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AbstractBackground.Earlier studies examining structural brain abnormalities associated with cognitively derived subgroups were mainly cross-sectional in design and had mixed findings. Thus, we obtained cross-sectional and longitudinal data to characterize the extent and trajectory of brain structure abnormalities underlying distinct cognitive subtypes (“preserved,” “deteriorated,” and “compromised”) seen in psychotic spectrum disorders.Methods.Data from 364 subjects (225 patients with psychotic conditions and 139 healthy controls) were first used to determine the relationship of cognitive subtypes with cross-sectional measures of subcortical volume and cortical thickness. To probe neurodevelopmental abnormalities, brain structure laterality was examined. To examine whether neuroprogressive abnormalities persist, longitudinal brain structural changes over 5 years were examined within a subset of 101 subjects. Subsequent discriminant analysis using the identified brain measures was performed on an independent subject group.Results.Cross-sectional comparisons showed that cortical thinning and limbic volume reductions were most widespread in “deteriorated” cognitive subtype. Laterality comparisons showed more rightward amygdala lateralization in “compromised” than “preserved” subtype. Longitudinal comparisons revealed progressive hippocampal shrinkage in “deteriorated” compared with healthy controls and “preserved” subtype, which correlated with worse negative symptoms, cognitive and psychosocial functioning. Post-hoc discrimination analysis on an independent group of 52 subjects using the identified brain structures found an overall accuracy of 71% for classification of cognitive subtypes.Conclusion.These findings point toward distinct extent and trajectory of corticolimbic abnormalities associated with cognitive subtypes in psychosis, which can allow further understanding of the biological course of cognitive functioning over illness course and with treatment.

This study examined whether a three-month equine-assisted learning program improved measures of character skills in two independent cohorts of Year 1 youths, in a specialized secondary school for youths with difficulties coping with mainstream curriculum. In 2013, 75 students underwent intervention while 82 students did not. In 2014, 58 students underwent intervention and 59 students were waitlisted in semester 1; cross-over was performed in semester 2. The students were rated a week before, mid-way and a week post-intervention. Results from multi-level modeling indicated that the intervention led to progressive improvements in character skills over the school semester, in the majority of the constructs measured in both the 2013 and 2014 cohorts. The rate of change in measures of character skills over the semester correlated with the grade point average of the students at semester-end. Implications and limitations of the findings are discussed.

Single-nucleus analysis allows robust cell-type classification and helps to establish relationships between chromatin accessibility and cell-type-specific gene expression. Here, using samples from 92 women of several genetic ancestries, we developed a comprehensive chromatin accessibility and gene expression atlas of the breast tissue. Integrated analysis revealed ten distinct cell types, including three major epithelial subtypes (luminal hormone sensing, luminal adaptive secretory precursor (LASP) and basal-myoepithelial), two endothelial and adipocyte subtypes, fibroblasts, T cells, and macrophages. In addition to the known cell identity genes FOXA1 (luminal hormone sensing), EHF and ELF5 (LASP), TP63 and KRT14 (basal-myoepithelial), epithelial subtypes displayed several uncharacterized markers and inferred gene regulatory networks. By integrating breast epithelial cell gene expression signatures with spatial transcriptomics, we identified gene expression and signaling differences between lobular and ductal epithelial cells and age-associated changes in signaling networks. LASP cells and fibroblasts showed genetic ancestry-dependent variability. An estrogen receptor-positive subpopulation of LASP cells with alveolar progenitor cell state was enriched in women of Indigenous American ancestry. Fibroblasts from breast tissues of women of African and European ancestry clustered differently, with accompanying gene expression differences. Collectively, these data provide a vital resource for further exploring genetic ancestry-dependent variability in healthy breast biology., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Structural neuroimaging data have been used to compute an estimate of the biological age of the brain (brain-age) which has been associated with other biologically and behaviorally meaningful measures of brain development and aging. The ongoing research interest in brain-age has highlighted the need for robust and publicly available brain-age models pre-trained on data from large samples of healthy individuals. To address this need we have previously released a developmental brain-age model. Here we expand this work to develop, empirically validate, and disseminate a pre-trained brain-age model to cover most of the human lifespan. To achieve this, we selected the best-performing model after systematically examining the impact of seven site harmonization strategies, age range, and sample size on brain-age prediction in a discovery sample of brain morphometric measures from 35,683 healthy individuals (age range: 5-90 years; 53.59% female). The pre-trained models were tested for cross-dataset generalizability in an independent sample comprising 2101 healthy individuals (age range: 8-80 years; 55.35% female) and for longitudinal consistency in a further sample comprising 377 healthy individuals (age range: 9-25 years; 49.87% female). This empirical examination yielded the following findings: (1) the accuracy of age prediction from morphometry data was higher when no site harmonization was applied; (2) dividing the discovery sample into two age-bins (5-40 and 40-90 years) provided a better balance between model accuracy and explained age variance than other alternatives; (3) model accuracy for brain-age prediction plateaued at a sample size exceeding 1600 participants. These findings have been incorporated into CentileBrain (https://centilebrain.org/#/brainAGE2), an open-science, web-based platform for individualized neuroimaging metrics., (© 2024 The Author(s). Human Brain Mapping published by Wiley Periodicals LLC.)

