An Empirical Dietary Pattern Associated with the Gut Microbial Features in Relation to Colorectal Cancer Risk.

BACKGROUND & AIMS: Epidemiologic evidence for dietary influence on colorectal cancer (CRC) risk through the gut microbiome remains limited. METHODS: Leveraging 307 men and 212 women with stool metagenomes and dietary data, we characterized and validated a sex-specific dietary pattern associated with the CRC-related gut microbial signature (CRC Microbial Dietary Score [CMDS]). We evaluated the associations of CMDS with CRC risk according to Fusobacterium nucleatum, pks+Escherichia coli, and enterotoxigenic Bacteroides fragilis status in tumor tissue using Cox proportional hazards regression in the Health Professionals Follow-Up Study (1986-2018), Nurses' Health Study (1984-2020), and Nurses' Health Study II (1991-2019). RESULTS: The CMDS was characterized by high industrially processed food and low unprocessed fiber-rich food intakes. In 259,200 participants, we documented 3854 incident CRC cases over 6,467,378 person-years of follow-up. CMDS was associated with a higher risk of CRC (Ptrend < .001), with a multivariable hazard ratio (HRQ5 vs Q1) of 1.25 (95% CI, 1.13-1.39). The association remained after adjusting for previously established dietary patterns, for example, the Western and prudent diets. Notably, the association was stronger for tumoral F nucleatum-positive (HRQ5 vs Q1, 2.51; 95% CI, 1.68-3.75; Ptrend < .001; Pheterogeneity = .03, positivity vs negativity), pks+E coli-positive (HRQ5 vs Q1, 1.68; 95% CI, 0.84-3.38; Ptrend = .005; Pheterogeneity = .01, positivity vs negativity), and enterotoxigenic Bacteroides fragilis-positive CRC (HRQ5 vs Q1, 2.06; 95% CI, 1.10-3.88; Ptrend = .016; Pheterogeneity = .06, positivity vs negativity), compared with their negative counterparts. CONCLUSIONS: CMDS was associated with increased CRC risk, especially for tumors with detectable F nucleatum, pks+E coli, and enterotoxigenic Bacteroides fragilis in tissue. Our findings support a potential role of the gut microbiome underlying the dietary effects on CRC.

Post-diagnostic multivitamin supplement use and colorectal cancer survival: A prospective cohort study.

BACKGROUND: Use of multivitamin supplements has been associated with lower incidence of colorectal cancer (CRC). However, its influence on CRC survival remains unknown. METHODS: Among 2424 patients with stage I-III CRC who provided detailed information about multivitamin supplements in the Nurses' Health Study and Health Professionals Follow-up Study, the authors calculated multivariable hazard ratios (HRs) of multivitamin supplements for all-cause and CRC-specific mortality according to post-diagnostic use and dose of multivitamin supplements. RESULTS: During a median follow-up of 11 years, the authors documented 1512 deaths, among which 343 were of CRC. Compared to non-users, post-diagnostic users of multivitamin supplements at a dose of 3-5 tablets/week had lower CRC-specific mortality (HR, 0.55; 95% confidence interval [CI], 0.36-0.83, p = .005), and post-diagnostic users at doses of 3-5 and 6-9 tablets/week had lower all-cause mortality (HR, 0.81; 95% CI, 0.67-0.99, p = .04; HR, 0.79; 95% CI, 0.70-0.88), p < .001). The dose-response analysis showed a curvilinear relationship for both CRC-specific (pnonlinearity < .001) and all-cause mortality (pnonlinearity = .004), with the maximum risk reduction observed at 3-5 tablets/week and no further reduction at higher doses. Compared to non-users in both pre- and post-diagnosis periods, new post-diagnostic users at dose of <10 tablets/week had a lower all-cause mortality (HR, 0.81; 95% CI, 0.71-0.94, p = .005), whereas new users at a dose of ≥10 tablets/week (HR, 1.58; 95% CI, 1.07-2.33) and discontinued users (HR, 1.35; 95% CI, 1.14-1.59) had a higher risk of mortality. CONCLUSIONS: Use of multivitamin supplements at a moderate dose after a diagnosis of nonmetastatic CRC is associated with lower CRC-specific and overall mortality, whereas a high dose (≥10 tablets/week) use is associated with higher CRC-specific mortality.

