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As an exercise in the ‘theology of disclosure’, the present essay proposes a kind of phenomenological analysis of the act of reading the Bible as Scripture with the goal of bringing to light the theoretical commitments which it implicitly demands. This sort of analysis can prove helpful for the continuing disputes among Protestants, Catholics, and Orthodox insofar as it is relevant for one of the principal points of controversy between them: namely, the relationship between Scripture, Tradition, and Church as theological authorities. It proceeds by analyzing both the objective and subjective ‘poles’ of the act, and it illuminates the presence of the Church and her Tradition on both sides. The Church—i.e., the community of God’s people—is both that which is immediately encountered in the text, as well as the factor which enables scriptural reading in the first place. The article terminates with an application of the insights of the preceding discussion to the controversy about icons.

In a study to evaluate the drug treatment and aftercare efforts sponsored by the State Department's International Narcotics and Law Enforcement Affairs Bureau, residential Therapeutic Community (TC) treatment programs in three countries in Southeast Asia-Malaysia, Singapore, and Thailand-were examined to identify promising practices and to assess lessons learned. Based on field visits, in-person interviews, focus groups, and document analyses, the authors recommend the following promising practices for replication: (1) structured treatment environment tailored to meet cultural norms; (2) successful collaboration among training networks and agencies; (3) utilization of an active volunteer community; (4) inclusion of vocational training to facilitate successful reintegration; (5) use of religion to enhance treatment resident growth; (6) inclusion of family in the treatment process; and, (7) establishment of a systematic program re-entry process. [ABSTRACT FROM AUTHOR]

This paper describes a research project sponsored and funded by the State Department's Bureau of International Narcotics and Affairs (INL) on substance abuse and treatment in ten countries. The purpose of the study was to identify promising practices in drug treatment in Europe, Latin America, and Southeast Asia. The steps taken to complete this evaluation are described, including the instruments used and the types of data collected. Also discussed are translation and communication issues as well as examples of other challenges of international evaluation and how these challenges were overcome by the evaluation team. [ABSTRACT FROM AUTHOR]

This essay discusses the nature and relative priority of the sources for analytic theology with an eye to the manner in which the analytic theologian ought to orient herself to them. Of Tradition, Scripture, and (analytic) philosophy, the Tradition of the Church has ultimate priority as analytic-theological source insofar as it infallibly mediates the genuine, divinely revealed content of Scripture and justifies the utilization of analytic philosophy for theological purposes. The argument proposes a fundamental gap between the biblical text, which can be held in the hands and read, and Scripture, which is the revealed content communicated by the former and grasped by the intellect of the reader. Because of this gap, it is possible to be quite familiar with the biblical text and yet remain ignorant of Scripture, of the revealed truth of God. The Tradition of the Church functions as the bridge by which this “grand canyon” becomes crossable by offering normative interpretations of the biblical text. Consequently, the analytic theologian ought to be a committed adherent of this Tradition above all, making it the measure of all other things. This same Tradition also provides the theoretical justification for the appeal to (analytic) philosophy in the performance of the analytic theologian’s task through its teaching about the fundamental openness of the world to God, i.e. the world’s capacity to serve as medium for the divine-human dialog.

There is much controversy among social scientists and clinicians over the proper measurement of antisocial personality disorder (ASPD). The degree to which various diagnostic measures differ in their assessment of ASPD among substance abusers is not known. This study assessed the degree of agreement between a semistructured clinical interview and a self-report inventory on a diagnosis of ASPD among substance abusers. The Structured Clinical Interview for DSM-III-R (SCID-II), a clinically generated instrument, and the Millon Clinical Multiaxial Inventory (MCMI-II), a self-report inventory, were administered to 275 clients randomly assigned to two therapeutic communities (TCs). Based on the limited existing literature, it was hypothesized that there would be minimal agreement between the diagnosis of ASPD by the two scales. This hypothesis was supported. The kappa statistic indicated low agreement between the scales (kappa = 0.27), with the MCMI-II diagnosing ASPD more often than the SCID-II. The low agreement on a diagnosis of ASPD may be due to the different types of information collected by the two scales. The SCID-II emphasizes observable behavioral criteria, while the MCMI-II emphasizes pathological personality traits. The focus of the MCMI-II on pathological personality traits may more accurately diagnose ASPD in substance-abusing populations in which the majority of the clients have extensive criminal histories. Definite conclusions regarding the proper measurement of ASPD in substance-abusing samples is difficult without additional empirical evidence. [ABSTRACT FROM AUTHOR]

This study compared factors that predict treatment outcomes in men and women randomly assigned to two therapeutic communities differing primarily in length of inpatient and outpatient treatment. Based on the prior research literature comparing treatment outcomes of men and women, we formulated the following research question: Do factors that predict drug use at follow-up, postdischarge arrest, and employment at follow-up differ for men and women? Self-reports and objective measures of criminal activity and substance abuse were collected at pre- and posttreatment interviews. Separate regression analyses were conducted for men and women for each of the three outcome variables. The results showed that the predictors of outcome for men and women were similar. Clients who completed the 12-month treatment programs had better outcomes regardless of gender. Men and women who completed treatment were characterized at follow-up by substantial reductions in drug use and arrests and by increased employment. Results further suggested that the longer residential treatment program had a particularly beneficial impact on women. Number of prior arrests was also associated with postdischarge outcomes for women. Women with more arrests at admission were more likely to have a postdischarge arrest and less likely to be employed at follow-up. This finding provides invaluable information about which women may be at greater risk for relapse and in need of additional services. We conclude that completion of treatment is the key predictor of treatment outcomes for both men and women. [ABSTRACT FROM AUTHOR]