The value of normative models in research and clinical practice relies on their robustness and a systematic comparison of different modelling algorithms and parameters; however, this has not been done to date. We aimed to identify the optimal approach for normative modelling of brain morphometric data through systematic empirical benchmarking, by quantifying the accuracy of different algorithms and identifying parameters that optimised model performance. We developed this framework with regional morphometric data from 37 407 healthy individuals (53% female and 47% male; aged 3-90 years) from 87 datasets from Europe, Australia, the USA, South Africa, and east Asia following a comparative evaluation of eight algorithms and multiple covariate combinations pertaining to image acquisition and quality, parcellation software versions, global neuroimaging measures, and longitudinal stability. The multivariate fractional polynomial regression (MFPR) emerged as the preferred algorithm, optimised with non-linear polynomials for age and linear effects of global measures as covariates. The MFPR models showed excellent accuracy across the lifespan and within distinct age-bins and longitudinal stability over a 2-year period. The performance of all MFPR models plateaued at sample sizes exceeding 3000 study participants. This model can inform about the biological and behavioural implications of deviations from typical age-related neuroanatomical changes and support future study designs. The model and scripts described here are freely available through CentileBrain., Competing Interests: Declaration of interests SSH is supported by the US National Institutes of Health (NIH)'s National Institute of Mental Health (T32MH122394) and received a travel award from the Society of Biological Psychiatry to attend the annual meeting in 2023. HB declares an institutional grant from the Australian National Health and Medical Research Council; has received compensation for being on an advisory board or a consultant to Biogen, Eisai, Eli Lilly, Roche, and Skin2Neuron; payment for being on the Cranbrook Care Medical Advisory Board; and honoraria for being on the Montefiore Homes Clinical Advisory Board. RMB and HEHP declare partial funding through the Geestkracht programme of the Dutch Health Research Council (Zon-Mw, grant No 10–000–1001) and matching funds from participating pharmaceutical companies (ie, Lundbeck, AstraZeneca, Eli Lilly, and Janssen Cilag), universities (Academic Psychiatric Centre of the Academic Medical Center, University Medical Center Groningen, Maastricht University Medical Centre, and University Medical Center Utrecht), and mental health care organisations (GGZ Ingeest, Arkin, Dijk en Duin, GGZ Rivierduinen, Erasmus Medical Centre, GGZ Noord Holland Noord, Lentis, GGZ Friesland, GGZ Drenthe, Dimence, Mediant, GGNet Warnsveld, Yulius Dordrecht, Parnassia psycho-medical center The Hague, GGzE, GGZ Breburg, GGZ Oost-Brabant, Vincent van Gogh voor Geestelijke Gezondheid, Mondriaan, Virenze riagg, Zuyderland GGZ, MET GGZ, Universitair Centrum Sint-Jozef Kortenberg, CAPRI University of Antwerp, PC Ziekeren Sint-Truiden, PZ Sancta Maria Sint-Truiden, GGZ Overpelt, OPZ Rekem, Altrecht, and GGZ Centraal and Delta); and received funding from Nederlandse Organisatie voor Wetenschappelijk Onderzoek (NWO 51·02·061 to HEHP, NWO 51·02·062 to DIB, NWO–NIHC Programs of excellence 433–09–220 to HEHP, NWO-MagW 480–04–004 to DIB, and NWO/SPI 56–464–14192 to DIB), FP7 Ideas: European Research Council (ERC-230374 to DIB), and Universiteit Utrecht (High Potential Grant to HEHP). RB declares funding by the NIH's National Institute on Aging (R01AG067420); received compensation for being on the scientific advisory board from Alkermes and Cognito Therapeutics with no conflict to the present work; received honoraria from academic institutions for talks (all under $1000) and $1000 for speaking at a Massachusetts General Hospital and Harvard Medical School course; received travel fees for services to attend the annual meeting from the Simons Foundation; serves as a Director on the Simons Foundation Collaborative Initiative on Aging; is a paid scientific advisory board member for philanthropic grants for The Foundation for OCD Research and the Klarman Family Foundation. BF has received educational speaking fees from Medice. DG reports funding from the NIH. UD is funded through the German Research Foundation (DFG; DA 1151/9–1, DA 1151/10–1, DA 1151/11–1). GS declares funding from the European Commission, DFG, and National Science Foundation of China. CKT has received grants from the Research Council of Norway and the Norwegian Regional Health Authority, unrelated to the current work. HW reports funding from the German Research Foundation (WA 1539/11–1). NJ reports funding from the NIH and compensation from the International Neuropsychological Society. PMT declares a grant from the NIH and travel funded by NIH grants. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Rationale: Within chronic obstructive pulmonary disease (COPD), emphysema is characterized by a significant yet partially understood B cell immune component. Objectives: To characterize the transcriptomic signatures from lymphoid follicles (LFs) in ever-smokers without COPD and patients with COPD with varying degrees of emphysema. Methods: Lung sections from 40 patients with COPD and ever-smokers were used for LF proteomic and transcriptomic spatial profiling. Formalin- and O.C.T.-fixed lung samples obtained from biopsies or lung explants were assessed for LF presence. Emphysema measurements were obtained from clinical chest computed tomographic scans. High-confidence transcriptional target intersection analyses were conducted to resolve emphysema-induced transcriptional networks. Measurements and Main Results: Overall, 115 LFs from ever-smokers and Global Initiative for Chronic Obstructive Lung Disease (GOLD) 1-2 and GOLD 3-4 patients were analyzed. No LFs were found in never-smokers. Differential gene expression analysis revealed significantly increased expression of LF assembly and B cell marker genes in subjects with severe emphysema. High-confidence transcriptional analysis revealed activation of an abnormal B cell activity signature in LFs ( q -value = 2.56E-111). LFs from patients with GOLD 1-2 COPD with emphysema showed significantly increased expression of genes associated with antigen presentation, inflammation, and B cell activation and proliferation. LFs from patients with GOLD 1-2 COPD without emphysema showed an antiinflammatory profile. The extent of centrilobular emphysema was significantly associated with genes involved in B cell maturation and antibody production. Protein-RNA network analysis showed that LFs in emphysema have a unique signature skewed toward chronic B cell activation. Conclusions: An off-targeted B cell activation within LFs is associated with autoimmune-mediated emphysema pathogenesis.