Association of Ultra-processed Food and Unprocessed or Minimally Processed Food Consumption With Bowel Habits Among U.S. Adults.

BACKGROUND & AIMS: Ultra-processed foods (UPFs) may have a negative impact on bowel habits. We aimed to assess the association between UPF and unprocessed or minimally processed food (MPF) intake and bowel habits among adults in the United States (U.S.). METHODS: We performed a cross-sectional study using data from the National Health and Nutrition Examination Survey (2005-2010). We used two 24-hour dietary recalls and, based on the Nova classification, calculated intakes of UPFs and MPFs. Constipation and diarrhea were defined using the Bristol Stool Form Scale and stool frequency. We performed survey-weighted logistic regression and substitution analysis to estimate the odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Among 12,716 U.S. adults, there were 1290 cases of constipation and 1067 cases of diarrhea. Median UPF and MPF intakes were 26.5% and 66.2% of total grams per day, respectively. Greater UPF consumption (in % gram/d) was associated with higher odds of constipation (adjusted OR [aORQ4 vs Q1], 2.20; 95% CI, 1.76-2.74) (Ptrend < .001) but not diarrhea (aORQ4 vs Q1, 0.82; 95% CI, 0.62-1.09) (Ptrend = .12). Increased MPF consumption was associated with lower odds of constipation (aORQ4 vs Q1, 0.46; 95% CI, 0.370-0.57) (Ptrend < .001). Associations with constipation were attenuated after adjusting for diet quality (aORQ4 vs Q1, UPF, 1.53; MPF, 0.69). Substituting 10% of UPF intake with an equivalent proportion of MPFs was associated with lower odds of constipation (aOR, 0.90; 95% CI, 0.87-0.93). CONCLUSIONS: UPF intake was associated with higher odds of constipation, whereas the odds were lower with greater MPF consumption. The effect of food processing on bowel habits was independent of diet quality.

Kinetics and Retention of Polystyrenesulfonate for Proteoglycan Replacement in Cartilage.

Tissue hydration provides articular cartilage with dynamic viscoelastic properties. Early stage osteoarthritis (OA) is marked by loss of proteoglycans and glycosaminoglycans (GAG), lowering fixed charge density, and impairing tissue osmotic function. The most common GAG replacement, chondroitin sulfate (CS), has failed to show effectiveness. Here, we investigated a synthetic polyelectrolyte, poly(styrenesulfonate) (PSS), both as a model compound to investigate polyelectrolyte transport in cartilage, and as a potential candidate to restore bulk fixed charge density in cartilage with GAG loss. Through bovine explants and histology, we determined zonal-based effective diffusion coefficients for three different molecular weights of PSS. Compared to CS, PSS was retained longer in GAG-depleted cartilage in static and compression-based desorption experiments. We explained enhanced solute performance of PSS by its more compact morphology and higher charge density by small-angle X-ray scattering. This study may improve design of GAG mimetic molecules for repairing osmotic function in OA cartilage.

Esophageal cancer mortality disparities between Black and White adults in the United States, 1999-2020: insights from CDC-WONDER.

BACKGROUND AND AIM: Esophageal cancer significantly contributes to US cancer mortality, with notable racial disparities. This study aims to provide updated esophageal cancer mortality trends among Black and White adults from 1999 to 2020. METHODS: CDC-WONDER was used to identify Black and White adults in the United States from 1999 to 2020. We calculated age-standardized mortality rates, absolute rate differences, and rate ratios to compare the mortality differences between these populations. RESULTS: From 1999 to 2020 in the United States, there were 303 267 esophageal cancer deaths, with significant racial disparities. The age-adjusted mortality rate for Black adults fell from 6.52 to 2.62 per 100 000, while for White adults, it declined from 4.19 to 3.97 per 100 000, narrowing the racial mortality gap. Gender-wise, the study showed a decrease in the mortality rate from 3.31 to 2.29 per 100 000 in Black women, but an increase from 1.52 to 1.99 per 100 000 in White women. Among young men, the rate dropped in Black men from 12.82 to 6.26 per 100 000 but rose in White men from 9.90 to 10.57 per 100 000. Regionally, Black adults in the Midwest and South initially had higher mortality rates than Whites, but this gap reduced over time. By 2020, Black men had lower mortality rates across all regions. CONCLUSIONS: Over the last two decades, age-adjusted esophageal cancer mortality decreased in Black adults but stabilized in White adults, reflecting distinct cancer trends and risk factors. The study highlights the importance of tailored public health strategies for healthcare access and risk factor management.