Abstract Background Previously, we performed analysis of gene expression in 46 axillary lymph node negative tumors and identified molecular gene signatures that resulted in different clinical outcomes. The aim of this study was to determine the correlation of γ-glutamyl hydrolase (GGH), fatty acid amide hydrolase (FAAH), Pirin (PIR) and TAF5-like RNA polymerase II, p300/CBP-associated factor (PCAF)-associated factor, 65 kDa (TAF5L), selected from identified gene signatures, with clinical outcomes as well as classical clinicopathological characteristics in primary invasive breast cancer patients. Methods The protein levels of GGH, FAAH, PIR and TAF5L were assessed by immunohistochemistry (IHC) on a panel of 80 primary invasive breast tumors. Quantitative real-time PCR (qRT-PCR) and western blot analysis were performed to verify the expression levels of the candidate biomarkers. Patient disease-specific survival (DSS) and recurrence-free survival (RFS) were evaluated using the Kaplan-Meier method. The prognostic biomarkers were identified by univariate analysis with a log-rank test and by multivariate analysis with Cox proportional hazards regression models. Results The GGH and FAAH protein levels were significantly up-regulated in invasive breast cancer tumors compared with adjacent non-cancerous tissues. Furthermore, the protein levels of GGH and FAAH were significantly correlated in tumor tissues. Tumoral GGH protein expression was significantly correlated with shorter DSS and RFS. Furthermore, the protein expression of GGH was positively correlated with undifferentiated tumors (BRE grade III) and ER/PR expressing tumors. Multivariate regression analysis showed that only GGH protein expression independently predicts DSS. No such correlations were found for FAAH, PIR and TAF5L protein expression. However, elevated protein levels of FAAH were positively associated with high number of lymph node involvement and upregulated levels of PIR were positively related with lymph node metastasis. The TAF5L was pronouncedly down-regulated in primary invasive breast cancer tissues compared to matched adjacent non-cancerous tissues. Conclusion These data show for the first time that cytoplasmic GGH might play a relevant role in the development and progression of invasive breast cancer, warranting further investigations. Our findings suggest that GGH serve as a potential biomarker of unfavorable clinical outcomes over short-term follow-up in breast cancer. The GGH may be a very attractive targeted therapy for selected patients.

Abstract Background Breast cancer is a potentially fatal malignancy in females despite the improvement in therapeutic techniques. The identification of novel molecular signatures is needed for earlier detection, monitoring effects of treatment, and predicting prognosis. We have previously used microarray analysis to identify differentially expressed genes in aggressive breast tumors. The purpose of the present study was to investigate the prognostic value of the candidate biomarkers CCNB2, ASPM, CDCA7, KIAA0101, and SLC27A2 in breast cancer. Methods The expression levels and subcellular localization of the CCNB2, ASPM, CDCA7, KIAA0101, and SLC27A2 proteins were measured using immunohistochemistry (IHC) on a panel of 80 primary invasive breast tumors. Furthermore, the mRNA levels of CCNB2, KIAA0101, and SLC27A2 were subsequently examined by qRT-PCR to validate IHC results. Patient disease-specific survival (DSS) was evaluated in correlation to protein levels using the Kaplan-Meier method. Multivariate Cox regression analysis was used to determine the impact of aberrant protein expression of the candidate biomarkers on patient DSS and to estimate the hazard ratio at 8-year follow-up. Results Elevated cytoplasmic CCNB2 protein levels were strongly associated with short-term disease-specific survival of breast cancer patients (≤ 8 years; PP= 0.04). However, no association with other clinicopathological parameters was observed. Multivariate Cox regression analysis specified that CCNB2 protein expression is an independent prognostic marker of DSS in breast cancer. The predictive ability of several classical clinicopathological parameters was improved when used in conjunction with CCNB2 protein expression (C-index = 0.795) in comparison with a model without CCNB2 expression (C-index = 0.698). The protein levels of ASPM, CDCA7, KIAA0101, and SLC27A2 did not correlate with any clinicopathological parameter and had no influence on DSS. However, a significant correlation between the expression of the CCNB2 and ASPM proteins was detected (P = 0.03). Conclusion These findings suggest that cytoplasmic CCNB2 may function as an oncogene and could serve as a potential biomarker of unfavorable prognosis over short-term follow-up in breast cancer.

Abstract Background Automatic variable selection methods are usually discouraged in medical research although we believe they might be valuable for studies where subject matter knowledge is limited. Bayesian model averaging may be useful for model selection but only limited attempts to compare it to stepwise regression have been published. We therefore performed a simulation study to compare stepwise regression with Bayesian model averaging. Methods We simulated data corresponding to five different data generating processes and thirty different values of the effect size (the parameter estimate divided by its standard error). Each data generating process contained twenty explanatory variables in total and had between zero and two true predictors. Three data generating processes were built of uncorrelated predictor variables while two had a mixture of correlated and uncorrelated variables. We fitted linear regression models to the simulated data. We used Bayesian model averaging and stepwise regression respectively as model selection procedures and compared the estimated selection probabilities. Results The estimated probability of not selecting a redundant variable was between 0.99 and 1 for Bayesian model averaging while approximately 0.95 for stepwise regression when the redundant variable was not correlated with a true predictor. These probabilities did not depend on the effect size of the true predictor. In the case of correlation between a redundant variable and a true predictor, the probability of not selecting a redundant variable was 0.95 to 1 for Bayesian model averaging while for stepwise regression it was between 0.7 and 0.9, depending on the effect size of the true predictor. The probability of selecting a true predictor increased as the effect size of the true predictor increased and leveled out at between 0.9 and 1 for stepwise regression, while it leveled out at 1 for Bayesian model averaging. Conclusions Our simulation study showed that under the given conditions, Bayesian model averaging had a higher probability of not selecting a redundant variable than stepwise regression and had a similar probability of selecting a true predictor. Medical researchers building regression models with limited subject matter knowledge could thus benefit from using Bayesian model averaging.

