ATG16L1 in myeloid cells limits colorectal tumor growth in ApcMin/+ mice infected with colibactin-producing Escherichia coli via decreasing inflammasome activation.

Escherichia coli strains producing the genotoxin colibactin, designated as CoPEC (colibactin-producing E. coli), have emerged as an important player in the etiology of colorectal cancer (CRC). Here, we investigated the role of macroautophagy/autophagy in myeloid cells, an important component of the tumor microenvironment, in the tumorigenesis of a susceptible mouse model infected with CoPEC. For that, a preclinical mouse model of CRC, the ApcMin/+ mice, with Atg16l1 deficiency specifically in myeloid cells (ApcMin/+/Atg16l1[∆MC]) and the corresponding control mice (ApcMin/+), were infected with a clinical CoPEC strain 11G5 or its isogenic mutant 11G5∆clbQ that does not produce colibactin. We showed that myeloid cell-specific Atg16l1 deficiency led to an increase in the volume of colonic tumors in ApcMin/+ mice under infection with 11G5, but not with 11G5∆clbQ. This was accompanied by increased colonocyte proliferation, enhanced inflammasome activation and IL1B/IL-1ß secretion, increased neutrophil number and decreased total T cell and cytotoxic CD8+ T cell numbers in the colonic mucosa and tumors. In bone marrow-derived macrophages (BMDMs), compared to uninfected and 11G5∆clbQ-infected conditions, 11G5 infection increased inflammasome activation and IL1B secretion, and this was further enhanced by autophagy deficiency. These data indicate that ATG16L1 in myeloid cells was necessary to inhibit colonic tumor growth in CoPEC-infected ApcMin/+ mice via inhibiting colibactin-induced inflammasome activation and modulating immune cell response in the tumor microenvironment. Abbreviation: AOM, azoxymethane; APC, APC regulator of WNT signaling pathway; ATG, autophagy related; Atg16l1[∆MC] mice, mice deficient for Atg16l1 specifically in myeloid cells; CASP1, caspase 1; BMDM, bone marrow-derived macrophage; CFU, colony-forming unit; CoPEC, colibactin-producing Escherichia coli; CRC, colorectal cancer; CXCL1/KC, C-X-C motif chemokine ligand 1; ELISA, enzyme-linked immunosorbent assay; IL, interleukin; MC, myeloid cell; MOI, multiplicity of infection; PBS, phosphate-buffered saline; pks, polyketide synthase; qRT-PCR, quantitative real-time reverse-transcription polymerase chain reaction; siRNA, small interfering RNA; TME, tumor microenvironment; TNF/TNF-α, tumor necrosis factor.

Translation and validation of Vietnamese version of the Birth Satisfaction Scale-Revised (BSS-R).

BACKGROUND: The 10-item Birth Satisfaction Scale-Revised (BSS-R) is a quick and easy survey instrument recommended by the International Consortium for Health Outcome Measures as the tool of choice for measuring women's birth satisfaction. AIM: To translate and validate a Vietnamese-language version of the BSS-R. METHOD: A quantitative cross-sectional method was used to gather data post translation and back-translation of a Vietnamese version of the BSS-R (VN-BSS-R). Data collected were psychometrically evaluated using key indices of validity and reliability. PARTICIPANTS: Vietnamese women who were within one month postpartum of birth (N = 383) took part in the study. RESULTS: Findings illustrate that a two-factor model offered excellent psychometric properties. With the two-factor VN-BSS-R, five items loaded onto a subscale 'Positive birth experiences' and the other five onto a second subscale 'Negative birth experiences'. This two-factor model offered a fit to data (root mean square error of approximation [RMSEA] = 0.07, 90% confidence interval [CI] [0.05, 0.09], root square mean residual [RMSE] = 0.04 and comparative fit index [CFI] = 0.97). Mean scores for the exploratory factor analysis [EFA]-derived 'positive' and 'negative' sub-scales were 17.12 (SD 2.34) and 8.40 (SD 4.18) respectively. CONCLUSION: The translated and validated VN-BSS-R is a psychometrically robust tool for measuring birth satisfaction in Vietnamese postpartum women.The VN-BSS-R is available for use to measure experiences and perceptions of intrapartum care received by Vietnamese women.

Identification of autophagy receptors for the Crohn's disease-associated adherent-invasive Escherichia coli.