Endothelial cell Orai1 is essential for endothelium-dependent contraction of mouse carotid arteries in normotensive and hypertensive mice.

Endothelium-dependent contraction (EDC) exists in blood vessels of normotensive animals, but is exaggerated in hypertension. An early signal in EDC is cytosolic Ca2+ rise in endothelial cells. In this study we investigated the functional role of Orai1, a major endothelial cell Ca2+ entry channel, in EDC. Hypertension model was established in WT mice by intake of L-NNA in the drinking water (0.5 g/L) for 4 weeks or osmotic pump delivery of Ang II (1.5 mg·kg-1·d-1) for 2 weeks. In TRPC5 KO mice, the concentration of L-NNA and Ang II were increased to 1 g/L or 2 mg·kg-1·d-1, respectively. Arterial segments were prepared from carotid arteries and aortas, and EDC was elicited by acetylcholine in the presence of Nω-nitro-L-arginine methyl ester. We showed that low concentration of acetylcholine (3-30 nM) initiated relaxation in phenylephrine-precontracted carotid arteries of both normotensive and hypertensive mice, while high concentration of acetylcholine (0.1-2 µM) induced contraction. Application of selective Orai1 inhibitors AnCoA4 (100 µM) or YM58483 (400 nM) had no effect on ACh-induced relaxation but markedly reduced acetylcholine-induced EDC. We found that EDC was increased in hypertensive mice compared with that of normotensive mice, which was associated with increased Orai1 expression in endothelial cells of hypertensive mice. Compared to TRPC5 and TRPV4, which were also involved in EDC, endothelial cell Orai1 had relatively greater contribution to EDC than either TRPC5 or TRPV4 alone. We identified COX-2, followed by PGF2α, PGD2 and PGE2 as the downstream signals of Orai1/TRPC5/TRPV4. In conclusion, Orai1 coordinates together with TRPC5 and TRPV4 in endothelial cells to regulate EDC responses. This study demonstrates a novel function of Orai1 in EDC in both normotensive and hypertensive mice, thus providing a general scheme about the control of EDC by Ca2+-permeable channels.

Cell-Electrode Models for Impedance Analysis of Epithelial and Endothelial Monolayers Cultured on Microelectrodes.

Electric cell-substrate impedance sensing has been used to measure transepithelial and transendothelial impedances of cultured cell layers and extract cell parameters such as junctional resistance, cell-substrate separation, and membrane capacitance. Previously, a three-path cell-electrode model comprising two transcellular pathways and one paracellular pathway was developed for the impedance analysis of MDCK cells. By ignoring the resistances of the lateral intercellular spaces, we develop a simplified three-path model for the impedance analysis of epithelial cells and solve the model equations in a closed form. The calculated impedance values obtained from this simplified cell-electrode model at frequencies ranging from 31.25 Hz to 100 kHz agree well with the experimental data obtained from MDCK and OVCA429 cells. We also describe how the change in each model-fitting parameter influences the electrical impedance spectra of MDCK cell layers. By assuming that the junctional resistance is much smaller than the specific impedance through the lateral cell membrane, the simplified three-path model reduces to a two-path model, which can be used for the impedance analysis of endothelial cells and other disk-shaped cells with low junctional resistances. The measured impedance spectra of HUVEC and HaCaT cell monolayers nearly coincide with the impedance data calculated from the two-path model.