Rationale: Within chronic obstructive pulmonary disease (COPD), emphysema is characterized by a significant yet partially understood B cell immune component., Objective: To characterize the transcriptomic signatures from lymphoid follicles (LFs) in ever-smokers without COPD and COPD patients with varying degrees of emphysema., Methods: Lung sections from 40 COPD patients and ever-smokers were used for LF proteomic and transcriptomic spatial profiling. Formalin and OCT-fixed lung samples obtained from biopsies or lung explants, were assessed for LF presence. Emphysema measurements were obtained from clinical chest CT scans. High confidence transcriptional (HCT) target intersection analyses were conducted to resolve emphysema-induced transcriptional networks., Measurements and Main Results: Overall, 115 LFs from ever-smokers and GOLD 1-2 and GOLD 3-4 patients were analyzed. No LFs were found in never-smokers. Differential gene expression analysis revealed significantly increased expression of LF assembly and B cell markers genes in subjects with severe emphysema. HCT analysis revealed activation of abnormal B cell activity signature in LFs (q-value: 2.56E-111). LFs from GOLD 1-2 COPD patients with emphysema showed significantly increased expression of genes associated with antigen presentation, inflammation, and B cell activation and proliferation. LFs from GOLD 1-2 COPD patients without emphysema showed an anti-inflammatory profile. The extent of centrilobular emphysema was significantly associated with genes involved in B cell maturation and antibody production. Protein-RNA network analysis showed that LFs in emphysema have a unique signature skewed towards chronic B cell activation., Conclusions: An off-targeted B cell activation within LFs is associated with autoimmune-mediated emphysema pathogenesis.

