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The quantitative determination of topically applied substances in the skin is severely limited and represents a challenging task. The porcine skin ex vivo was topically treated with a gel containing caffeine (CF) and propylene glycol (PG), and depth‐resolved Raman spectra were recorded with two confocal Raman microscopes. We applied a novel tailored multivariate curve resolution‐alternating least squares method to the selected spectral regions (512–604 and 778–1148 cm−1) of gel‐treated skin and quantitatively determined the concentrations of CF and PG in the stratum corneum (SC). The highest concentration of CF (181 mg/cm3) was found at the surface, while PG (384 mg/cm3) was found at 10% SC depth, indicating the formation of a reservoir at the superficial SC. The concentrations of CF and PG decreased monotonically and reached the detection limit at ≈60% and ≈80% SC depth, respectively, indicating that neither permeate the SC. [ABSTRACT FROM AUTHOR]

Ineffective medication is a major healthcare problem causing significant patient suffering and economic costs. This issue stems from the complex nature of diseases, which involve altered interactions among thousands of genes across multiple cell types and organs. Disease progression can vary between patients and over time, influenced by genetic and environmental factors. To address this challenge, digital twins have emerged as a promising approach, which have led to international initiatives aiming at clinical implementations. Digital twins are virtual representations of health and disease processes that can integrate real-time data and simulations to predict, prevent, and personalize treatments. Early clinical applications of DTs have shown potential in areas like artificial organs, cancer, cardiology, and hospital workflow optimization. However, widespread implementation faces several challenges: (1) characterizing dynamic molecular changes across multiple biological scales; (2) developing computational methods to integrate data into DTs; (3) prioritizing disease mechanisms and therapeutic targets; (4) creating interoperable DT systems that can learn from each other; (5) designing user-friendly interfaces for patients and clinicians; (6) scaling DT technology globally for equitable healthcare access; (7) addressing ethical, regulatory, and financial considerations. Overcoming these hurdles could pave the way for more predictive, preventive, and personalized medicine, potentially transforming healthcare delivery and improving patient outcomes. [ABSTRACT FROM AUTHOR]

Ixodes ricinus is an important vector of infectious human and livestock diseases in Europe. Co-infections of pathogens in ticks and hosts have been reported. Tick cell lines offer a useful model system for study of co-infections. We present a review of the existing literature on co-infections in tick cell lines. Previous studies have demonstrated the usefulness of tick cell lines in studies on co-infection of different pathogens and their interaction with the tick microbiome. We also carried out a preliminary study to investigate the effects of co-culturing Borrelia burgdorferi and Anaplasma phagocytophilum on their growth and interactions with the Ixodes ricinus cell line IRE/CTVM19 over a 13-day period. Replication of both pathogens was quantified by real-time PCR. The presence of A. phagocytophilum appeared to have a slight inhibitory effect on the multiplication of B. burgdorferi, that were added subsequently. In contrast, the prior presence of B. burgdorferi appeared to have a stimulatory effect on A. phagocytophilum after 6 days in culture. We conclude that the IRE/CTVM19 tick cell line is suitable for simultaneous and continuous cultivation of both bacteria and can be applied in future research. [ABSTRACT FROM AUTHOR]

Background: Systemic changes in multiple diseases may influence the onset of dementia. However, the specific temporality between exposure diseases and dementia remains uncertain. Aims: By characterising the full spectrum of temporal disease trajectories before dementia, this study aims to yield a global picture of precursor diseases to dementia and to provide detailed instructions for risk management and primary prevention of dementia. Method: Using the multicentre, community-based prospective UK Biobank, we constructed disease trajectories before dementia utilising the phenome-wide association analysis, paired directional test and association quantification. Stratified disease trajectories were constructed by dementia subtypes, gender, age of diagnosis and Apolipoprotein E (ApoE) status, respectively. Results: Our study population comprised 434 266 participants without baseline dementia and 4638 individuals with all-cause dementia. In total, 1253 diseases were extracted as potential components of the disease trajectory before dementia. We identified three clusters of disease trajectories preceding all-cause dementia, initiated by circulatory, metabolic and respiratory diseases occurring approximately 5–15 years before dementia. Cerebral infarction or chronic renal failure following chronic ischaemic heart disease was the specific trajectory before vascular dementia. Apolipoprotein E (ApoE) ε4 non-carriers exhibited more complex trajectories compared with carriers. Lipid metabolism disorders remained in the trajectories regardless of dementia subtypes, gender, age of diagnosis and ApoE status. Conclusions: This study provides a comprehensive view of the longitudinal disease trajectories before dementia and highlights the potential targets of midlife cardiometabolic dysfunction for dementia screening and prevention. [ABSTRACT FROM AUTHOR]

We analysed serum samples of 209 subjects immunized with yellow fever vaccine 17D by different assays: neutralization test, immunofluorescence assay, haemagglutination inhibition test and ELISA, for presence of 17D-specific antibodies. Serum samples were taken from a few weeks up to 35 years after vaccination. The neutralization test had the highest sensitivity. There was no correlation of results between the serological assays. Considering NT titres > 1:10 as indicating protection, we found that about 75% of subjects remained immune even 10 years after vaccination, with a median NT titre of 1:40 in reactive sera. [ABSTRACT FROM AUTHOR]

Skin moisturizing is important in dermatology and cosmetics. Raman microspectroscopy is a well‐suited method to determine water concentration profiles in the stratum corneum (SC) of untreated and formulation‐treated skin in vivo. Until now, the water in the SC was quantified using the ratio of water to proteins, and other SC components were neglected. Here, we apply the tailored multivariate curve resolution‐alternating least squares (tMCR‐ALS) method to improve the quantitative determination of water in the SC of cosmetic oil‐treated skin accounting Raman spectra of proteins, lipids, and oils in the high wavenumber region. We compared the water concentration profiles in the SC of petrolatum‐treated skin calculated using the tMCR‐ALS method and two existing conventional and extended methods, which are both based on the analysis of the water‐to‐protein‐ratio. The results show that in petrolatum‐treated skin, the conventional method calculates an incorrect water profile in the depth of 0–70% of the SC thickness; the extended method shows an incorrect profile in the depth of 0–10% of the SC thickness; the applied tMCR‐ALS method show results, which coincide well with the modern knowledge of the moisturizing effect of cosmetic oils on the SC. Almond, jojoba, and paraffin oils exhibit a similar moisturizing effect that manifests itself in an increase of water concentration in the intermediate SC depth. However, the effect of petrolatum is more pronounced. In the context of treated skin, the proposed method calculates water concentration profiles throughout the SC correctly and thus has a great potential in dermatology and cosmetics. [ABSTRACT FROM AUTHOR]