Abstract Background Previous studies have shown that the ADIPOR1, ADORA1, BTG2 and CD46 genes differ significantly between long-term survivors of breast cancer and deceased patients, both in levels of gene expression and DNA copy numbers. The aim of this study was to characterize the expression of the corresponding proteins in breast carcinoma and to determine their correlation with clinical outcome. Methods Protein expression was evaluated using immunohistochemistry in an independent breast cancer cohort of 144 samples represented on tissue microarrays. Fisher's exact test was used to analyze the differences in protein expression between dead and alive patients. We used Cox-regression multivariate analysis to assess whether the new markers predict the survival status of the patients better than the currently used markers. Results BTG2 expression was demonstrated in a significantly lower proportion of samples from dead patients compared to alive patients, both in overall expression (P = 0.026) and cell membrane specific expression (P = 0.013), whereas neither ADIPOR1, ADORA1 nor CD46 showed differential expression in the two survival groups. Furthermore, a multivariate analysis showed that a model containing BTG2 expression in combination with HER2 and Ki67 expression along with patient age performed better than a model containing the currently used prognostic markers (tumour size, nodal status, HER2 expression, hormone receptor status, histological grade, and patient age). Interestingly, BTG2 has previously been described as a tumour suppressor gene involved in cell cycle arrest and p53 signalling. Conclusions We conclude that high-level BTG2 protein expression correlates with prolonged survival in patients with breast carcinoma.

Abstract Background In epidemiological studies researchers use logistic regression as an analytical tool to study the association of a binary outcome to a set of possible exposures. Methods Using a simulation study we illustrate how the analytically derived bias of odds ratios modelling in logistic regression varies as a function of the sample size. Results Logistic regression overestimates odds ratios in studies with small to moderate samples size. The small sample size induced bias is a systematic one, bias away from null. Regression coefficient estimates shifts away from zero, odds ratios from one. Conclusion If several small studies are pooled without consideration of the bias introduced by the inherent mathematical properties of the logistic regression model, researchers may be mislead to erroneous interpretation of the results.

Abstract Background In this paper, we show how counselors and psychologists can use emails for online management of substance abusers, including the anatomy and content of emails that clinicians should send substance abusers. Some investigators have attempted to determine if providing mental health services online is an efficacious delivery of treatment. The question of efficacy is an empirical issue that cannot be settled unless we are explicitly clear about the content and nature of online treatment. We believe that it is not the communications via internet that matters, but the content of these communications. The purpose of this paper is to provide the content of our online counseling services so others can duplicate the work and investigate its efficacy. Results We have managed nearly 300 clients online for recovery from substance abuse. Treatment included individual counseling (motivational interviewing, cognitive-behavior therapy, relapse prevention assignments), participation in an electronic support group and the development of a recovery team. Our findings of success with these interventions are reported elsewhere. Our experience has led to development of a protocol of care that is described more fully in this paper. This protocol is based on stages of change and relapse prevention theories and follows a Motivational Interviewing method of counseling. Conclusion The use of electronic media in providing mental health treatment remains controversial due to concerns about confidentiality, security and legal considerations. More research is needed to validate and generalize the use of online treatment for mental health problems. If researchers have to build on each others work, it is paramount that we share our protocols of care, as we have done in this paper.

Background: In epidemiological studies researchers use logistic regression as an analytical tool to study the association of a binary outcome to a set of possible exposures.Methods: Using a simulation study we illustrate how the analytically derived bias of odds ratios modelling in logistic regression varies as a function of the sample size.Results: Logistic regression overestimates odds ratios in studies with small to moderate samples size. The small sample size induced bias is a systematic one, bias away from null. Regression coefficient estimates shifts away from zero, odds ratios from one.Conclusion: If several small studies are pooled without consideration of the bias introduced by the inherent mathematical properties of the logistic regression model, researchers may be mislead to erroneous interpretation of the results. [ABSTRACT FROM AUTHOR]

This study examines the efficacy of providing Enhanced Abbreviated or Standard Inpatient treatment and Outpatient treatment to drug-abusing clients. The experiment randomly assigned 412 clients to two therapeutic community programs, which differed primarily in planned duration. This study addressed limitations of prior research, as it used random assignment of clients to treatment programs, achieved high follow-up rates and used objective measures of drug use and criminal history. Self-reports and objective measures of criminal activity and substance abuse were collected at pre- and posttreatment interviews. Completing the entire 12-month program (inpatient and outpatient) was more important than duration of inpatient program attended. Regardless of program, completers had substantial reductions in posttreatment drug abuse and arrests. A 12-month course of treatment including at least 6 months in a therapeutic community followed by outpatient treatment can produce marked reductions in drug abuse and crime among persons who complete both phases. [ABSTRACT FROM AUTHOR]

Aims: Corticosteroids are the treatment of choice for many inflammatory diseases but often lead to adverse effects, including hyperglycaemia. This study investigated the mechanisms driving differential effects on glucose control for AZD9567, an oral nonsteroidal selective glucocorticoid receptor modulator vs. prednisolone in 46 patients with type 2 diabetes mellitus., Methods: In this randomized, double-blind, 2-way cross-over study (NCT04556760), participants received either AZD9567 72 mg and prednisolone 40 mg daily (cohort 1); AZD9567 40 mg and prednisolone 20 mg daily (cohort 2); or placebo and prednisolone 5 mg daily (cohort 3). Treatment duration was 3 days with a 3-week washout between treatment periods. Glycaemic control was assessed after a standardized meal and with continuous glucose monitoring., Results: A significant difference between AZD9567 and prednisolone in favour of AZD9567 was observed for the change from baseline to Day 4 glucose excursions postmeal in cohort 1 (glucose area under the curve from 0 to 4 h -4.54%; 95% confidence interval [CI]: -8.88, -0.01; P = .049), but not in cohort 2 (-5.77%; 95% CI: -20.92, 12.29; P = .435). In cohort 1, significant differences between AZD9567 and prednisolone were also seen for the change from baseline to day 4 in insulin and glucagon secretion postmeal (P < .001 and P = .005, respectively) and change from baseline to Day 4 in GLP-1 response (P = .022). Significant differences between AZD9567 and prednisolone for 24-h glucose control were observed for both cohort 1 (-1.507 mmol/L; 95% CI: -2.0820, -0.9314; P < .001) and cohort 2 (-1.110 mmol/L; 95% CI -1.7257, -0.4941; P < .001)., Conclusion: AZD9567 significantly reduced treatment-induced hyperglycaemia compared with prednisolone., (© 2024 British Pharmacological Society.)