Introduction: Crohn's disease (CD) is a chronic inflammatory bowel disease, of which the etiology involves genetic, environmental and microbial factors. Adherent-invasive Escherichia coli (AIEC) and polymorphisms in autophagy-related genes have been implicated in CD etiology. Autophagy is a key process for the maintenance of cellular homeostasis, which allows the degradation of damaged cytoplasmic components and pathogens via lysosome. We have shown that a functional autophagy is necessary for AIEC clearance. Here, we aimed at identifying the autophagy receptor(s) responsible to target AIEC to autophagy for degradation. Methods: The levels of autophagy receptors p62, NDP52, NBR1, TAX1BP1 and Optineurin were knocked down in human intestinal epithelial cells T84 using siRNAs. The NDP52 knock-out (KO) and p62 KO HeLa cells, as well as NDP52 KO HeLa cells expressing the wild-type NDP52 or the mutated NDP52Val248Ala protein were used. Results and discussion: We showed that, among the tested autophagy receptors (p62, NDP52, NBR1, TAX1BP1 and Optineurin), diminished expression of p62 or NDP52 increased the number of the clinical AIEC LF82 strain inside epithelial cells. This was associated with increased pro-inflammatory cytokine production. Moreover, p62 or NDP52 directly colocalized with AIEC LF82 and LC3, an autophagy marker. As the NDP52Val248Ala polymorphism has been associated with increased CD susceptibility, we investigated its impact on AIEC control. However, in HeLa cell and under our experimental condition, no effect of this polymorphism neither on AIEC LF82 intracellular number nor on pro-inflammatory cytokine production was observed. Together, our results suggest that p62 and NDP52 act as autophagy receptors for AIEC recognition, controlling AIEC intracellular replication and inflammation.

A protocol for annotation of total body photography for machine learning to analyze skin phenotype and lesion classification.

Introduction: Artificial Intelligence (AI) has proven effective in classifying skin cancers using dermoscopy images. In experimental settings, algorithms have outperformed expert dermatologists in classifying melanoma and keratinocyte cancers. However, clinical application is limited when algorithms are presented with 'untrained' or out-of-distribution lesion categories, often misclassifying benign lesions as malignant, or misclassifying malignant lesions as benign. Another limitation often raised is the lack of clinical context (e.g., medical history) used as input for the AI decision process. The increasing use of Total Body Photography (TBP) in clinical examinations presents new opportunities for AI to perform holistic analysis of the whole patient, rather than a single lesion. Currently there is a lack of existing literature or standards for image annotation of TBP, or on preserving patient privacy during the machine learning process. Methods: This protocol describes the methods for the acquisition of patient data, including TBP, medical history, and genetic risk factors, to create a comprehensive dataset for machine learning. 500 patients of various risk profiles will be recruited from two clinical sites (Australia and Spain), to undergo temporal total body imaging, complete surveys on sun behaviors and medical history, and provide a DNA sample. This patient-level metadata is applied to image datasets using DICOM labels. Anonymization and masking methods are applied to preserve patient privacy. A two-step annotation process is followed to label skin images for lesion detection and classification using deep learning models. Skin phenotype characteristics are extracted from images, including innate and facultative skin color, nevi distribution, and UV damage. Several algorithms will be developed relating to skin lesion detection, segmentation and classification, 3D mapping, change detection, and risk profiling. Simultaneously, explainable AI (XAI) methods will be incorporated to foster clinician and patient trust. Additionally, a publicly released dataset of anonymized annotated TBP images will be released for an international challenge to advance the development of new algorithms using this type of data. Conclusion: The anticipated results from this protocol are validated AI-based tools to provide holistic risk assessment for individual lesions, and risk stratification of patients to assist clinicians in monitoring for skin cancer.

Bacterial genome sequences of uncharacterized Chitinophaga species isolated from the International Space Station.

We report four Chitinophaga sp. strains isolated from wastewater collected onboard the International Space Station. Here, we present three finished and one draft genome. Taxonomic ranks established by genome-based analysis indicate that these Chitinophaga sp. strains represent candidates for a new species.

Novel Variant and Known Mutation in 23S rRNA Gene of Mycoplasma pneumoniae, Northern Vietnam, 2023.