In the central nervous system, oligodendrocytes wrap around neuronal axons to form myelin, an insulating layer or sheath that allows for the efficient conductance of action potentials. In addition to structural insulation, myelin provides encased axons with nutrient, metabolic and defensive support. Demyelination, or myelin loss, can therefore cause axonal dysfunction, leading to neurological impairment and disease. In Alzheimer’s disease (AD), progressive white matter demyelination is acknowledged as one of the earliest pathologies preceding symptom onset. Unfortunately, current pharmacotherapy for slowing demyelination or promoting remyelination in AD is nonexistent. Exercise is recognized for its wide-ranging benefits to human health, including improved mental health and the prevention of lifestyle-related diseases. Mounting evidence suggests the contribution of physical activity in delaying the progression of dementia in elderly populations. Recent mechanistic studies have shown that exercise facilitates myelination in the brain through the vitalization of intrinsic pro-myelination cues, such as increased neurotrophic factors and electrical activity. In this review, we summarize and discuss the potential of physical exercise on counteracting aging-associated white matter demyelination, which causes cognitive decline in AD. We highlight the need of further basic and clinical research investigations on this topic to establish novel approaches for healthy and improved brain aging. [ABSTRACT FROM AUTHOR]

Salivary gland pleomorphic adenoma (SGPA) is the most common type of benign epithelial tumor; it is observed more commonly in females (with a female-to-male ratio of 1.43:1), and the age at diagnosis ranges between 40 and 59 years, with only 2% of cases diagnosed before age 18. Cri du Chat (CdC) is a rare syndrome caused by deletions of various sizes in the short arm of chromosome 5. Tumors in CdC patients are extremely rare: in Danish, Spanish, Australian, and Japanese groups of cases, no tumors have been reported, while a few cases have been described among 321 CdC patients collected in Italy and Germany. These cases all involve tumors that appear at a young age. We here report the case of a parotid pleomorphic adenoma in an 8-year-old boy with CdC. Exome analysis did not identify variants certainly significant for the development of SGPA. A CGH array, analyzed both in peripheral blood and tumor samples, failed to recognize anomalies previously associated with SGPA but identified a de novo duplication in 7p15.2, which contains part of a gene, SKAP2, in which the increased copy number is associated with the development of a different type of tumor such as pancreatic duct adenocarcinoma. The assumption that the duplication in 7p15.2 is relevant for the development of SGPA in our patient implies that CGH array studies must be included early in life in routine work-ups of CdC to identify CNVs with possible pathogenic roles for tumor development. This is particularly also relevant in relation to the severely impaired possibility for patients with CdC to report discomfort or pain related to tumor development. Constitutional CNVs in addition to the deletion in 5p should also be extensively studied to verify if their presence in some patients could explain why, in these cases, tumors develop at an age younger than expected. [ABSTRACT FROM AUTHOR]

Reconstructed epidermal equivalents (REEs) consist of two distinct cell layers – the stratum corneum (SC) and the keratinocyte layer (KL). The interplay of these layers is particularly crucial in pruritic inflammatory disorders, like psoriasis, where a defective SC barrier is associated with immune dysregulation. However, independent evaluation of the skin barrier function of the SC and KL in REEs is highly challenging because of the lack of quantitative methodologies that do not disrupt the counter layer. Here, a non‐invasive impedance spectroscopy technique is introduced for dissecting the distinct contributions of the SC and KL to overall skin barrier function without disrupting the structure. These findings, inferred from the impedance spectra, highlight the individual barrier resistances and maturation levels of each layer. Using an equivalent circuit model, a correlation between impedance parameters and specific skin layers, offering insights beyond traditional impedance methods that address full‐thickness skin only is established. This approach successfully detects subtle changes, such as increased paracellular permeability due to mild irritants and the characterization of an immature SC in psoriatic models. This research has significant implications, paving the way for detailed mechanistic investigations and fostering the development of therapies for skin irritation and inflammatory disorders. [ABSTRACT FROM AUTHOR]

Dementia is a highly prevalent condition with devastating clinical and socioeconomic sequela. It is expected to triple in prevalence by 2050. No treatment is currently known to be effective. Symptomatic late-onset dementia and predementia (SLODP) affects 95% of patients with the syndrome. In contrast to trials of pharmacological prevention, no treatment is suggested to remediate or cure these symptomatic patients. SLODP but not young onset dementia is intensely associated with multimorbidity (MUM), including brain-perturbating conditions (BPCs). Recent studies showed that MUM/BPCs have a major role in the pathogenesis of SLODP. Fortunately, most MUM/BPCs are medically treatable, and thus, their treatment may modify and improve SLODP, relieving suffering and reducing its clinical and socioeconomic threats. Regrettably, the complex system features of SLODP impede the diagnosis and treatment of the potentially remediable conditions (PRCs) associated with them, mainly due to failure of pattern recognition and a flawed diagnostic workup. We suggest incorporating two SLODP-specific conceptual themes into the diagnostic workup: MUM/BPC and multilevel phenomenological themes. By doing so, we were able to improve the diagnostic accuracy of SLODP components and optimize detecting and favorably treating PRCs. These revolutionary concepts and their implications for remediability and other parameters are discussed in the paper. [ABSTRACT FROM AUTHOR]

The dengue virus, the primary cause of dengue fever, dengue hemorrhagic fever, and dengue shock syndrome, is the most widespread mosquito-borne virus worldwide. In recent decades, the prevalence of dengue fever has increased markedly, presenting substantial public health challenges. Consequently, the development of an efficacious vaccine against dengue remains a critical goal for mitigating its spread. Our research utilized Celcradle™, an innovative tidal bioreactor optimized for high-density cell cultures, to grow Vero cells for dengue virus production. By maintaining optimal pH levels (7.0 to 7.4) and glucose concentrations (1.5 g/L to 3.5 g/L) during the proliferation of cells and viruses, we achieved a peak Vero cell count of approximately 2.46 × 109, nearly ten times the initial count. The use of Celcradle™ substantially decreased the time required for cell yield and virus production compared to conventional Petri dish methods. Moreover, our evaluation of the immunogenicity of the Celcradle™-produced inactivated DENV4 through immunization of mice revealed that sera from these mice demonstrated cross-reactivity with DENV4 cultured in Petri dishes and showed elevated antibody titers compared to those from mice immunized with virus from Petri dishes. These results indicate that the dengue virus cultivated using the Celcradle™ system exhibited enhanced immunogenicity relative to that produced in traditional methods. In conclusion, our study highlights the potential of the Celcradle™ bioreactor for large-scale production of inactivated dengue virus vaccines, offering significant promise for reducing the global impact of dengue virus infections and accelerating the development of effective vaccination strategies. [ABSTRACT FROM AUTHOR]