Association of Proton Pump Inhibitor Use With All-Cause and Cause-Specific Mortality.

BACKGROUND & AIMS: The use of proton pump inhibitors (PPIs) has increased rapidly in the past 2 decades. Concerns about the regular use of PPIs contributing to mortality have been raised. METHODS: We conducted a prospective cohort study using data collected from the Nurses' Health Study (2004-2018) and the Health Professionals Follow-up Study (2004-2018). Cox proportional hazards models were used to estimate the hazard ratios (HRs) and 95% CIs for mortality according to PPI use. We used a modified lag-time approach to minimize reverse causation (ie, protopathic bias). RESULTS: Among 50,156 women and 21,731 men followed for 831,407 person-years and a median of 13.8 years, we documented 22,125 deaths, including 4592 deaths from cancer, 5404 from cardiovascular diseases, and 12,129 deaths from other causes. Compared with nonusers of PPIs, PPI users had significantly higher risks of all-cause mortality (HR, 1.19; 95% CI, 1.13-1.24) and mortality due to cancer (HR, 1.30; 95% CI, 1.17-1.44), cardiovascular diseases (HR, 1.13; 95% CI, 1.02-1.26), respiratory diseases (HR, 1.32; 95% CI, 1.12-1.56), and digestive diseases (HR, 1.50; 95% CI, 1.10-2.05). Upon applying lag times of up to 6 years, the associations were attenuated and no longer statistically significant (all-cause: HR, 1.04; 95% CI, 0.97-1.11; cancer: HR, 1.07; 95% CI, 0.89-1.28; cardiovascular diseases: HR, 0.94; 95% CI, 0.81-1.10; respiratory diseases: HR, 1.20; 95% CI, 0.95-1.50; digestive diseases: HR, 1.38; 95% CI, 0.88-2.18). Longer duration of PPI use did not confer higher risks for all-cause and cause-specific mortality. CONCLUSIONS: After accounting for protopathic bias, PPI use was not associated with higher risks of all-cause mortality and mortality due to major causes.

Clinical and Genomic Characterization of Interval Colorectal Cancer in 3 Prospective Cohorts.

BACKGROUND & AIMS: Interval colorectal cancers (CRCs), cancers diagnosed after a screening/surveillance examination in which no cancer is detected, and before the date of next recommended examination, reflect an unprecedented challenge in CRC detection and prevention. To better understand this poorly characterized CRC variant, we examined the clinical and mutational characteristics of interval CRCs in comparison with screen detected CRCs. METHODS: We included 1175 CRCs documented in the Prostate, Lung, Colorectal, and Ovarian (PLCO) cancer screening trial and 3661 CRCs in the Nurses' Health Study (NHS) and Health Professionals Follow-up Study (HPFS). Multivariable Cox models were performed to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of death risk. Whole exome sequencing was conducted in 147 PLCO cases and 796 NHS/HPFS cases. RESULTS: A total of 619 deaths (312 CRC-specific) and 2404 deaths (1904 CRC-specific) were confirmed during follow-up of PLCO and NHS/HPFS, respectively. Compared with screen detected CRCs, interval CRCs had a multivariate-adjusted HR (95% CI) of 1.47 (1.21-1.78) for CRC-specific mortality and 1.27 (1.09-1.47) for overall mortality (meta-analysis combining all 3 cohorts). However, we did not observe significant differences in mutational features between interval and screen detected CRCs (false discovery rate adjusted P > .05). CONCLUSION: Interval CRCs had a significantly increased risk of death compared with screen detected CRCs that were not explained by established clinical prognostic factors, including stage at diagnosis. The survival disadvantage of interval CRCs did not appear to be explained by differences in the genomic landscape of tumors characterized by whole exome sequencing.

Sex disparity of cerebral white matter hyperintensity in the hypertensive elderly: The Shanghai Changfeng study.