During a 2023 outbreak of Mycoplasma pneumoniae-associated community-acquired pneumonia among children in northern Vietnam, we analyzed M. pneumoniae isolated from nasopharyngeal samples. In almost half (6 of 13) of samples tested, we found known A2063G mutations (macrolide resistance) and a novel C2353T variant on the 23S rRNA gene.

Avian H6 Influenza Viruses in Vietnamese Live Bird Markets during 2018-2021.

Avian influenza viruses of the H6 subtype are prevalent in wild ducks and likely play an important role in the ecology of influenza viruses through reassortment with other avian influenza viruses. Yet, only 152 Vietnamese H6 virus sequences were available in GISAID (Global Initiative on Sharing All Influenza Data) prior to this study with the most recent sequences being from 2018. Through surveillance in Vietnamese live bird markets from 2018 to 2021, we identified 287 samples containing one or several H6 viruses and other influenza A virus subtypes, demonstrating a high rate of co-infections among birds in Vietnamese live bird markets. For the 132 H6 samples with unique influenza virus sequences, we conducted phylogenetic and genetic analyses. Most of the H6 viruses were similar to each other and closely related to other H6 viruses; however, signs of reassortment with other avian influenza viruses were evident. At the genetic level, the Vietnamese H6 viruses characterized in our study encode a single basic amino acid at the HA cleavage site, consistent with low pathogenicity in poultry. The Vietnamese H6 viruses analyzed here possess an amino acid motif in HA that confers binding to both avian- and human-type receptors on host cells, consistent with their ability to infect mammals. The frequent detection of H6 viruses in Vietnamese live bird markets, the high rate of co-infections of birds with different influenza viruses, and the dual receptor-binding specificity of these viruses warrant their close monitoring for potential infection and spread among mammals.

Promising clinical and immunological efficacy of Bacillus clausii spore probiotics for supportive treatment of persistent diarrhea in children.

Persistent diarrhea is a severe gastroenteric disease with relatively high risk of pediatric mortality in developing countries. We conducted a randomized, double-blind, controlled clinical trial to evaluate the efficacy of liquid-form Bacillus clausii spore probiotics (LiveSpo CLAUSY; 2 billion CFU/5 mL ampoule) at high dosages of 4-6 ampoules a day in supporting treatment of children with persistent diarrhea. Our findings showed that B. clausii spores significantly improved treatment outcomes, resulting in a 2-day shorter recovery period (p < 0.05) and a 1.5-1.6 folds greater efficacy in reducing diarrhea symptoms, such as high frequency of bowel movement of ≥ 3 stools a day, presence of fecal mucus, and diapered infant stool scale types 4-5B. LiveSpo CLAUSY supportive treatment achieved 3 days (p < 0.0001) faster recovery from diarrhea disease, with 1.6-fold improved treatment efficacy. At day 5 of treatment, a significant decrease in blood levels of pro-inflammatory cytokines TNF-α, IL-17, and IL-23 by 3.24% (p = 0.0409), 29.76% (p = 0.0001), and 10.87% (p = 0.0036), respectively, was observed in the Clausy group. Simultaneously, there was a significant 37.97% decrease (p = 0.0326) in the excreted IgA in stool at day 5 in the Clausy group. Overall, the clinical study demonstrates the efficacy of B. clausii spores (LiveSpo CLAUSY) as an effective symptomatic treatment and immunomodulatory agent for persistent diarrhea in children.Trial registration: NCT05812820.

Colibactin-producing Escherichia coli enhance resistance to chemotherapeutic drugs by promoting epithelial to mesenchymal transition and cancer stem cell emergence.

Human colorectal cancers (CRCs) are readily colonized by colibactin-producing E. coli (CoPEC). CoPEC induces DNA double-strand breaks, DNA mutations, genomic instability, and cellular senescence. Infected cells produce a senescence-associated secretory phenotype (SASP), which is involved in the increase in tumorigenesis observed in CRC mouse models infected with CoPEC. This study investigated whether CoPEC, and the SASP derived from CoPEC-infected cells, impacted chemotherapeutic resistance. Human intestinal epithelial cells were infected with the CoPEC clinical 11G5 strain or with its isogenic mutant, which is unable to produce colibactin. Chemotherapeutic resistance was assessed in vitro and in a xenograft mouse model. Expressions of cancer stem cell (CSC) markers in infected cells were investigated. Data were validated using a CRC mouse model and human clinical samples. Both 11G5-infected cells, and uninfected cells incubated with the SASP produced by 11G5-infected cells exhibited an increased resistance to chemotherapeutic drugs in vitro and in vivo. This finding correlated with the induction of the epithelial to mesenchymal transition (EMT), which led to the emergence of cells exhibiting CSC features. They grew on ultra-low attachment plates, formed colonies in soft agar, and overexpressed several CSC markers (e.g. CD133, OCT-3/4, and NANOG). In agreement with these results, murine and human CRC biopsies colonized with CoPEC exhibited higher expression levels of OCT-3/4 and NANOG than biopsies devoid of CoPEC. Conclusion: CoPEC might aggravate CRCs by inducing the emergence of cancer stem cells that are highly resistant to chemotherapy.