Background: Posterior cortical atrophy is a rare syndrome characterised by early, prominent, and progressive impairment in visuoperceptual and visuospatial processing. The disorder has been associated with underlying neuropathological features of Alzheimer's disease, but large-scale biomarker and neuropathological studies are scarce. We aimed to describe demographic, clinical, biomarker, and neuropathological correlates of posterior cortical atrophy in a large international cohort., Methods: We searched PubMed between database inception and Aug 1, 2021, for all published research studies on posterior cortical atrophy and related terms. We identified research centres from these studies and requested deidentified, individual participant data (published and unpublished) that had been obtained at the first diagnostic visit from the corresponding authors of the studies or heads of the research centres. Inclusion criteria were a clinical diagnosis of posterior cortical atrophy as defined by the local centre and availability of Alzheimer's disease biomarkers (PET or CSF), or a diagnosis made at autopsy. Not all individuals with posterior cortical atrophy fulfilled consensus criteria, being diagnosed using centre-specific procedures or before development of consensus criteria. We obtained demographic, clinical, biofluid, neuroimaging, and neuropathological data. Mean values for continuous variables were combined using the inverse variance meta-analysis method; only research centres with more than one participant for a variable were included. Pooled proportions were calculated for binary variables using a restricted maximum likelihood model. Heterogeneity was quantified using I 2 ., Findings: We identified 55 research centres from 1353 papers, with 29 centres responding to our request. An additional seven centres were recruited by advertising via the Alzheimer's Association. We obtained data for 1092 individuals who were evaluated at 36 research centres in 16 countries, the other sites having not responded to our initial invitation to participate to the study. Mean age at symptom onset was 59·4 years (95% CI 58·9-59·8; I 2 =77%), 60% (56-64; I 2 =35%) were women, and 80% (72-89; I 2 =98%) presented with posterior cortical atrophy pure syndrome. Amyloid β in CSF (536 participants from 28 centres) was positive in 81% (95% CI 75-87; I 2 =78%), whereas phosphorylated tau in CSF (503 participants from 29 centres) was positive in 65% (56-75; I 2 =87%). Amyloid-PET (299 participants from 24 centres) was positive in 94% (95% CI 90-97; I 2 =15%), whereas tau-PET (170 participants from 13 centres) was positive in 97% (93-100; I 2 =12%). At autopsy (145 participants from 13 centres), the most frequent neuropathological diagnosis was Alzheimer's disease (94%, 95% CI 90-97; I 2 =0%), with common co-pathologies of cerebral amyloid angiopathy (71%, 54-88; I 2 =89%), Lewy body disease (44%, 25-62; I 2 =77%), and cerebrovascular injury (42%, 24-60; I 2 =88%)., Interpretation: These data indicate that posterior cortical atrophy typically presents as a pure, young-onset dementia syndrome that is highly specific for underlying Alzheimer's disease pathology. Further work is needed to understand what drives cognitive vulnerability and progression rates by investigating the contribution of sex, genetics, premorbid cognitive strengths and weaknesses, and brain network integrity., Funding: None., Competing Interests: Declaration of interests MC received research support from the Fonds de Recherche du Québec–Santé (FRQS). MF, FA, EC, FC, and GM receive research support from the Foundation Research on Alzheimer Disease and Italian Ministry of Healthy (#GR-2010-2303035). MEM receives research support from the NIH (R01 AG054449, R01 AG075802, U01-AG057195 and P30 AG062677). Data from Mayo Clinic (Jacksonville) was supported by the State of Florida Alzheimer's Disease Initiative and the Mayo Clinic Alzheimer's Disease Research Center. BD receives research funding from NIA R21-AG051987, P50-AG005134, and R01-DC014296 and philanthropic funding to the MGH FTD Unit including the Mooney Family Fund. KY is an Etherington posterior cortical atrophy Senior Research Fellow and is funded by the Alzheimer's Society, grant number 453 (AS-JF-18-003). The work was also supported by an Alzheimer's Research UK Senior Research Fellowship and ESRC/NIHR (ES/L001810/1) grant to SC. JMS acknowledges the support of the National Institute for Health Research University College London Hospitals Biomedical Research Centre, ARUK (ARUK-PG2017–1946), Weston Brain Institute (UB170045), Medical Research Council, and British Heart Foundation. TL is supported by an Alzheimer's Research UK senior fellowship. The Queen Square Brain Bank is supported by the Reta Lila Weston Institute for Neurological Studies and the Medical Research Council. The Dementia Research Centre is supported by Alzheimer's Research UK, Brain Research Trust, and The Wolfson Foundation. This work was also supported by the NIHR Queen Square Dementia Biomedical Research Unit, and the NIHR UCL/H Biomedical Research Centre. This work was supported by the MRC Dementia Platform UK and the UK Dementia Research Institute at UCL, which receives its funding from UK DRI, funded by the UK Medical Research Council, Alzheimer's Society and Alzheimer's Research UK. DG, AH, and GL receive research support from Shiley-Marcos ADRC P30 AG062429. KJ, JW, and JGR receive research funding from the NIH (R01-AG50603). BDCB receives funding from Alzheimer Nederland (#WE.15-2019-13, WE.03-2021-15, and #WE.06-2023-01). MM, JR, and KA were supported by the NIHR Cambridge Biomedical Research Centre including the Cambridge Brain Bank (BRC-1215-20014. The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care) and the Race Against Dementia. M.F.M. receives research support from the NIA (1RF1AG050967). RM is supported by France Alzheimer, Fondation Recherche Alzheimer, Philippe Chatrier Foundation and by Rosita Gomez Association. OH has acquired research support (for the institution) from ADx, AVID Radiopharmaceuticals, Biogen, Eli Lilly, Eisai, Fujirebio, GE Healthcare, Pfizer, and Roche and has received consultancy or speaker fees from AC Immune, Amylyx, Alzpath, BioArctic, Biogen, Cerveau, Fujirebio, Genentech, Novartis, Roche, and Siemens. Work at the Lund University was supported by the Swedish Research Council (2016-00906), the Knut and Alice Wallenberg foundation (2017-0383), the Marianne and Marcus Wallenberg foundation (2015·0125), the Strategic Research Area MultiPark (Multidisciplinary Research in Parkinson's disease) at Lund University, the Swedish Alzheimer Foundation (AF-939932), the Swedish Brain Foundation (FO2021-0293), The Parkinson foundation of Sweden (1280/20), the Konung Gustaf V:s och Drottning Victorias Frimurarestiftelse, the Skåne University Hospital Foundation (2020-O000028), Regionalt Forskningsstöd (2020-0314), and the Swedish federal Government under the ALF agreement (2018-Projekt0279). PN is supported by The Mater Foundation. DP, SPC, and GT are supported by The Italian Ministry of Health (Ricerca Finalizzata Progetto Reti Nazionale AD NET-2011-02346784). OP, NC, JB, JH, and DF were supported by funding to ForeFront, a collaborative research group dedicated to the study of frontotemporal dementia and motor neuron disease, from the National Health and Medical Research Council (NHMRC) (GNT1037746) and the Australian Research Council (ARC) Centre of Excellence in Cognition and its Disorders Memory Program (CE11000102). OP is supported by an NHMRC Leadership Fellowship (GNT2008020). LA receives research support from Indiana Alzheimer's Disease Research Center (P30 AG010133 and LEADS (U01AG6057195). ER, SW, and MM received research support from the NIH (P30AG13854 and P30AG072977). BDCB receives funding from Alzheimer Nederland (#WE.15-2019-13, WE.03-2021-15, and #WE.06-2023-01). Data from Geneva was supported by Alzheimer's Disease Research Center (ADRC) grants (NIA P50 AG005138 and P30 AG066514). Data from Xuanwu Hospital was supported by the National Natural Science Foundation of China (81971011) and Beijing Municipal Science and Technology Committee (7202060). Research of Alzheimer Center Amsterdam has been funded by ZonMW, NWO, EU-FP7, EU-JPND, Alzheimer Nederland, Hersenstichting CardioVascular Onderzoek Nederland, Health Holland, Topsector Life Sciences & Health, stichting Dioraphte, Gieskes-Strijbis fonds, stichting Equilibrio, Edwin Bouw fonds, Pasman stichting, stichting Alzheimer & Neuropsychiatrie Foundation, Philips, Biogen MA, Novartis-NL, Life-MI, AVID, Roche BV, Fujifilm, and Combinostics. Data from Penn Frontotemporal Degeneration Center was funded by NIH grants (R01-AG054519 and K01-AG061277). Data from MASS's group comes from The Sant Pau Initiative on Neurodegeneration cohort. LTG receives research support from the NIH (K24053435) and R01AG075802. GDR receives research support from the NIH/NIA (R35 AG072362, P30-AG062422, U01-AG057195, and P01-AG019724). Other support to GDR includes National Institute of Neurological Disorders and Stroke, Alzheimer's Association, American College of Radiology, Rainwater Charitable Foundation, Shanendoah Foundation, Avid Radiopharmaceuticals, GE Healthcare, Life Molecular Imaging, and Genentech. LA has received personal compensation for serving as a consultant for Biogen, Two Labs, FL Dept Health, Genentech, NIH Biobank, Eli Lilly, GE Healthcare, Eisai, and Roche Diagnostics and for serving on a Data Safety and Monitoring Board for IQVIA. LA receives research support from the National Institute on Aging, the Alzheimer's Association, Roche Diagnostics, AVID radiopharmaceuticals, Life Molecular Imaging, and Eli Lilly. MFM is the section editor for Behavioral Neurology for UpToDate. JGR serves on the Drug Safety Monitoring Board for the National Institute of Neurological Disorders and Stroke StrokeNET. KAJ is an Associate Editor for Annals of Clinical and Translational Neurology and is on the editorial boards of Journal of Neurology, Acta Neuropathologica, and Neuropathology and Applied Neurobiology. JLW is an Associate Editor for Brain Connectivity and Journal of Alzheimer's Disease. RO has received research support from Avid Radiopharmaceuticals, has given lectures in symposia sponsored by GE Healthcare and is an editorial board member of Alzheimer's Research & Therapy and the European Journal of Nuclear Medicine and Molecular Imaging. FA is Associate Editor of NeuroImage: Clinical, has received speaker honoraria from Biogen Idec, Italfarmaco, Roche and Zambon, and receives or has received research supports from the Italian Ministry of Health, the Italian Ministry of University and Research, AriSLA (Fondazione Italiana di Ricerca per la SLA), and the European Research Council and Foundation Research on Alzheimer Disease. MF is Editor-in-Chief of the Journal of Neurology, Associate Editor of Human Brain Mapping, Neurological Sciences, and Radiology; received compensation for consulting services from Alexion, Almirall, Biogen, Merck, Novartis, Roche, and Sanofi; speaking activities from Bayer, Biogen, Celgene, Chiesi Italia SpA, Eli Lilly, Genzyme, Janssen, Merck-Serono, Neopharmed Gentili, Novartis, Novo Nordisk, Roche, Sanofi, Takeda, and TEVA; participation in Advisory Boards for Alexion, Biogen, Bristol-Myers Squibb, Merck, Novartis, Roche, Sanofi, Sanofi-Aventis, Sanofi-Genzyme, and Takeda; scientific direction of educational events for Biogen, Merck, Roche, Celgene, Bristol-Myers Squibb, Lilly, Novartis, and Sanofi-Genzyme; and receives research support from Biogen Idec, Merck-Serono, Novartis, Roche, Italian Ministry of Health, and Fondazione Italiana Sclerosi Multipla. GDR has served on Scientific Advisory Boards for Alector, Eli Lilly, Genentech, Merck, and Roche. He serves on a Data Safety and Monitoring Board for Johnson & Johnson. He is an Associate Editor for JAMA Neurology. The 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.)