White matter hyperintensity (WMH) is associated with vascular hemodynamic alterations and reflects white matter injury. To date, the sex difference of tract-specific WMH and the relationship between high blood pressure (BP) and tract-specific WMH remain unclear. We recruited 515 subjects from the Shanghai Changfeng study (range 53-89 years, mean age 67.33 years). Systolic and diastolic blood pressure (SBP and DBP) were collected and used to calculate pulse pressure (PP). Magnetic resonance T1 and T2 FLAIR images were acquired to measure WMH and calculate WMH index. The ANCOVA test was performed to test the difference between sexes, and the linear regression model was used to examine the associations between BP and WMH index. Men showed higher WMH index than women in all white matter tracts (p < .001, respectively) except for the bilateral superior longitudinal fasciculus (SLF) and its left temporal part (tSLF). High SBP and PP was associated with a lower WMH index on the left corticospinal tract (CST), SLF, tSLF and right cingulum in hippocampus (p ≤ .001, respectively) in women, while high DBP was associated with a higher WMH index on the bilateral CST (left p < .001; right p = .001), left inferior longitudinal fasciculus (p < .001) and inferior fronto-occipital fasciculus (p = .002) in men. Men tend to have more WMH compared to women. A high SBP/PP relates to a lower WMH burden in women. This suggests that women could benefit from higher blood pressure in older age.

N-acylphosphatidylethanolamine, a gut- derived circulating factor induced by fat ingestion, inhibits food intake.

N-acylphosphatidylethanolamines (NAPEs) are a relatively abundant group of plasma lipids of unknown physiological significance. Here, we show that NAPEs are secreted into circulation from the small intestine in response to ingested fat and that systemic administration of the most abundant circulating NAPE, at physiologic doses, decreases food intake in rats without causing conditioned taste aversion. Furthermore, (14)C-radiolabeled NAPE enters the brain and is particularly concentrated in the hypothalamus, and intracerebroventricular infusions of nanomolar amounts of NAPE reduce food intake, collectively suggesting that its effects may be mediated through direct interactions with the central nervous system. Finally, chronic NAPE infusion results in a reduction of both food intake and body weight, suggesting that NAPE and long-acting NAPE analogs may be novel therapeutic targets for the treatment of obesity.

Adherence to a healthy lifestyle in relation to colorectal cancer incidence and all-cause mortality after endoscopic polypectomy: A prospective study in three U.S. cohorts.

It remains unknown whether maintenance of a healthy lifestyle after endoscopic polypectomy could still confer benefit for colorectal cancer (CRC) incidence and mortality. In this study, we defined a healthy lifestyle score based on body mass index, smoking, physical activity, alcohol consumption and diet (range, 0-5). We used Cox proportional hazards regression to estimate the hazard ratios (HRs) for the associations of healthy lifestyle score and individual lifestyle factors with CRC incidence and all-cause mortality. During a median of 10 years of follow-up of 24 668 participants who underwent endoscopic polypectomy, we documented 161 CRC cases and 4857 all-cause deaths. A higher healthy lifestyle score after endoscopic polypectomy was associated with lower risk of CRC and all-cause mortality. Compared with individuals with 0 to 1 healthy lifestyle factors, those with 2, 3 and 4 to 5 healthy lifestyle factors had a HR for CRC risk of 0.86 (95% confidence interval [CI], 0.60-1.24), 0.73 (95% CI, 0.47-1.14) and 0.52 (95% CI, 0.27-1.01), respectively (Ptrend  = .03). The corresponding HR (95% CI) for all-cause mortality was 0.83 (95% CI, 0.76-0.90), 0.63 (95% CI, 0.56-0.70) and 0.56 (95% CI, 0.48-0.65), respectively (Ptrend < .0001). In the joint analysis of pre- and postpolypectomy periods, patients with a healthy postpolypectomy lifestyle had a lower incidence of CRC regardless of their prepolypectomy exposure, whereas those with a healthy lifestyle in both periods had a lower mortality than those with an unhealthy lifestyle in either period. In conclusion, adherence to a healthy lifestyle after polypectomy may confer significant benefit for CRC prevention and reduction in all-cause mortality.

Gallstones and risk of cancers of the liver, biliary tract and pancreas: a prospective study within two U.S. cohorts.