Background: The COVID-19 pandemic has been associated with increased levels of depression and anxiety with implications for the use of antidepressant medications., Methods: The incident rate of antidepressant fills before and during the COVID-19 pandemic were compared using interrupted time-series analysis followed by comprehensive sensitivity analyses on data derived from electronic medical records from a large health management organization providing nationwide services to 14% of the Israeli population. The dataset covered the period from 1 January 2013 to 1 February 2021, with 1 March 2020 onwards defined as the period of the COVID-19 pandemic. Forecasting analysis was implemented to test the effect of the vaccine roll-out and easing of social restrictions on antidepressant use., Results: The sample consisted of 852 233 persons with a total antidepressant incident fill count of 139 535.4 (total cumulative rate per 100 000 = 16 372.91, 95% CI 16 287.19-16 459.01). We calculated the proportion of antidepressant prescription fills for the COVID-19 period, and the counterfactual proportion for the same period, assuming COVID-19 had not occurred. The difference in these proportions was significant [Cohen's h = 10 -3 (0.16), 95% CI 10 -3 ( - 0.71 to 1.03)]. The pandemic was associated with a significant increase in the slope of the incident rate of antidepressant fills (slope change = 0.01, 95% CI 0.00-0.03; p = 0.04) and a monthly increase of 2% compared to the counterfactual (the estimated rate assuming no pandemic occurred). The increased rate was more pronounced in women, and was not modified by lockdown on/off periods, socioeconomic or SARS-CoV-2 status. The rate of observed antidepressant fills was similar to that forecasted under the assumption of ongoing COVID-19 distress., Conclusion: These findings underscore the toll of the pandemic on mental health and inform mental health policy and service delivery during and after implementing COVID-19 attenuation strategies.

A deeper understanding of complex biological processes, including tumor development and immune response, requires ultra high-plex, spatial interrogation of multiple "omes". Here we present the development and implementation of a novel spatial proteogenomic (SPG) assay on the GeoMx Digital Spatial Profiler platform with next-generation sequencing readout that enables ultra high-plex digital quantitation of proteins (>100-plex) and RNA (whole transcriptome, >18,000-plex) from a single formalin-fixed paraffin-embedded (FFPE) sample. This study highlighted the high concordance, R > 0.85 and <15% change in sensitivity between the SPG assay and the single-analyte assays on various cell lines and tissues from human and mouse. Furthermore, we demonstrate that the SPG assay was reproducible across multiple users. When used in conjunction with advanced cellular neighborhood segmentation, distinct immune or tumor RNA and protein targets were spatially resolved within individual cell subpopulations in human colorectal cancer and non-small cell lung cancer. We used the SPG assay to interrogate 23 different glioblastoma multiforme (GBM) samples across four pathologies. The study revealed distinct clustering of both RNA and protein based on pathology and anatomic location. The in-depth investigation of giant cell glioblastoma multiforme (gcGBM) revealed distinct protein and RNA expression profiles compared with that of the more common GBM. More importantly, the use of spatial proteogenomics allowed simultaneous interrogation of critical protein posttranslational modifications alongside whole transcriptomic profiles within the same distinct cellular neighborhoods., Significance: We describe ultra high-plex spatial proteogenomics; profiling whole transcriptome and high-plex proteomics on a single FFPE tissue section with spatial resolution. Investigation of gcGBM versus GBM revealed distinct protein and RNA expression profiles., (© 2023 The Authors; Published by the American Association for Cancer Research.)

Background: Spinal cord injury (SCI) patients are at increased risk of developing urolithiasis. Ureteroscopic management for stone disease in SCI patients is underreported. Endourologists face many challenges in the management of stone disease in SCI patients including decreased stone free rates (SFR), increased infection risk, increased complication rate, anatomical variation, increased comorbidity level and challenges to nursing care. We present our experience at a regional SCI centre., Methods: Retrospective data was collected from 2005-2017 from a single SCI unit for patients who underwent ureteroscopy for stone disease., Results: A total of 21 patients underwent 41 procedures, 7 cases being a planned multi-stage approach. Bladder management included sheath catheter, urethral catheter, suprapubic catheter, intermittent self-catheterisation, mitrofanoff, and ileal conduit. Spinal cord level was cervical (71%) or thoracic (29%), with American Spinal Injury Association (ASIA) grade classification A (86%), C (9%) and D (5%). Median follow-up time for patients was 46 months. Average stone size was 27 mm (range, 5-59 mm) access was achieved 98% of patients, with an access sheath used in 63%. The SFR was 47% with a recurrence rate (RR) of 42%. The complication rate was 24% all being Clavien Dindo grade 2., Conclusions: Ureteroscopy in SCI can be challenging and careful multidisciplinary team planning for intervention is needed. Ureteroscopy offers a useful treatment option for SCI, however, is associated with a lower SFR and greater complication rate compared to that of the general population., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare., (2019 Translational Andrology and Urology. All rights reserved.)