Oral corticosteroid use is limited by side effects, some caused by off-target actions on the mineralocorticoid receptor that disrupt electrolyte balance. AZD9567 is a selective, nonsteroidal glucocorticoid receptor modulator. The efficacy, safety, and tolerability of AZD9567 and prednisolone were assessed in a phase IIa study. Anti-inflammatory mechanism of action was also evaluated in vitro in monocytes from healthy donors. In this randomized, double-blind, parallel-group, multicenter study, patients with active rheumatoid arthritis were randomized 1:1 to AZD9567 40 mg or prednisolone 20 mg once daily orally for 14 days. The primary end point was change from baseline in DAS28-CRP at day 15. Secondary end points included components of DAS28-CRP, American College of Rheumatology (ACR) response criteria (ACR20, ACR50, and ACR70), and safety end points, including serum electrolytes. Overall, 21 patients were randomized to AZD9567 (n = 11) or prednisolone (n = 10), and all completed the study. As anticipated, AZD9567 had a similar efficacy profile to prednisolone, with no clinically meaningful (i.e., >1.0) difference in change from baseline to day 15 in DAS28-CRP between AZD9567 and prednisolone (least-squares mean difference: 0.47, 95% confidence interval: -0.49 to 1.43). Similar results were observed for the secondary efficacy end points. In vitro transcriptomic analysis showed that anti-inflammatory responses were similar for AZD9567, prednisolone, and dexamethasone. Unlike prednisolone, AZD9567 had no effect on the serum sodium:potassium ratio. The safety profile was not different from that of prednisolone. Larger studies of longer duration are required to determine whether AZD9567 40 mg may in the future be an alternative to prednisolone in patients with inflammatory disease., (© 2023 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Objective: Investigation of learning slopes in early-onset dementias has been limited. The current study aimed to highlight the sensitivity of learning slopes to discriminate disease severity in cognitively normal participants and those diagnosed with early-onset dementia with and without β-amyloid positivity METHOD: Data from 310 participants in the Longitudinal Early-Onset Alzheimer's Disease Study (aged 41 to 65) were used to calculate learning slope metrics. Learning slopes among diagnostic groups were compared, and the relationships of slopes with standard memory measures were determined RESULTS: Worse learning slopes were associated with more severe disease states, even after controlling for demographics, total learning, and cognitive severity. A particular metric-the learning ratio (LR)-outperformed other learning slope calculations across analyses CONCLUSIONS: Learning slopes appear to be sensitive to early-onset dementias, even when controlling for the effect of total learning and cognitive severity. The LR may be the learning measure of choice for such analyses., Highlights: Learning is impaired in amyloid-positive EOAD, beyond cognitive severity scores alone. Amyloid-positive EOAD participants perform worse on learning slopes than amyloid-negative participants. Learning ratio appears to be the learning metric of choice for EOAD participants., (© 2023 the Alzheimer's Association.)