BACKGROUND: Gallstones may result in inflammation, altered bile flow, and changes in metabolic hormone levels, thereby increasing cancer risk. However, previous studies for gallstones and cancers of the liver, biliary tract and pancreas in the U.S. were relatively limited. METHODS: We followed 115,036 women from the Nurses' Health Study (1982-2012) and 49,729 men from the Health Professionals Follow-up Study (1986-2012). History of gallstones, including with or without performed cholecystectomy, was reported at baseline and updated through biennial questionnaires. The Cox proportional hazard regression model was used to calculate multivariable hazard ratios (HRs) and 95% confidence intervals (95% CIs). RESULTS: During up to 30-year follow-up, we identified 204 incidents of liver cancer, 225 biliary tract cancer and 1147 pancreatic cancer cases. Compared to those without gallstones diagnosis, the multivariable HRs for individuals with gallstones (untreated or with cholecystectomy) were 1.60 for liver cancer (95% CI: 1.14-2.26), 4.79 for biliary tract cancer (95% CI: 3.02-7.58), and 1.13 for pancreatic cancer (95% CI: 0.96-1.32). The multivariable HRs for individuals with cholecystectomy were 1.33 for liver cancer (95% CI: 0.90-1.95) and 1.15 for pancreatic cancer (95% CI: 0.98-1.36). CONCLUSIONS: Gallstones were associated with a higher risk of cancers of the liver, biliary tract and possibly pancreas.

Ultra-processed Foods and Risk of Crohn's Disease and Ulcerative Colitis: A Prospective Cohort Study.

BACKGROUND & AIMS: The rising incidence of inflammatory bowel disease in regions undergoing Westernization has coincided with the increase in ultra-processed food (UPF) consumption over the past few decades. We aimed to examine the association between consumption of UPFs and the risk of Crohn's disease (CD) and ulcerative colitis (UC). METHODS: We performed a prospective cohort study of 3 nationwide cohorts of health professionals in the United States-the Nurses' Health Study (1986-2014), the Nurses' Health Study II (1991-2017), and the Health Professionals Follow-up Study (1986-2012). We employed Cox proportional hazards models with adjustment for confounders to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) for CD and UC according to self-reported consumption of UPFs. RESULTS: The study included 245,112 participants. Over 5,468,444 person-years of follow-up, we documented 369 incident cases of CD and 488 incident cases of UC. The median age at diagnosis was 56 years (range, 29-85 years). Compared with participants in the lowest quartile of simple updated UPF consumption, those in the highest quartile had a significantly increased risk of CD (HR, 1.70; 95% CI, 1.23-2.35; Ptrend = .0008). Among different UPF subgroups, ultra-processed breads and breakfast foods; frozen or shelf-stable ready-to-eat/heat meals; and sauces, cheeses, spreads, and gravies showed the strongest positive associations with CD risk (HR per 1 standard deviation increase in intake, 1.18 [95% CI, 1.07-1.29], 1.11 [95% CI, 1.01-1.22], and 1.14 [95% CI, 1.02-1.27], respectively). There was no consistent association between UPF intake and UC risk. CONCLUSIONS: Higher UPF intake was associated with an increased risk of incident CD. Further studies are needed to identify specific contributory dietary components.

Controlling fine touch sensations with polymer tacticity and crystallinity.

The friction generated between a finger and an object forms the mechanical stimuli behind fine touch perception. To control friction, and therefore tactile perception, current haptic devices typically rely on physical features like bumps or pins, but chemical and microscale morphology of surfaces could be harnessed to recreate a wider variety of tactile sensations. Here, we sought to develop a new way to create tactile sensations by relying on differences in microstructure as quantified by the degree of crystallinity in polymer films. To isolate crystallinity, we used polystyrene films with the same chemical formula and number averaged molecular weights, but which differed in tacticity and annealing conditions. These films were also sufficiently thin as to be rigid which minimized effects from bulk stiffness and had variations in roughness lower than detectable by humans. To connect crystallinity to human perception, we performed mechanical testing with a mock finger to form predictions about the degree of crystallinity necessary to result in successful discrimination by human subjects. Psychophysical testing verified that humans could discriminate surfaces which differed only in the degree of crystallinity. Although related, human performance was not strongly correlated with a straightforward difference in the degree of crystallinity. Rather, human performance was better explained by quantifying transitions in steady to unsteady sliding and the generation of slow frictional waves (r2 = 79.6%). Tuning fine touch with polymer crystallinity may lead to better engineering of existing haptic interfaces or lead to new classes of actuators based on changes in microstructure.