Introduction: Spinal cord injury (SCI) patients are at increased risk of bladder cancer. A rare variation of this is a malignancy arising or including the suprapubic catheter (SPC) tract., Case Series: We present the first case series of malignancy of the SPC tract in SCI patients, including a case of mucinous adenocarcinoma, squamous cell carcinoma and sarcoma. Presentation of patients ranged from bleeding at the site of the SPC to a rapidly growing mass. All three patients were thoroughly investigated, and management was bespoke to the extent of disease and their physiological state at the time of diagnosis. This ranged from extensive surgical intervention including cystectomy, partial sigmoidectomy, excision of the abdominal wall with reconstruction and ileal conduit formation to palliation., Discussion: SCI patients represent 50% of all known published cases of malignancy of the SPC tract. Presentation and diagnosis can be challenging; however, prompt investigation and intervention are essential given the high degree of morbidity and mortality. Routine check of the SPC site may be indicated in those patients in whom the SPC has been present for more than 5 years., Competing Interests: Compliance with ethical standardsThe authors declare that they have no conflict of interest.

Introduction: Prostate cancer is the most common cancer amongst men in the UK. Treatments for malignant ureteric obstruction consist of percutaneous nephrostomy, ureteric stent insertion, or occasionally other forms of urinary diversion. Our aim was to look at the outcomes of percutaneous nephrostomy (PCN) in patients with advanced prostate cancer and to look at the impact on patient's general health, quality of life, life expectancy and complications after PCN insertion., Material and Methods: A systematic review of the literature was done for all prospective English language articles on PCN in patients with prostate cancer using PubMed, MEDLINE, EMBASE, Scopus, CINAHL, Cochrane library, Clinicaltrials.gov, Google Scholar and individual urological journals from inception to August 2017. While studies involving prostate cancer patients were included, studies on all other mixed pelvic malignancies were excluded., Results: Seven articles met the inclusion criteria. There were 184 patients, with a mean age of 70 years (range: 51-94 years). PCN was performed for ureteric obstruction due to advanced prostate cancer, patients underwent unilateral (n = 66) or bilateral PCN (n = 118) with conversion to an antegrade stent in 25 patients. Their post-PCN survival varied between 4-31 months and this was longer if they were hormone naïve or showed a good recovery in their renal function. Although the complication rates were low (1-3%), patients spend a high proportion of their lives in the hospital., Conclusions: PCNs should only be pursued after thoughtful counselling regarding further treatment options and prognosis as these patients with advanced malignancies seem to have reduced survival duration and spend a significant amount of time in hospital.

Purpose of Review: The purpose of this study was to review the current evidence for quality of life (QOL) in patients with kidney stone disease (KSD)., Recent Findings: A review of literature from inception to May 2016 for all prospective English language articles on QOL in patients with KSD was done. QOL studies post urological procedures or ureteric stents were excluded. Nine studies (1570 patients) were included of which most (n = 6) used the SF-36 QOL tool. Overall, seven of the nine studies demonstrated a lower QOL in patients with KSD. Bodily pain and general health were significantly lower in patients with KSD compared to their control groups. Patients with KSD have an overall lower QOL with most impact on bodily pain and general health domains. Compared to the scale of patients suffering from KSD, more work needs to be done in measuring QOL both in terms of 'Stone specific' QOL measuring tools and the quality/number of studies in this field., Competing Interests: Francesca New reports personal fees from Coloplast and other from Storz. Bhaskar K. Somani declares no potential conflicts of interest. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.

The discoveries of the Human Genome Project (HGP), established in 1990 at the National Institutes of Health and the United States Department of Energy, are bringing important new technologies for genetic diagnosis and treatment to nearly all areas of health care delivery. Nurses, who play an integral role in supporting health consumers as they respond to health and illness, require up-to-date genetic knowledge for conducting clinical practice, engaging in nursing research, and educating a new generation of nurses.