Pathogenic/likely pathogenic mutations identified in Vietnamese children diagnosed with autism spectrum disorder using high-resolution SNP genotyping platform.

Among the most prevalent neurodevelopmental disorders, Autism Spectrum Disorder (ASD) is highly diverse showing a broad phenotypic spectrum. ASD also couples with a broad range of mutations, both de novo and inherited. In this study, we used a proprietary SNP genotyping chip to analyze the genomic DNA of 250 Vietnamese children diagnosed with ASD. Our Single Nucleotide Polymorphism (SNP) genotyping chip directly targets more than 800 thousand SNPs in the genome. Our primary focus was to identify pathogenic/likely pathogenic mutations that are potentially linked to more severe symptoms of autism. We identified and validated 23 pathogenic/likely pathogenic mutations in this initial study. The data shows that these mutations were detected in several cases spanning multiple biological pathways. Among the confirmed SNPs, mutations were identified in genes previously known to be strongly associated with ASD such as SLCO1B1, ACADSB, TCF4, HCP5, MOCOS, SRD5A2, MCCC2, DCC, and PRKN while several other mutations are known to associate with autistic traits or other neurodevelopmental disorders. Some mutations were found in multiple patients and some patients carried multiple pathogenic/likely pathogenic mutations. These findings contribute to the identification of potential targets for therapeutic solutions in what is considered a genetically heterogeneous neurodevelopmental disorder.

The diagnostic performance of AFP and PIVKA-II models for non-B non-C hepatocellular carcinoma.

OBJECTIVE: This study aims to describe the diagnostic performance of alpha-fetoprotein (AFP), alpha-fetoprotein L3 isoform (AFP-L3), protein induced by vitamin K absence II (PIVKA-II), and combined biomarkers for non-B non-C hepatocellular carcinoma (NBNC-HCC). RESULTS: A total of 681 newly-diagnosed primary liver disease subjects (385 non-HCC, 296 HCC) who tested negativity for the hepatitis B surface antigen (HBsAg) and hepatitis C antibody (anti-HCV) enrolled in this study. At the cut-off point of 3.8 ng/mL, AFP helps to discriminate HCC from non-HCC with an area under the curve (AUC) value of 0.817 (95% confidence interval [CI]: 0.785-0.849). These values of AFP-L3 (cut-off 0.9%) and PIVKA-II (cut-off 57.7 mAU/mL) were 0.758 (95%CI: 0.725-0.791) and 0.866 (95%CI: 0.836-0.896), respectively. The Bayesian Model Averaging (BMA) statistic identified the optimal model, including patients' age, aspartate aminotransferase, AFP, and PIVKA-II combination, which helps to classify HCC with better performance (AUC = 0.896, 95%CI: 0.872-0.920, P < 0.001). The sensitivity and specificity of the optimal model reached 81.1% (95%CI: 76.1-85.4) and 83.2% (95%CI: 78.9-86.9), respectively. Further analyses indicated that AFP and PIVKA-II markers and combined models have good-to-excellent performance detecting curative resected HCC, separating HCC from chronic hepatitis, dysplastic, and hyperplasia nodules.

Investigating the different transformations of tetracycline using birnessite under different reaction conditions and various humic acids.