Introduction: We used sex and apolipoprotein E ε4 (APOE ε4) carrier status as predictors of pathologic burden in early-onset Alzheimer's disease (EOAD)., Methods: We included baseline data from 77 cognitively normal (CN), 230 EOAD, and 70 EO non-Alzheimer's disease (EOnonAD) participants from the Longitudinal Early-Onset Alzheimer's Disease Study (LEADS). We stratified each diagnostic group by males and females, then further subdivided each sex by APOE ε4 carrier status and compared imaging biomarkers in each stratification. Voxel-wise multiple linear regressions yielded statistical brain maps of gray matter density, amyloid, and tau PET burden., Results: EOAD females had greater amyloid and tau PET burdens than males. EOAD female APOE ε4 non-carriers had greater amyloid PET burdens and greater gray matter atrophy than female ε4 carriers. EOnonAD female ε4 non-carriers also had greater gray matter atrophy than female ε4 carriers., Discussion: The effects of sex and APOE ε4 must be considered when studying these populations., Highlights: Novel analysis examining the effects of biological sex and apolipoprotein E ε4 (APOE ε4) carrier status on neuroimaging biomarkers among early-onset Alzheimer's disease (EOAD), early-onset non-AD (EOnonAD), and cognitively normal (CN) participants. Female sex is associated with greater pathology burden in the EOAD cohort compared to male sex. The effect of APOE ε4 carrier status on pathology burden was the most impactful in females across all cohorts., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Cephalopods are remarkable among invertebrates for their cognitive abilities, adaptive camouflage, novel structures, and propensity for recoding proteins through RNA editing. Due to the lack of genetically tractable cephalopod models, however, the mechanisms underlying these innovations are poorly understood. Genome editing tools such as CRISPR-Cas9 allow targeted mutations in diverse species to better link genes and function. One emerging cephalopod model, Euprymna berryi, produces large numbers of embryos that can be easily cultured throughout their life cycle and has a sequenced genome. As proof of principle, we used CRISPR-Cas9 in E. berryi to target the gene for tryptophan 2,3 dioxygenase (TDO), an enzyme required for the formation of ommochromes, the pigments present in the eyes and chromatophores of cephalopods. CRISPR-Cas9 ribonucleoproteins targeting tdo were injected into early embryos and then cultured to adulthood. Unexpectedly, the injected specimens were pigmented, despite verification of indels at the targeted sites by sequencing in injected animals (G0s). A homozygote knockout line for TDO, bred through multiple generations, was also pigmented. Surprisingly, a gene encoding indoleamine 2,3, dioxygenase (IDO), an enzyme that catalyzes the same reaction as TDO in vertebrates, was also present in E. berryi. Double knockouts of both tdo and ido with CRISPR-Cas9 produced an albino phenotype. We demonstrate the utility of these albinos for in vivo imaging of Ca 2+ signaling in the brain using two-photon microscopy. These data show the feasibility of making gene knockout cephalopod lines that can be used for live imaging of neural activity in these behaviorally sophisticated organisms., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: We studied the effect of apolipoprotein E (APOE) ε4 status and sex on rates of cognitive decline in early- (EO) and late- (LO) onset Alzheimer's disease (AD)., Method: We ran mixed-effects models with longitudinal cognitive measures as dependent variables, and sex, APOE ε4 carrier status, and interaction terms as predictor variables in 998 EOAD and 2562 LOAD participants from the National Alzheimer's Coordinating Center., Results: APOE ε4 carriers showed accelerated cognitive decline relative to non-carriers in both EOAD and LOAD, although the patterns of specific cognitive domains that were affected differed. Female participants showed accelerated cognitive decline relative to male participants in EOAD only. The effect of APOE ε4 was greater in EOAD for executive functioning (p < 0.0001) and greater in LOAD for language (p < 0.0001)., Conclusion: We found APOE ε4 effects on cognitive decline in both EOAD and LOAD and female sex in EOAD only. The specific patterns and magnitude of decline are distinct between the two disease variants., Highlights: Apolipoprotein E (APOE) ε4 carrier status and sex differentiate rates of cognitive decline in early-onset (EO) and late-onset (LO) Alzheimer's disease (AD). APOE ε4 in EOAD accelerated decline in memory, executive, and processing speed domains. Female sex in EOAD accelerated decline in language, memory, and global cognition. The effect of APOE ε4 was stronger for language in LOAD and for executive function in EOAD. Sex effects on language and executive function decline differed between EOAD and LOAD., (© 2022 the Alzheimer's Association.)