Background: Evidence for substance use‐related problems in individuals with mild intellectual disability is sparse and mainly limited to selected psychiatric populations. We evaluated the risk of substance use‐related problems in individuals with mild intellectual disability compared to the general population. Additionally, we have performed secondary sibling comparison analyses to account for familial confounding. Methods: We conducted a population‐based cohort study of individuals born in Sweden between 1973 and 2003. A total of 18,307 individuals with mild intellectual disability were compared to 915,350 reference individuals from the general population and 18,996 full siblings of individuals with mild intellectual disability. Information on mild intellectual disability and substance use‐related problems was obtained from several Swedish national and regional school and healthcare registers. Substance use‐related problems were measured via corresponding diagnostic and legal codes and included alcohol use disorder, drug use disorder, alcohol‐related somatic disease, conviction for a substance‐related crime, and substance‐related death. Results: Individuals with mild intellectual disability had a higher risk of any substance use‐related problem compared to the general population (HR, 1.81; 95% CI, 1.72–1.91), both in males (HR, 1.76; 95% CI, 1.65–1.89) and females (HR, 1.89; 95% CI, 1.74–2.05). The risks of substance use‐related problems were particularly elevated among individuals with mild intellectual disability and psychiatric comorbidities (HR, 2.21–8.24). The associations were attenuated in the sibling comparison models. Conclusions: Individuals with mild intellectual disability, especially those with psychiatric comorbidity, are at an elevated risk of substance use‐related problems. Familial factors shared by full siblings contribute considerably to the association between mild intellectual disability and substance use‐related problems. [ABSTRACT FROM AUTHOR]

Background: The co-administration of drugs known to interact greatly impacts morbidity, mortality, and health economics. This study aims to examine the drug–drug interaction (DDI) phenomenon with a large-scale longitudinal analysis of age and gender differences found in drug administration data from three distinct healthcare systems. Methods: This study analyzes drug administrations from population-wide electronic health records in Blumenau (Brazil; 133 K individuals), Catalonia (Spain; 5.5 M individuals), and Indianapolis (USA; 264 K individuals). The stratified prevalences of DDI for multiple severity levels per patient gender and age at the time of administration are computed, and null models are used to estimate the expected impact of polypharmacy on DDI prevalence. Finally, to study actionable strategies to reduce DDI prevalence, alternative polypharmacy regimens using drugs with fewer known interactions are simulated. Results: A large prevalence of co-administration of drugs known to interact is found in all populations, affecting 12.51%, 12.12%, and 10.06% of individuals in Blumenau, Indianapolis, and Catalonia, respectively. Despite very different healthcare systems and drug availability, the increasing prevalence of DDI as patients age is very similar across all three populations and is not explained solely by higher co-administration rates in the elderly. In general, the prevalence of DDI is significantly higher in women — with the exception of men over 50 years old in Indianapolis. Finally, we show that using proton pump inhibitor alternatives to omeprazole (the drug involved in more co-administrations in Catalonia and Blumenau), the proportion of patients that are administered known DDI can be reduced by up to 21% in both Blumenau and Catalonia and 2% in Indianapolis. Conclusions: DDI administration has a high incidence in society, regardless of geographic, population, and healthcare management differences. Although DDI prevalence increases with age, our analysis points to a complex phenomenon that is much more prevalent than expected, suggesting comorbidities as key drivers of the increase. Furthermore, the gender differences observed in most age groups across populations are concerning in regard to gender equity in healthcare. Finally, our study exemplifies how electronic health records' analysis can lead to actionable interventions that significantly reduce the administration of known DDI and its associated human and economic costs. [ABSTRACT FROM AUTHOR]

The human stratum corneum (SC) contains an abundant amount of carotenoid antioxidants, quenching free radicals and thereby protecting the skin. For the precise measurements of the depth‐dependent carotenoid concentration, confocal Raman microscopy is a suitable method. The quantitative concentration can be determined by the carotenoid‐related peak intensity of a Gaussian function approached at ≈1524 cm−1 using non‐linear regression. Results show that the carotenoid concentration is higher at the superficial layers of the SC then decreases to a minimum at 20% SC depth and increases again towards the bottom of the SC. In the present work, two carotenoid penetration pathways into the SC are postulated. The first pathway is from the stratum granulosum to the bottom of the SC, while in the second pathway, the carotenoids are delivered to the skin surface by sweat and/or sebum secretion and penetrate from outside. The carotenoids are aggregated at the superficial layers, which are shown by high correlation between the aggregation states of carotenoids and the lateral organization of lipids. At the 30%‐40% SC depths, the ordered and dense lipid molecules intensify the lipid‐carotenoid interactions and weaken the carotenoid‐carotenoid interaction and thus exhibit the disaggregation of carotenoids. At 90%‐100% SC depths, the carotenoid‐lipid interaction is weakened and the carotenoids have a tendency to be aggregated. Thus, the molecular structural correlation of carotenoid and SC lipid might be reserved in the intercellular space of the SC and also serves as the skeleton of the intercellular lipids. [ABSTRACT FROM AUTHOR]

The quantitative determination of substance concentration in the stratum corneum (SC) is important for profiling of the skin barrier function‐related parameters and for investigating drug delivery through the SC. Hereby, confocal Raman microscopy (CRM) is a widely used method, which can be applied noninvasively and in vivo. Most analysis methods are based on the assumption that keratin is distributed homogeneously throughout the SC. In this study, the depth profiles of keratin‐related Raman peaks (1,003, 1,450, 1,650, and 2,935 cm−1) are investigated in detail. It was shown that each of these Raman peaks can be used for the precise determination of the skin surface position, which is important in case of overlapping of these with Raman bands associated to a formulation for treated skin. For correction of the depth‐dependent signal attenuation, that is, normalization, the 1,450, 1,650, and 2,935 cm−1 peaks can be used, whereas the 1,003 cm−1 peak cannot. Further analysis shows that the keratin concentration is nonhomogeneous throughout the SC and decreases towards its bottom due to water increase. Thus, the concentration of certain substances in the SC, such as urea, lipids, water, or natural moisturizing factor, determined using normalization on the keratin peak intensity, is overestimated in the deep SC layers starting from 30% SC depth. The correction coefficients were calculated for all four Raman peaks and for all SC depths with 10% increments. It was determined that at the bottom of the SC, the values obtained using keratin normalization should be multiplied by 0.88 (for 1,003 or 1,450 cm−1), 0.94 (for 1,650 cm−1), and 0.92 (for 2,935 cm−1) in order to compensate nonhomogeneous distribution of keratin in the SC. Thus, original values are overestimated at the SC bottom by 6–12%. The presented correction mechanism is proposed to be used for further correction. [ABSTRACT FROM AUTHOR]