The Human Brain Is Best Described as Being on a Female/Male Continuum: Evidence from a Neuroimaging Connectivity Study.

Psychological androgyny has long been associated with greater cognitive flexibility, adaptive behavior, and better mental health, but whether a similar concept can be defined using neural features remains unknown. Using the neuroimaging data from 9620 participants, we found that global functional connectivity was stronger in the male brain before middle age but became weaker after that, when compared with the female brain, after systematic testing of potentially confounding effects. We defined a brain gender continuum by estimating the likelihood of an observed functional connectivity matrix to represent a male brain. We found that participants mapped at the center of this continuum had fewer internalizing symptoms compared with those at the 2 extreme ends. These findings suggest a novel hypothesis proposing that there exists a neuroimaging concept of androgyny using the brain gender continuum, which may be associated with better mental health in a similar way to psychological androgyny.

Differential associations of visual memory with hippocampal subfields in subjective cognitive decline and amnestic mild cognitive impairment.

BACKGROUND: Although previous studies have demonstrated that the hippocampus plays a role in verbal memory, the role of hippocampal subfields in visual memory is uncertain, especially in those with preclinical Alzheimer's disease (AD). This study aimed to examine relationships between hippocampal subfield volumes and visual memory in SCD (subjective cognitive decline) and aMCI (amnestic mild cognitive impairment). METHODS: The study sample included 47 SCD patients, 62 aMCI patients, and 51 normal controls (NCs) and was recruited from Shanghai Jiao Tong University Affiliated Sixth People's Hospital. Visual memory was measured by the subtests of BVMT-R (Brief Visuospatial Memory Test-Revised), PLT (Pictorial Learning Test), DMS (Delayed Matching to Sample), and PAL (Paired Associates Learning). Hippocampal subfield volumes were estimated using FreeSurfer software (version 6.0). We modeled the association between visual memory and relative hippocampal subfield volumes (dividing by estimated total intracranial volume) using Pearson's correlation and linear regression. RESULTS: Compared with the NC group, patients with SCD did not find any relative hippocampal subregion atrophy, and the aMCI group found atrophy in CA1, molecular layer, subiculum, GC-ML-DG, CA4, and CA3. After adjusting for covariates (age, sex, and APOE ε4 status) and FDR (false discovery rate) correction of p (q values) < 0.05, in NC group, DMS delay matching scores were significant and negatively associated with presubiculum (r = -0.399, FDR q = 0.024); in SCD group, DMS delay matching scores were negatively associated with CA3 (r = -0.378, FDR q = 0.048); in the aMCI group, BVMT-R immediate recall scores were positively associated with CA1, molecular layer, subiculum, and GC-ML-DG (r = 0.360-0.374, FDR q < 0.036). Stepwise linear regression analysis confirmed the association. CONCLUSIONS: Our results indicate a different and specific correction of visual memory with relative hippocampal subfield volumes between SCD and aMCI. The correlations involved different and more subfields as cognitive decline. Whether these associations predict future disease progression needs dynamic longitudinal studies.

Charge Conversion Polymer-Liposome Complexes to Overcome the Limitations of Cationic Liposomes in Mitochondrial-Targeting Drug Delivery.