Prior studies have successfully used manganese oxides to facilitate the transformation of tetracycline in aqueous solution. To further understand the kinetic and the transformation pathway of tetracycline via birnessite (δ-MnO2) under different conditions, experiments were conducted at pH levels of 3, 6, and 9 in the presence or absence of Aldrich humic acid (ADHA). Tetracycline removal followed the pseudo-second-order reaction model in all investigated cases, and the removal efficiency (g mg-1 h -1) followed the following trend: pH 3 (0.45/0.27) > pH 6 (0.036/0.087) > pH 9 (0.036/0.103) in the absence/presence of ADHA. Liquid chromatography-mass spectrometry/mass spectrometry results identified five main transformation products at m/z 495, 477, 493, 459, and 415, produced by the transformation reactions, including hydration, oxidation, desaturation, and oxy reduction. Notably, in the presence of ADHA at pH 3, products with higher toxicity secondary (m/z 477 and 495) were reduced, while less toxicity products (m/z 459 and 415) were enhanced. The experiments utilizing tetracycline and δ-MnO2 with varied humic acids (HA) revealed that HA with high polar organic carbon groups, such as O-alkyl, exhibited higher removal efficiency at pH 6. This research offers the first comprehensive insights into the pathway transformations of tetracycline via δ-MnO2 under different pH conditions and HA types. For further understanding, future work should investigate the binding of HA, TTC, and/or Mn2+ and the oxidation capacity of MnO2 after the reaction to clarify Mn2+ elution mechanisms.

Oral administration of a 2-aminopyrimidine robenidine analogue (NCL195) significantly reduces Staphylococcus aureus infection and reduces Escherichia coli infection in combination with sub-inhibitory colistin concentrations in a bioluminescent mouse model.

We have previously reported promising in vivo activity of the first-generation 2-aminopyramidine robenidine analogue NCL195 against Gram-positive bacteria (GPB) when administered via the systemic route. In this study, we examined the efficacy of oral treatment with NCL195 (± low-dose colistin) in comparison to oral moxifloxacin in bioluminescent Staphylococcus aureus and Escherichia coli peritonitis-sepsis models. Four oral doses of 50 mg/kg NCL195, commencing immediately post-infection, were administered at 4 h intervals in the S. aureus peritonitis-sepsis model. We used a combination of four oral doses of 50 mg/kg NCL195 and four intraperitoneal doses of colistin at 0.125 mg/kg, 0.25 mg/kg, or 0.5 mg/kg in the E. coli peritonitis-sepsis model. Subsequently, the dose rates of four intraperitoneal doses of colistin were increased to 0.5 mg/kg, 1 mg/kg, or 2 mg/kg at 4 h intervals to treat a colistin-resistant E. coli infection. In the S. aureus infection model, oral treatment of mice with NCL195 resulted in significantly reduced S. aureus infection loads (P < 0.01) and longer survival times (P < 0.001) than vehicle-only treated mice. In the E. coli infection model, co-administration of NCL195 and graded doses of colistin resulted in a dose-dependent significant reduction in colistin-susceptible (P < 0.01) or colistin-resistant (P < 0.05) E. coli loads compared to treatment with colistin alone at similar concentrations. Our results confirm that NCL195 is a potential candidate for further preclinical development as a specific treatment for multidrug-resistant infections, either as a stand-alone antibiotic for GPB or in combination with sub-inhibitory concentrations of colistin for Gram-negative bacteria.

Erratum: Closing the gap for cervical cancer research in Vietnam: current perspectives and future opportunities: a report from the 5th Gynecologic Cancer InterGroup (GCIG) Cervical Cancer Research Network (CCRN) Education Symposium.

This corrects the article on p. e88 in vol. 34, PMID: 37668081.

Case of Esophageal Actinomycosis Occurred after Endoscopic Mucosal Resection for Subepithelial Tumor.

Esophageal actinomycosis is a rare, chronic granulomatous disease caused by Actinomyces species. Endoscopy and biopsy are essential for making a diagnosis. This paper reports a case of esophageal actinomycosis that developed after an endoscopic mucosal resection (EMR) for a subepithelial tumor (SET). A 74-year-old male patient had a 3 cm flat, smooth elevation in the esophagus without symptoms. The SET was partially resected, and histology revealed "nonspecific degenerated mesenchymal tissue". Three months later, the patient exhibited a persistently large ulceration at the EMR site, and a biopsy revealed actinomycosis. CT of the chest and abdomen revealed no abnormal findings. Ampicillin treatment was administered for six months, and the ulceration on the esophageal SET improved.

Fluorescence spectroscopy in the detection and management of disinfection by-product precursors in drinking water treatment processes: A review.