Background: Given the increased risk of chronic diseases and comorbidity among middle-aged and older adults in China, it is pivotal to identify the disease trajectory of developing chronic multimorbidity and address the temporal correlation among chronic diseases. Method: The data of 15895 participants from the China Health and Retirement Longitudinal Study (CHARLS 2011 – 2018) were analyzed in the current study. Binomial tests and the conditional logistic regression model were conducted to estimate the associations among 14 chronic diseases, and the disease trajectory network analysis was adopted to visualize the relationships. Results: The analysis showed that hypertension is the most prevalent disease among the 14 chronic conditions, with the highest cumulative incidence among all chronic diseases. In the disease trajectory network, arthritis was found to be the starting point, and digestive diseases, hypertension, heart diseases, and dyslipidemia were at the center, while memory-related disease (MRD), stroke, and diabetes were at the periphery of the network. Conclusions: With the chronic disease trajectory network analysis, we found that arthritis was prone to the occurrence and development of various other diseases. In addition, patients of heart diseases/hypertension/digestive disease/dyslipidemia were under higher risk of developing other chronic conditions. For patients with multimorbidity, early prevention can preclude them from developing into poorer conditions, such as stroke, MRD, and diabetes. By identifying the trajectory network of chronic disease, the results provided critical insights for developing early prevention and individualized support services to reduce disease burden and improve patients’ quality of life. [ABSTRACT FROM AUTHOR]

Bioinert materials such as the zirconium dioxide and aluminum oxide are widely used in surgery and dentistry due to the absence of cytotoxicity of the materials in relation to the surrounding cells of the body. However, little attention has been paid to the study of metabolic processes occurring at the implant–cell interface. The metabolic activity of mouse 3T3 fibroblasts incubated on yttrium-stabilized zirconium ceramics cured with aluminum oxide (ATZ) and stabilized zirconium ceramics (Y-TZP) was analyzed based on the ratio of the free/bound forms of cofactors NAD(P)H and FAD obtained using two-photon microscopy. The results show that fibroblasts incubated on ceramics demonstrate a shift towards the free form of NAD(P)H, which is observed during the glycolysis process, which, according to our assumptions, is related to the porosity of the surface of ceramic structures. Consequently, despite the high viability and good proliferation of fibroblasts assessed using an MTT test and a scanning electron microscope, the cells are in a state of hypoxia during incubation on ceramic structures. The FLIM results obtained in this work can be used as additional information for scientists who are interested in manufacturing osteoimplants. [ABSTRACT FROM AUTHOR]

Background: In Cri du Chat (CdC), cancer as comorbidity is extremely rare. In databases from Denmark, Spain, Australia, New Zealand, and Japan, no cancer was reported; in Italy and Germany, four cancers were identified out of 321 CdCs. Methods: In a 29-year-old CdC patient, clinical investigations following hematemesis led to the diagnosis of esophageal adenocarcinoma (EAC). A high pain threshold was also observed. Conventional and molecular cytogenetic defined the size of the deletion, and exome analysis on the trio completed the molecular work. Results: Cytogenetic analysis showed a de novo chromosomal alteration: 46,XY,ishdel(5)(p14.3)(D5S28-) and arr[GRCh37] 5p15.33p14.3(1498180_19955760)x1. A quantitative sensory test demonstrated a high heat threshold. A 18f-fluorodeoxyglucose PET/TC scan of the brain failed to detect reduction of metabolism in the somatosensory area or insular cortex. Exome analysis in the trio (patient and parents) failed to identify variants to be interpreted as a likely risk factor for EAC. Conclusion: We conclude that the presence of well-known risk factors (maleness, obesity, gastroesophageal reflux, and Barrett's metaplasia) in a patient with very limited capability of expressing discomfort or referring clinical symptoms have been the main risk factors for developing EAC. At present, based on the available data, there is no evidence of any increased risk of developing cancer in CdC patients. [ABSTRACT FROM AUTHOR]

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Fibroblasts are among the most common cell types in the stroma responsible for creating and maintaining the structural organization of the extracellular matrix in the dermis, skin regeneration, and a range of immune responses. Until now, the processes of fibroblast adaptation and functioning in a varying environment have not been fully understood. Modern laser microscopes are capable of studying fibroblasts in vitro and ex vivo. One‐photon‐ and two‐photon‐excited fluorescence microscopy, Raman spectroscopy/microspectroscopy are well‐suited noninvasive optical methods for fibroblast imaging in vitro and ex vivo. In vivo staining‐free fibroblast imaging is not still implemented. The exception is fibroblast imaging in tattooed skin. Although in vivo noninvasive staining‐free imaging of fibroblasts in the skin has not yet been implemented, it is expected in the future. This review summarizes the state‐of‐the‐art in fibroblast visualization using optical methods and discusses the advantages, limitations, and prospects for future noninvasive imaging. [ABSTRACT FROM AUTHOR]

Introduction: Current vaccines vary widely in both their efficacy against infection and disease, and the durability of the efficacy. Some vaccines provide practically lifelong protection with a single dose, while others provide only limited protection following annual boosters. What variables make vaccine-induced immune responses last? Can breakthroughs in these factors and technologies help us produce vaccines with better protection and fewer doses? The durability of vaccine-induced protection is now a hot area in vaccinology research, especially after COVID-19 vaccines lost their luster. It has fueled discussion on the eventual utility of existing vaccines to society and bolstered the anti-vaxxer camp. To sustain public trust in vaccines, lasting vaccines must be developed. Areas covered: This review summarizes licensed vaccines' protection. It analyses immunological principles and vaccine and vaccinee parameters that determine longevity of antibodies. The review concludes with challenges and the way forward to improve vaccine durability. Expert opinion: Despite enormous advances, we still lack essential markers and reliable correlates of lasting protection. Most research has focused on humoral immune responses, but we must also focus on innate, mucosal, and cellular responses – their assessment, correlates, determinants, and novel adjuvants. Suitable vaccine designs and platforms for durable immunity must be found. [ABSTRACT FROM AUTHOR]