Mitochondrial-targeting therapy is considered an important strategy for cancer treatment. (3-Carboxypropyl) triphenyl phosphonium (CTPP) is one of the candidate molecules that can drive drugs or nanomedicines to target mitochondria via electrostatic interactions. However, the mitochondrial-targeting effectiveness of CTPP is low. Therefore, pH-sensitive polymer-liposome complexes with charge-conversion copolymers and CTPP-containing cationic liposomes were designed for efficiently delivering an anti-cancer agent, ceramide, into cancer cellular mitochondria. The charge-conversion copolymers, methoxypoly(ethylene glycol)-block-poly(methacrylic acid-g-histidine), were anionic and helped in absorbing and shielding the positive charges of cationic liposomes at pH 7.4. In contrast, charge-conversion copolymers became neutral in order to depart from cationic liposomes and induced endosomal escape for releasing cationic liposomes into cytosol at acidic endosomes. The experimental results reveal that these pH-sensitive polymer-liposome complexes could rapidly escape from MCF-7 cell endosomes and target MCF-7 mitochondria within 3 h, thereby leading to the generation of reactive oxygen species and cell apoptosis. These findings provide a promising solution for cationic liposomes in cancer mitochondrial-targeting drug delivery.

Diet quality and risk and severity of COVID-19: a prospective cohort study.

OBJECTIVE: Poor metabolic health and unhealthy lifestyle factors have been associated with risk and severity of COVID-19, but data for diet are lacking. We aimed to investigate the association of diet quality with risk and severity of COVID-19 and its interaction with socioeconomic deprivation. DESIGN: We used data from 592 571 participants of the smartphone-based COVID-19 Symptom Study. Diet information was collected for the prepandemic period using a short food frequency questionnaire, and diet quality was assessed using a healthful Plant-Based Diet Score, which emphasises healthy plant foods such as fruits or vegetables. Multivariable Cox models were fitted to calculate HRs and 95% CIs for COVID-19 risk and severity defined using a validated symptom-based algorithm or hospitalisation with oxygen support, respectively. RESULTS: Over 3 886 274 person-months of follow-up, 31 815 COVID-19 cases were documented. Compared with individuals in the lowest quartile of the diet score, high diet quality was associated with lower risk of COVID-19 (HR 0.91; 95% CI 0.88 to 0.94) and severe COVID-19 (HR 0.59; 95% CI 0.47 to 0.74). The joint association of low diet quality and increased deprivation on COVID-19 risk was higher than the sum of the risk associated with each factor alone (Pinteraction=0.005). The corresponding absolute excess rate per 10 000 person/months for lowest vs highest quartile of diet score was 22.5 (95% CI 18.8 to 26.3) among persons living in areas with low deprivation and 40.8 (95% CI 31.7 to 49.8) among persons living in areas with high deprivation. CONCLUSIONS: A diet characterised by healthy plant-based foods was associated with lower risk and severity of COVID-19. This association may be particularly evident among individuals living in areas with higher socioeconomic deprivation.

Sensory, somatomotor and internal mentation networks emerge dynamically in the resting brain with internal mentation predominating in older age.

Age-related changes in the brain are associated with a decline in functional flexibility. Intrinsic functional flexibility is evident in the brain's dynamic ability to switch between alternative spatiotemporal states during resting state. However, the relationship between brain connectivity states, associated psychological functions during resting state, and the changes in normal aging remain poorly understood. In this study, we analyzed resting-state functional magnetic resonance imaging (rsfMRI) data from the Human Connectome Project (HCP; N = 812) and the UK Biobank (UKB; N = 6,716). Using signed community clustering to identify distinct states of dynamic functional connectivity, and text-mining of a large existing literature for functional annotation of each state, our findings from the HCP dataset indicated that the resting brain spontaneously transitions between three functionally specialized states: sensory, somatomotor, and internal mentation networks. The occurrence, transition-rate, and persistence-time parameters for each state were correlated with behavioural scores using canonical correlation analysis. We estimated the same brain states and parameters in the UKB dataset, subdivided into three distinct age ranges: 50-55, 56-67, and 68-78 years. We found that the internal mentation network was more frequently expressed in people aged 71 and older, whereas people younger than 55 more frequently expressed sensory and somatomotor networks. Furthermore, analysis of the functional entropy - a measure of uncertainty of functional connectivity - also supported this finding across the three age ranges. Our study demonstrates that dynamic functional connectivity analysis can expose the time-varying patterns of transition between functionally specialized brain states, which are strongly tied to increasing age.