor associated was severe dyslipidemia which is responsible for causing heart failure. High-grade hypertension is one-third most common risk factor in causing heart failure. GRA – Deng analysis showed that T2DM is the top risk factor associated with heart failure, followed by high-grade hypertension and severe dyslipidemia (uncontrolled). GRA-absolute analysis showed that severe dyslipidemia is the top risk factor associated with heart failure, followed by high-grade hypertension and T2DM (uncontrolled). GRA-SS analysis showed that high-grade hypertension is the top risk factor associated with heart failure, followed by severe dyslipidemia and T2DM (uncontrolled). Conclusions: The study reported that T2DM, severe dyslipidemia, and high-grade hypertension as strongly correlated with the development of heart failure after considering other several key risk factors (stroke, lung diseases, smoking, stress, obesity, and lack of exercise). Level of evidence: IV. Technical efficacy: Stage 5. [ABSTRACT FROM AUTHOR]

This editorial published in the journal Frontiers in Endocrinology discusses the advancements in thyroid cancer research, specifically focusing on molecular characterization and prediction models for recurrence. The article emphasizes the importance of accurate molecular and genetic characterization to differentiate between less aggressive and more aggressive thyroid tumors. It also explores the use of biomarkers and prediction models to improve the diagnosis and management of thyroid nodules. The document provides a summary of three studies related to thyroid cancer research, which identify genes associated with recurrence, analyze the genetic landscape of thyroid cancer in Chinese patients, and investigate the shared molecular mechanisms between thyroid cancer and Hashimoto's thyroiditis. These studies contribute to our understanding of thyroid cancer and may lead to personalized treatment options. [Extracted from the article]

Cognitive frailty (CF) is a heterogeneous syndrome that is becoming one of the most serious health problems as the world's population age is increasing. Elucidating its biological mechanisms as well as prevention and treatments is becoming increasingly significant, particularly in view of the associated health costs. We presented the study protocol of a research project funded by the Italian Ministry of Health (grant number RF-2016-02363298) aiming to investigate the cognitive and neuropsychological effects of a 5-week treatment with therapy based on the regenerative properties of ozone (O3) in a cohort of subjects stratified according to CF scores. We also studied the potential effects of O3 on blood-based biomarkers indicative of specific biological systems that may be altered in CF. Seventy-five older persons were recruited and randomly assigned to receive the active treatment (150 cc of oxygen-O2-O3 mixture at the concentration of 30 µg of O3 per cc of O2), O2, or the placebo (air) for 5 weeks. The main endpoints were the change in the scores of clinical scales from baseline (T0) to weeks 3 (T3), 9 (T9), and 15 (T15) after treatment and the change in biomarker levels resulting from transcriptomics, proteomics, and metabolomic patterns at the same times. The positive results from this study could have important clinical implications. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Suicidal behavior is heritable and is a major cause of death worldwide. Two large-scale genome-wide association studies (GWASs) recently discovered and cross-validated genome-wide significant (GWS) loci for suicide attempt (SA). The present study leveraged the genetic cohorts from both studies to conduct the largest GWAS meta-analysis of SA to date. Multi-ancestry and admixture-specific meta-analyses were conducted within groups of significant African, East Asian, and European ancestry admixtures. METHODS: This study comprised 22 cohorts, including 43,871 SA cases and 915,025 ancestry-matched controls. Analytical methods across multi-ancestry and individual ancestry admixtures included inverse variance-weighted fixed-effects meta-analyses, followed by gene, gene-set, tissue-set, and drug-target enrichment, as well as summary-data-based Mendelian randomization with brain expression quantitative trait loci data, phenome-wide genetic correlation, and genetic causal proportion analyses. RESULTS: Multi-ancestry and European ancestry admixture GWAS meta-analyses identified 12 risk loci at p values

The protozoan parasite Entamoeba gingivalis has long been detected in diseased gingival pockets. The parasite is found in 81% of diseased sites using PCR and in up to 100% using microscopy, whereas it is mostly absent from healthy gingival sites. The purpose of this study on 20 periodontitis patients was to analyze the characteristic biofilm using phase-contrast microscopy and evaluate the results of a novel antiparasitic, anti-inflammatory therapeutical approach. The therapeutic strategy, termed “Periodontal Healing Protocol Bonner Dunoyé” (PHPBD), is implemented in monthly appointments for 8 months, and a control visit at one year. It involves a disinfection protocol, subgingival calculus removal, patient training and the microscopic analysis of periodontal biofilm sulci. The practitioner also records bleeding on probing (BOP) and pocket depth (PD) to quantify healing. In all cases, the initial biofilm composed mainly of parasites, neutrophils, spirochetes, and other motile bacteria was progressively replaced by a white blood cell-free biofilm, consisting of motionless coccoid bacteria, filaments, and epithelial cells, indicative of healthy periodontium. Results were stable from month 8 to month 12. At one year, both BOP and PD values were greatly reduced (96%–100% decrease) compared to initial levels. The average sulcus clinical pocket healing toward the 1–3 mm PD group teeth was close to 99% overall patients. In conclusion, implementation of PHPBD appears to result in complete healing of periodontitis within 12 months, as determined by BOP, PD, biofilm microscopic monitoring and elimination of motile bacteria, parasites, and inflammatory cells. Thus, periodontal dysbiosis can be microscopically guided toward predictable eubiosis. Further studies are needed to evaluate long-term benefits.

Objective: To evaluate longitudinal associations of distress and inflammation with somatic and depressive symptom severity in breast cancer patients, from before to six months after neoadjuvant chemotherapy. We also explored feasibility and effects of an early mindfulness-based intervention for preventing or reducing somatic and depressive symptoms. Methods: Longitudinal pilot study with a randomized waitlist-controlled intervention design. Women with breast cancer were randomized to receive access to a smartphone application offering meditation exercises, either immediately after baseline testing (intervention group) or after study completion (control group) in a 1:1 ratio. Assessments (self-report questionnaires and a blood draw when feasible) were completed before, halfway through, immediately after, and 6 months after completing neoadjuvant chemotherapy. Results: Fifty evaluable women were enrolled. Somatic symptom severity increased during chemotherapy, whereas depressive symptom severity was at its peak before treatment and declined gradually thereafter. Distress was positively associated with depressive symptom severity. Only Distress Thermometer-results were positively associated with somatic symptom severity. Inflammation was positively associated with both types of symptoms, and distress did not moderate the associations between inflammation and symptom severity. Intervention adherence was low and no intervention effect on symptom experience was observed. Conclusion: Inflammation and distress are independently associated with somatic and depressive symptoms experienced during breast cancer treatment.