The study of aging and neurodegenerative processes in the human brain requires a comprehensive understanding of cytoarchitectonic, myeloarchitectonic, and vascular structures. Recent computational advances have enabled volumetric reconstruction of the human brain using thousands of stained slices, however, tissue distortions and loss resulting from standard histological processing have hindered deformation‐free reconstruction. Here, the authors describe an integrated serial sectioning polarization‐sensitive optical coherence tomography (PSOCT) and two photon microscopy (2PM) system to provide label‐free multi‐contrast imaging of intact brain structures, including scattering, birefringence, and autofluorescence of human brain tissue. The authors demonstrate high‐throughput reconstruction of 4 × 4 × 2cm3 sample blocks and simple registration between PSOCT and 2PM images that enable comprehensive analysis of myelin content, vascular structure, and cellular information. The high‐resolution 2PM images provide microscopic validation and enrichment of the cellular information provided by the PSOCT optical properties on the same sample, revealing the densely packed fibers, capillaries, and lipofuscin‐filled cell bodies in the cortex and white matter. It is shown that the imaging system enables quantitative characterization of various pathological features in aging process, including myelin degradation, lipofuscin accumulation, and microvascular changes, which opens up numerous opportunities in the study of neurodegenerative diseases in the future. [ABSTRACT FROM AUTHOR]

Background: Multimorbidity is better prevented in younger ages than in older ages. This study aims to identify the differences in comorbidity patterns in middle-aged inpatients from China and the United Kingdom (UK). Methods: We utilized 184,133 and 180,497 baseline hospitalization records in middle-aged populations (40–59 years) from Shaanxi, China, and UK Biobank. Logistic regression was used to calculate odds ratios and P values for 43,110 unique comorbidity patterns in Chinese inpatients and 21,026 unique comorbidity patterns in UK inpatients. We included the statistically significant (P values adjusted by Bonferroni correction) and common comorbidity patterns (the pattern with prevalence > 1/10,000 in each dataset) and employed network analysis to construct multimorbidity networks and compare feature differences in multimorbidity networks for Chinese and UK inpatients, respectively. We defined hub diseases as diseases having the top 10 highest number of unique comorbidity patterns in the multimorbidity network. Results: We reported that 57.12% of Chinese inpatients had multimorbidity, substantially higher than 30.39% of UK inpatients. The complete multimorbidity network for Chinese inpatients consisted of 1367 comorbidities of 341 diseases and was 2.93 × more complex than that of 467 comorbidities of 215 diseases in the UK. In males, the complexity of the multimorbidity network in China was 2.69 × more than their UK counterparts, while the ratio was 2.63 × in females. Comorbidities associated with hub diseases represented 68.26% of comorbidity frequencies in the complete multimorbidity network in Chinese inpatients and 55.61% in UK inpatients. Essential hypertension, dyslipidemia, type 2 diabetes mellitus, and gastritis and duodenitis were the hub diseases in both populations. The Chinese inpatients consistently demonstrated a higher frequency of comorbidities related to circulatory and endocrine/nutritional/metabolic diseases. In the UK, aside from these comorbidities, comorbidities related to digestive and genitourinary diseases were also prevalent, particularly the latter among female inpatients. Conclusions: Chinese inpatients exhibit higher multimorbidity prevalence and more complex networks compared to their UK counterparts. Multimorbidity with circulatory and endocrine/nutritional/metabolic diseases among both Chinese and UK inpatients necessitates tailored surveillance, prevention, and intervention approaches. Targeted interventions for digestive and genitourinary diseases are warranted for the UK. [ABSTRACT FROM AUTHOR]

Pneumocystis jirovecii pneumonia (PCP) is a significant cause of morbidity and mortality in immunocompromised people. The widespread use of trimethoprim-sulfamethoxazole (TMP-SMZ) for the treatment and prophylaxis of opportunistic infections (including PCP) has led to an increased selection of TMP-SMZ-resistant microorganisms. Sulfa/sulfone resistance has been demonstrated to result from specific point mutations in the DHPS gene. This study aims to investigate the presence of DHPS gene mutations among P. jirovecii isolates from Bulgarian patients with PCP. A total of 326 patients were examined via real-time PCR targeting the P. jirovecii mitochondrial large subunit rRNA gene and further at the DHPS locus. P. jirovecii DNA was detected in 50 (15.34%) specimens. A 370 bp DHPS locus fragment was successfully amplified in 21 samples from 19 PCP-positive patients, which was then purified, sequenced, and used for phylogenetic analysis. Based on the sequencing analysis, all (n = 21) P. jirovecii isolates showed DHPS genotype 1 (the wild type, with the nucleotide sequence ACA CGG CCT at codons 55, 56, and 57, respectively). In conclusion, infections caused by P. jirovecii mutants potentially resistant to sulfonamides are still rare events in Bulgaria. DHPS genotype 1 at codons 55 and 57 is the predominant P. jirovecii strain in the country. [ABSTRACT FROM AUTHOR]

Ceramide NP (Cer‐NP) has favorable effects in treating dry skin and barrier damage; nevertheless, their efficacy is hindered by a relatively low skin permeability. The most common used method to evaluate drug permeability in cosmetic filed is Franz diffusion cell, which have limitations in terms of experimental materials and manipulation, making it difficult to reliably quantify drug permeability in vivo on the human skin. In contrast, confocal Raman spectroscopy (CRM) is regarded as a versatile tool for tracking of the penetration of active molecules through the skin, which is non‐invasive, non‐destructive, and real‐time and allows in vivo testing of ceramide permeability and efficacy as well. The goal of this study was to track the skin penetration of Cer‐NP nanoemulsions (NEs) into the inner forearm skin, and to assess the short‐term effects of Cer‐NP on stratum corneum (SC) thickness, hydration, and intercellular lipids (ICL) conformation order using the water content and lateral packing order Slat = I2880/I2850, which were obtained by CRM data. Cer‐NP penetrated into the SC and epidermis, and the amount of penetration reduced with depth and increased with duration and finally retained in the SC. The results also uncovered Cer‐NP‐promoted SC hydration and increased SC thickness and Slat. The research mentioned above demonstrated that Cer‐NP NEs successfully penetrated the skin and performed moisturizing and barrier restoration functions. [ABSTRACT FROM AUTHOR]