Introduction: Ovarian cancer (OC) is the leading cause of gynecological cancer-related death. Of the main OC histologic subtypes, invasive mucinous carcinomas (MC) account for only 3% of OC cases and are frequently associated with favorable prognosis. Nevertheless, MCs differ greatly from the other OC histotypes in clinical, pathological, and biological behavior. However, the origin and molecular pathogenesis of MC are not yet fully understood. Therefore, identification of novel diagnostic markers could potentially facilitate early diagnosis of OC, particularly the MC histotype, thereby leading to the development of histotype-specific treatment regimens and improved survival rates., Methods: In the present study, Trefoil factor gene family members (TFF1, TFF2 and TFF3) were identified as MC histotype-specific biomarkers using RNA sequencing (RNA-seq) data for 95 stage I-II OCs. The diagnostic value of TFF1, TFF2 and TFF3 was then evaluated by immunohistochemistry on 206 stage I-II OCs stratified by histotype (high-grade serous carcinoma [HGSC], endometrioid carcinoma [EC], clear cell carcinoma [CCC], and MC)., Results: We showed significantly elevated intracytoplasmic protein expression levels for TFF1, TFF2 and TFF3 in MC samples, thereby revealing an association between expression of Trefoil factor gene family members and the MC histotype. Taken together, these findings suggest that the TFF proteins may play a pivotal role in tumor initiation and progression for the MC histotype., Conclusion: Taken together, these findings suggest that the TFF proteins may play a pivotal role in tumor initiation and progression for the MC histotype. Moreover, these novel histotype-specific diagnostic biomarkers may not only improve patient stratification of early-stage ovarian carcinomas but may also be candidates for the development of molecular targeted therapies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Werner Rönnerman, Pettersson, Nemes, Dahm-Kähler, Kovács, Karlsson, Parris and Helou.)