Monitoring and prevention of the formation of disinfection by-products (DBPs) is paramount in drinking water treatment plants (DWTP) to ensure human health safety. This review provides an overview of how fluorescence techniques are developed to predict DBP formation and to evaluate the reduction of fluorescence components and DBPs following individual DWTP processes. Evidence has shown that common DBPs, nitrogenous DBPs and specific emerging DBPs exhibit positive linear relationships with terrestrial, anthropogenic, tryptophan-like, and eutrophic humic-like fluorescence. Due to the interrelationships of both regulated and emerging DBP types with fluorescence components, the limitations arise when attempting to predict emerging DBPs solely through linear relationships. Monitoring the reduction of DBP precursors after each treatment process can be achieved by studying the relationship between fluorescence components and DBPs. During the coagulation process, highest reduction rates are observed for terrestrial humic-like fluorescence. Advanced treatments such as granular, powdered, silver-impregnated activated carbon, magnetic ion exchange resins, and reverse osmosis, have revealed a significant reduction of fluorescent DBP precursors, ranging from 53% to 100%. During chlorination, the reduction rate follows the order: terrestrial humic-like > microbial humic-like > protein/tryptophan-like fluorescence. This review provides insights into the reduction of fluorescence signatures following individual DWTP processes, which offers information regarding DBP formation. These insights could assist in optimizing the treatment process to more effectively manage DBP formation. For the identification of emerging DBP generation, the utilization of advanced models is imperative to precisely predict emerging DBPs and to more accurately trace DBP precursors within DWTPs.

Functionalization of an ionic honeycomb KF monolayer via doping.

Doping has been widely employed to functionalize two-dimensional (2D) materials because of its effectiveness and simplicity. In this work, the electronic and magnetic properties of pristine and doped KF monolayers are investigated using first-principles calculations based on density functional theory (DFT). Phonon dispersion curves and ab initio molecular dynamics (AIMD) snapshots indicate good stability of the pristine material. The band structure shows an insulating behavior of the KF monolayer, with indirect gaps of 4.80 (6.53) eV as determined using the PBE (HSE06) functional. Its ionic character is also confirmed by the valence charge distribution and Bader charge analysis, and is generated by charge transfer from the K-4s orbital to the F-2p orbital. Doping at both anion and cation sites is explored using N/O and Ca/Sr as dopants, respectively, due to their dissimilar valence electronic configuration in comparison with that of the host atoms. It is found that the KF monolayer is significantly magnetized, where total magnetic moments of 2.00 and 1.00 µB are obtained via N and O/Ca/Sr doping, respectively. Moreover, the appearance of new middle-gap energy states leads to the development of a magnetic semiconductor nature, which is regulated by N-2p, O-2p, Ca-3d, Ca-4s, Sr-4d, and Sr-5s orbitals. Further investigation of codoping indicates that a magnetic-semiconductor nature is preserved, where the synergistic effects of dopants play a key role in the electronic and magnetic properties of the codoped systems. The results presented herein introduce doping as an efficient approach to functionalize the ionic KF monolayer to obtain prospective d0 spintronic materials, a functionality that is not accounted for by the pristine monolayer.

Sex Difference in Cigarette-Smoking Status and Its Association with Brain Volumes Using Large-Scale Community-Representative Data.

BACKGROUND: Cigarette smoking is believed to accelerate age-related neurodegeneration. Despite significant sex differences in both smoking behaviors and brain structures, the active literature is equivocal in parsing out a sex difference in smoking-associated brain structural changes. OBJECTIVE: The current study examined subcortical and lateral ventricle gray matter (GM) volume differences among smokers, active, past, and never-smokers, stratified by sex. METHODS: The current study data included 1959 Dallas Heart Study (DHS) participants with valid brain imaging data. Stratified by gender, multiple-group comparisons of three cigarette-smoking groups were conducted to test whether there is any cigarette-smoking group differences in GM volumes of the selected regions of interest (ROIs). RESULTS: The largest subcortical GM volumetric loss and enlargement of the lateral ventricle were observed among past smokers for both females and males. However, these observed group differences in GM volumetric changes were statistically significant only among males after adjusting for age and intracranial volumes. CONCLUSIONS: The study findings suggest a sex difference in lifetime-smoking-associated GM volumetric changes, even after controlling for aging and intracranial volumes.