The presence of penetrated oils in the stratum corneum (SC), oil‐induced occlusion of the SC and formation of occluding homogeneous film on the skin surface are discussed in relation to their influence on results of water profile calculations using conventional and newly proposed extended methods. It is shown that the conventional method does not determine the water profiles in treated skin correctly due to the superposition of Raman bands of SC's proteins and penetrated and remnant oils. [ABSTRACT FROM AUTHOR]

Porcine skin is widely used as a human skin model in dermatology. For both, porcine stratum corneum (SC) ex vivo and human SC in vivo, the hydrogen bonding states of water, the secondary and tertiary structures of keratin, the natural moisturizing factor (NMF) concentrations and the intercellular lipids' (ICL) lateral organization are investigated depth‐dependently using confocal Raman microscopy. The SC depth profiles show that porcine SC ex vivo is characterized by lower hydrogen bonding states of water (10%‐30% SC depth), lower NMF concentration in the whole SC, more β‐sheet form of keratin (10%‐90% SC depth), more folded tertiary keratin structures (30%‐70% SC depth) and higher hexagonal lateral packing order of ICL (10%‐50% SC depth) compared to human SC in vivo. The results clearly show a higher value of skin barrier function of human SC in vivo than of porcine SC ex vivo. Thus, the human SC in vivo is less permeable for lipophilic and hydrophilic substances than porcine SC ex vivo. Considering the porcine SC as an ex vivo model of human SC in vivo, these findings should be taken into consideration. [ABSTRACT FROM AUTHOR]

Introduction: Diagnostic classification systems and guidelines posit distinguishing patterns of impairment in Alzheimer's (AD) and vascular dementia (VaD). In our study, we aim to identify which diagnostic instruments distinguish them. Methods: We searched PubMed and PsychInfo for empirical studies published until December 2020, which investigated differences in cognitive, behavioral, psychiatric, and functional measures in patients older than 64years and reported information on VaD subtype, age, education, dementia severity, and proportion of women. We systematically reviewed these studies and conducted Bayesian hierarchical metaregressions to quantify the evidence for differences using the Bayes factor (BF). The risk of bias was assessed using the Newcastle-Ottawa-Scale and funnel plots. Results: We identified 122 studies with 17,850 AD and 5,247 VaD patients. Methodological limitations of the included studies are low comparability of patient groups and an untransparent patient selection process. In the digit span backward task, AD patients were nine times more probable (BF = 9.38) to outperform VaD patients (βg = 0.33, 95% ETI = 0.12, 0.52). In the phonemic fluency task, AD patients outperformed subcortical VaD (sVaD) patients (βg = 0.51, 95% ETI = 0.22, 0.77, BF = 42.36). VaD patients, in contrast, outperformed AD patients in verbal (βg = -0.61, 95% ETI = -0.97, -0.26, BF = 22.71) and visual (βg = -0.85, 95% ETI = -1.29, -0.32, BF = 13.67) delayed recall. We found the greatest difference in verbal memory, showing that sVaD patients outperform AD patients (βg = -0.64, 95% ETI = -0.88, -0.36, BF = 72.97). Finally, AD patients performed worse than sVaD patients in recognition memory tasks (βg = -0.76, 95% ETI = -1.26, -0.26, BF = 11.50). Conclusion: Our findings show inferior performance of AD in episodic memory and superior performance in working memory. We found little support for other differences proposed by diagnostic systems and diagnostic guidelines. The utility of cognitive, behavioral, psychiatric, and functional measures in differential diagnosis is limited and should be complemented by other information. Finally, we identify research areas and avenues, which could significantly improve the diagnostic value of cognitive measures. [ABSTRACT FROM AUTHOR]

Background: Metabolic dysfunction-associated fatty liver disease (MAFLD) is a newly defined condition encompassing hepatic steatosis and metabolic dysfunction. However, the relationship between MAFLD and multi-system diseases remains unclear, and the time-dependent sequence of these diseases requires further clarification. Methods: After propensity score matching, 163,303 MAFLD subjects and 163,303 matched subjects were included in the community-based UK Biobank study. The International Classification of Diseases, Tenth Revision (ICD-10), was used to reclassify medical conditions into 490 and 16 specific causes of death. We conducted a disease trajectory analysis to map the key pathways linking MAFLD to various health conditions, providing an overview of their interconnections. Results: Participants aged 59 (51–64) years, predominantly males (62.5%), were included in the study. During the 12.9-year follow-up period, MAFLD participants were found to have a higher risk of 113 medical conditions and eight causes of death, determined through phenome-wide association analysis using Cox regression models. Temporal disease trajectories of MAFLD were established using disease pairing, revealing intermediary diseases such as asthma, diabetes, hypertension, hypothyroid conditions, tobacco abuse, diverticulosis, chronic ischemic heart disease, obesity, benign tumors, and inflammatory arthritis. These trajectories primarily resulted in acute myocardial infarction, disorders of fluid, electrolyte, and acid–base balance, infectious gastroenteritis and colitis, and functional intestinal disorders. Regarding death trajectories of MAFLD, malignant neoplasms, cardiovascular diseases, and respiratory system deaths were the main causes, and organ failure, infective disease, and internal environment disorder were the primary end-stage conditions. Disease trajectory analysis based on the level of genetic susceptibility to MAFLD yielded consistent results. Conclusions: Individuals with MAFLD have a risk of a number of different medical conditions and causes of death. Notably, these diseases and potential causes of death constitute many pathways that may be promising targets for preventing general health decline in patients with MAFLD. [ABSTRACT FROM AUTHOR]

Complex diseases are caused by a combination of genetic, lifestyle, and environmental factors and comprise common noncommunicable diseases, including allergies, cardiovascular disease, and psychiatric and metabolic disorders. More than 25% of Europeans suffer from a complex disease, and together these diseases account for 70% of all deaths. The use of genomic, molecular, or imaging data to develop accurate diagnostic tools for treatment recommendations and preventive strategies, and for disease prognosis and prediction, is an important step toward precision medicine. However, for complex diseases, precision medicine is associated with several challenges. There is a significant heterogeneity between patients of a specific disease—both with regards to symptoms and underlying causal mechanisms—and the number of underlying genetic and nongenetic risk factors is often high. Here, we summarize precision medicine approaches for complex diseases and highlight the current breakthroughs as well as the challenges. We conclude that genomic‐based precision medicine has been used mainly for patients with highly penetrant monogenic disease forms, such as cardiomyopathies. However, for most complex diseases—including psychiatric disorders and allergies—available polygenic risk scores are more probabilistic than deterministic and have not yet been validated for clinical utility. However, subclassifying patients of a specific disease into discrete homogenous subtypes based on molecular or phenotypic data is a promising strategy for improving diagnosis, prediction, treatment, prevention, and prognosis. The availability of high‐throughput molecular technologies, together with large collections of health data and novel data‐driven approaches, offers promise toward improved individual health through precision medicine. [ABSTRACT FROM AUTHOR]

The multifaceted nature and swift progression of Amyotrophic Lateral Sclerosis (ALS) pose considerable challenges to our understanding of its evolution and interplay with comorbid conditions. This study seeks to elucidate the temporal dynamics of ALS progression and its interaction with associated diseases. We employed a principal tree-based model to decipher patterns within clinical data derived from a population-based database in Taiwan. The disease progression was portrayed as branched trajectories, each path representing a series of distinct stages. Each stage embodied the cumulative occurrence of co-existing diseases, depicted as nodes on the tree, with edges symbolizing potential transitions between these linked nodes. Our model identified eight distinct ALS patient trajectories, unveiling unique patterns of disease associations at various stages of progression. These patterns may suggest underlying disease mechanisms or risk factors. This research re-conceptualizes ALS progression as a migration through diverse stages, instead of the perspective of a sequence of isolated events. This new approach illuminates patterns of disease association across different progression phases. The insights obtained from this study hold the potential to inform doctors regarding the development of personalized treatment strategies, ultimately enhancing patient prognosis and quality of life. [ABSTRACT FROM AUTHOR]

Periodic revisions of the international classification of diseases (ICD) ensure that the classification reflects new practices and knowledge; however, this complicates retrospective research as diagnoses are coded in different versions. For longitudinal disease trajectory studies, a crosswalk is an essential tool and a comprehensive mapping between ICD-8 and ICD-10 has until now been lacking. In this study, we map all ICD-8 morbidity codes to ICD-10 in the expanded Danish ICD version. We mapped ICD-8 codes to ICD-10, using a many-to-one system inspired by general equivalence mappings such that each ICD-8 code maps to a single ICD-10 code. Each ICD-8 code was manually and unidirectionally mapped to a single ICD-10 code based on medical setting and context. Each match was assigned a score (1 of 4 levels) reflecting the quality of the match and, if applicable, a "flag" signalling choices made in the mapping. We provide the first complete mapping of the 8596 ICD-8 morbidity codes to ICD-10 codes. All Danish ICD-8 codes representing diseases were mapped and 5106 (59.4%) achieved the highest consistency score. Only 334 (3.9%) of the ICD-8 codes received the lowest mapping consistency score. The mapping provides a scaffold for translation of ICD-8 to ICD-10, which enable longitudinal disease studies back to and 1969 in Denmark and to 1965 internationally with further adaption. [ABSTRACT FROM AUTHOR]

Solar radiation and cigarette smoke are two environmental risk factors known to affect skin integrity. Although the toxic effects of these factors on skin have been widely studied separately, few studies have focused on their interaction. The objective of this study was to evaluate and understand the synergistic harmful effects of cigarette smoke and solar rays on human primary keratinocytes. The keratinocytes were exposed to cigarette smoke extract (CSE) and then irradiated with a solar simulator light (SSL). The viability, as determined by measuring metabolic activity of skin cells, and the levels of global reactive oxygen species (ROS) were evaluated after exposure to CSE and SSL. The combination of 3% CSE with 29 kJ m−2 UVA caused a decrease of 81% in cell viability, while with 10% to 20% CSE, the cell viability was null. This phototoxicity was accompanied by an increase in singlet oxygen but a decrease in type I ROS when CSE and SSL were combined in vitro. Surprisingly, an increase in the CSE's total antioxidant capacity was also observed. These results suggest a synergy between the two environmental factors in their effect on skin cells, and more precisely a phototoxicity causing a drastic decrease in cell viability. [ABSTRACT FROM AUTHOR]

The accelerated kinetic behaviour of charge carrier transfer and its unhindered surface reaction dynamic process involving oxygenated‐intermediate activation and conversion are urgently required in photocatalytic water (H2O) overall splitting, which has not been nevertheless resolved yet. Herein, localized CdS homojunctions with optimal collocation of high and low index facets to regulate d‐band center for chemically adsorbing and activating key intermediates (*‐OH and *‐O) have been achieved in H2O overall splitting into hydrogen. Density functional theory, hall effect, and in situ diffuse reflectance infrared Fourier transform spectroscopy confirm that, electrons and holes are kinetically transferred to reductive high index facet (002) and oxidative low index facet (110) of the localized CdS homojunction induced by facet Fermi level difference to dehydrogenate *‐OH and couple *‐O for hydrogen and oxygen evolution, respectively, along with a solar conversion into hydrogen (STH) of 2.20 % by Air Mass 1.5 Global filter irradiation. These findings contribute to solving the kinetic bottleneck issues of photocatalytic H2O splitting, which will further enhance STH. [ABSTRACT FROM AUTHOR]

Excessive or persistent infection is a major contributing factor in impeding chronic wound healing. Wound bed preparations using antiseptics do not necessarily target the entire bacterial spectrum, and the highly proliferating granulation tissue may be sensitive to the cytotoxic effects, impairing tissue repair. Non-thermal gas atmospheric pressure plasmas are partially ionized gases that contain highly reactive particles while the gas phase remains near room temperature, thus having the capability of accessing small irregular cavities and fissures and killing bacteria because of the diffusive nature of gas phase plasma species that are chemically reactive, providing an ideal approach to topical wound disinfection. A non-thermal plasma brush device of novel design has been developed that is suitable for clinical application in the disinfection of oral and wound bacteria. In vivo studies have indicated that the plasma brush treatment rendered no harmful effect on healthy skin or tissues, while it could improve wound healing in Pseudomonas aeruginosa biofilm infected wounds exposed to an optimized treatment with argon plus 1% nitrogen (Ar + N2) plasma. [ABSTRACT FROM AUTHOR]

This paper describes a methodology to differentiate morphea from lichen sclerosus based on examination with multiphoton microscopy (MPM) composed of two‐photon excited fluorescence (TPEF) and second harmonic generation (SHG). Subcellular‐resolution images were acquired by MPM from unstained lesion tissues then process spectral analysis to quantify the TPEF and SHG signals. Moreover, U‐Net was employed to segment elastic fiber in TPEF images to combine with collagen fiber in SHG images for precise fiber quantification. Predictions of segmentation showed excellent performance on several evaluation indicators. The mIoU, mPA, and F1 score reach 0.8516, 0.9281, and 0.941. The quantitative analysis demonstrated the increase of collagen fibers in morphea compared to that in lichen sclerosus cases. Meanwhile, the great diminution of elastic fiber in the dermis of lichen sclerosus was depicted based on MPM imaging. Thus, MPM was comparable to the histopathological examination and our experimental results accurately distinguish between morphea and lichen sclerosus. [ABSTRACT FROM AUTHOR]

Vascular cognitive impairment and dementia (VCID) is commonly caused by vascular injuries in cerebral large and small vessels and is a key driver of age-related cognitive decline. Severe VCID includes post-stroke dementia, subcortical ischemic vascular dementia, multi-infarct dementia, and mixed dementia. While VCID is acknowledged as the second most common form of dementia after Alzheimer's disease (AD) accounting for 20% of dementia cases, VCID and AD frequently coexist. In VCID, cerebral small vessel disease (cSVD) often affects arterioles, capillaries, and venules, where arteriolosclerosis and cerebral amyloid angiopathy (CAA) are major pathologies. White matter hyperintensities, recent small subcortical infarcts, lacunes of presumed vascular origin, enlarged perivascular space, microbleeds, and brain atrophy are neuroimaging hallmarks of cSVD. The current primary approach to cSVD treatment is to control vascular risk factors such as hypertension, dyslipidemia, diabetes, and smoking. However, causal therapeutic strategies have not been established partly due to the heterogeneous pathogenesis of cSVD. In this review, we summarize the pathophysiology of cSVD and discuss the probable etiological pathways by focusing on hypoperfusion/hypoxia, blood–brain barriers (BBB) dysregulation, brain fluid drainage disturbances, and vascular inflammation to define potential diagnostic and therapeutic targets for cSVD. [ABSTRACT FROM AUTHOR]

Background: Nation-wide hospitalization databases include diagnostic information at the level of an entire population over an extended period of time. Comorbidity network and early disease development can be unveiled. Chronic obstructive pulmonary disease (COPD) is an underdiagnosed condition for which it is crucial to identify early disease indicators. The identification of gender-specific conditions preceding the onset of COPD may reveal disease progression patterns allowing for early diagnosis and intervention. The objective of the study was to investigate the antecedent hospitalization history of patients newly diagnosed with COPD and to retrace a gender-specific trajectory of coded entities prior to the onset of COPD. Material and methods: A population-wide hospitalization database including information about all hospitalizations in Switzerland between 2002 and 2018 was used. COPD cases were extracted from the database and comorbidities occurring prior to the onset of COPD identified. Comorbidities significantly over-represented in COPD compared with a 1:1, age- and sex-matched control population were identified and their longitudinal evolution was analyzed. Results: Between 2002 and 2018, 697,714 hospitalizations with coded COPD were recorded in Switzerland. Sixty-two diagnoses were significantly over-represented before onset of COPD. These preceding comorbidities included both well-established conditions and novel links to COPD. Early pre-conditions included nicotine and alcohol abuse, obesity and cardiovascular diseases. Later comorbidities included atrial fibrillation, diseases of the genitourinary system and pneumonia. Atherosclerotic heart diseases were more prevalent in males, whereas hypothyroidism, varicose and intestinal disorders were more frequent in females. Disease trajectories were validated using an independent data set. Conclusions: Gender-specific disease trajectories highlight early indicators and pathogenetic links between COPD and antecedent diseases and could allow for early detection and intervention. [ABSTRACT FROM AUTHOR]

This work aims at studying Raman spectroscopy in combination with chemometrics as an alternative fast noninvasive method to detect chronic heart failure (CHF) cases. Optical analysis is focused on the changes in the spectral features associated with the biochemical composition changes of skin tissues. A portable spectroscopy setup with the 785 nm excitation wavelength was used to record skin Raman features. In this in vivo study, 127 patients and 57 healthy volunteers were involved in measuring skin spectral features by Raman spectroscopy. The spectral data were analyzed with a projection on the latent structures and discriminant analysis. 202 skin spectra of patients with CHF and 90 skin spectra of healthy volunteers were classified with 0.888 ROC AUC for the 10‐fold cross validated algorithm. To identify CHF cases, the performance of the proposed classifier was verified by means of a new test set that is equal to 0.917 ROC AUC. [ABSTRACT FROM AUTHOR]

Antioxidants exhibit a powerful defense mechanism against aging and chronic disease. The human skin reflects the overall antioxidant status of the body. The cutaneous carotenoid concentration is a biomarker for individual nutritional intake of antioxidants, as it correlates with the overall antioxidant status. The cutaneous carotenoid concentrations of 44 adults were measured using a multiple spatially resolved reflection spectroscopy. During the first phase of the study, measurements of carotenoid concentrations were performed without revealing the antioxidant status, followed by an intervention phase during which the volunteers were informed about their individual values by biofeedback. During the third phase, biofeedback was combined with an additional intake of fruit juices. Across time points, participants showed increasing levels of carotenoid status. Thus, biofeedback leads to an improvement of the carotenoid value of the skin. Providing a biofeedback measurement to monitor the individual antioxidative status may be an easy and cost‐effective way of primary prevention. [ABSTRACT FROM AUTHOR]

Vascular cognitive impairment (VCI) describes a wide spectrum of cognitive deficits related to cerebrovascular diseases. Although the loss of blood flow to cortical regions critically involved in cognitive processes must feature as the main driver of VCI, the underlying mechanisms and interactions with related disease processes remain to be fully elucidated. Recent clinical studies of cerebral blood flow measurements have supported the role of chronic cerebral hypoperfusion (CCH) as a major driver of the vascular pathology and clinical manifestations of VCI. Here we review the pathophysiological mechanisms as well as neuropathological changes of CCH. Potential interventional strategies for VCI are also reviewed. A deeper understanding of how CCH can lead to accumulation of VCI-associated pathology could potentially pave the way for early detection and development of disease-modifying therapies, thus allowing preventive interventions instead of symptomatic treatments. [ABSTRACT FROM AUTHOR]