Objectives: To assess the risk of new-onset or worsening hyperglycaemia, hypertension, weight gain and hyperlipidaemia with systemic corticosteroid therapy (CST) as reported in published randomised control trial (RCT) studies., Data Sources: Literature search using MEDLINE, EMBASE, Cochrane library, Web of Science and Scopus STUDY ELIGIBILITY CRITERIA: Published articles on results of RCT with a systemic CST arm with numerical data presented on adverse effect (AE)., Participants and Interventions: Reports of hyperglycaemia, hypertension, weight gain and hyperlipidaemia associated with systemic CST in patients or healthy volunteer's ≥17 years of age., Study Appraisal Methods: Risk of bias tool, assessment at the level of AE and key study characteristics., Results: A total of 5446 articles were screened to include 118 studies with 152 systemic CST arms (total participants=17 113 among which 8569 participants treated with CST). Pooled prevalence of hyperglycaemia in the CST arms within the studies was 10% (95% CI 7% to 14%), with the highest prevalence in respiratory illnesses at 22% (95% CI 9% to 35%). Pooled prevalence of severe hyperglycaemia, hypertension, weight gain and hyperlipidaemia within the corticosteroid arms was 5% (95% CI 2% to 9%), 6% (95% CI 4% to 8%), 13% (95% CI 8% to 18%), 8% (95% CI 4% to 17%), respectively. CST was significantly associated hyperglycaemia, hypertension and weight gain as noted in double-blinded placebo-controlled parallel-arms studies: OR of 2.13 (95% CI 1.66 to 2.72), 1.68 (95% CI 0.96 to 2.95) and 5.20 (95% CI 2.10 to 12.90), respectively. Intravenous therapy posed higher risk than oral therapy: OR of 2.39 (95% CI 1.16 to 4.91)., Limitations: There was significant heterogeneity in the AE definitions and quality of AE reporting in the primary studies and patient populations in the studies. The impact of cumulative dose effect on incidental AE could not be calculated., Conclusions and Implications of Key Findings: Systemic CST use is associated with increased risk of metabolic AEs, which differs for each disease group and route of administration., Prospero Registration Number: CRD42020161270., Competing Interests: Competing interests: LC, SN, PB and PA are employees of AstraZeneca and may own stock or stock options. None other conflicts of interests by other coauthors. SK is funded by UKRI-MRC Secondment Award (MR/W003538/1)., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Identification of novel therapeutics and risk assessment in early stages of Alzheimer's disease (AD) is a crucial aspect of addressing this complex disease. We characterized gene-expression patterns at the mild cognitive impairment (MCI) stage to identify critical mRNA measures and gene clusters associated with AD pathogenesis., Methods: We used a transcriptomics approach, integrating magnetic resonance imaging (MRI) and peripheral blood-based gene expression data using persistent homology (PH) followed by kernel-based clustering., Results: We identified three clusters of genes significantly associated with diagnosis of amnestic MCI. The biological processes associated with each cluster were mitochondrial function, NF-kB signaling, and apoptosis. Cluster-level associations with cortical thickness displayed canonical AD-like patterns. Driver genes from clusters were also validated in an external dataset for prediction of amyloidosis and clinical diagnosis., Discussion: We found a disease-relevant transcriptomic signature sensitive to prodromal AD and identified a subset of potential therapeutic targets associated with AD pathogenesis., (© 2022 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Restricted Mean Survival Time (RMST), the average time without an event of interest until a specific time point, is a model-free, easy to interpret statistic. The heavy reliance on non-parametric or semi-parametric methods in the survival analysis has drawn criticism, due to the loss of efficacy compared to parametric methods. This assumes that the parametric family used is the true one, otherwise the gain in efficacy might be lost to interpretability problems due to bias. The Focused Information Criterion (FIC) considers the trade-off between bias and variance and offers an objective framework for the selection of the optimal non-parametric or parametric estimator for scalar statistics. Herein, we present the FIC framework for the selection of the RMST estimator with the best bias-variance trade-off. The aim is not to identify the true underling distribution that generated the data, but to identify families of distributions that best approximate this process. Through simulation studies and theoretical reasoning, we highlight the effect of censoring on the performance of FIC. Applicability is illustrated with a real life example. Censoring has a non-linear effect on FICs performance that can be traced back to the asymptotic relative efficiency of the estimators. FICs performance is sample size dependent; however, with censoring percentages common in practical applications FIC selects the true model at a nominal probability (0.843) even with small or moderate sample sizes.

Aims: This 3-part, randomised, phase 1 first-in-human study (NCT03436316) investigated the safety, tolerability and pharmacokinetics (PK) of AZD8154, a dual phosphoinositide 3-kinase (PI3K) γδ inhibitor developed as a novel inhaled anti-inflammatory treatment for respiratory disease., Methods: Healthy men, and women of nonchildbearing potential, were enrolled to receive single and multiple ascending inhaled doses of AZD8154 in parts 1 and 3 of the study, respectively, while part 2 characterised the systemic PK after a single intravenous (IV) dose. In part 1, participants received 0.1-7.7 mg AZD8154 in 6 cohorts. In part 2, participants were given 0.15 mg AZD8154 as an IV infusion. In part 3, AZD8154 was given in 3 cohorts of 0.6, 1.8 and 3.1 mg, with a single dose on Day 1 followed by repeated once-daily doses on Days 4-12., Results: In total, 78 volunteers were randomised. All single inhaled, single IV and multiple inhaled doses were shown to be well tolerated without any safety concerns. A population PK model, using nonlinear mixed-effect modelling, was developed to describe the PK of AZD8154. The terminal mean half-life of AZD8154 was 18.0-32.0 hours. The geometric mean of the absolute pulmonary bioavailability of AZD8154 via the inhaled route was 94.1%., Conclusion: AZD8154 demonstrated an acceptable safety profile, with no reports of serious adverse events and no clinically significant drug-associated safety concerns reported in healthy volunteers. AZD8154 demonstrated prolonged lung retention and a half-life supporting once-daily dosing., (© 2021 Astrazeneca. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Diffusing capacity for carbon monoxide (DLCO) was measured in a phase I single ascending dose study after inhalation of AZD8154 or placebo in healthy participants at baseline (DLCO Baseline ) and follow-up (DLCO Follow-up ) 6 days after dosing. Initially, DLCO Follow-up timepoint was 2 h earlier than the DLCO Baseline timepoint and clinically significant decreases in DLCO Follow-up (absolute change up to 19% from baseline and DLCO % predicted values less than 70) were observed then. The observed reduction in DLCO Follow-up was confirmed as a false positive finding after alignment of DLCO timings. As a consequence, when DLCO is used in clinical studies, measurements should be strictly standardized in relation to time of the day., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Recurrent Clostridioides difficile infection (CDI) in patients with inflammatory bowel disease (IBD) is a clinical challenge. Fecal microbiota transplantation (FMT) has emerged as a recurrent CDI therapy. Anecdotal concerns exist regarding worsening of IBD activity; however, prospective data among IBD patients are limited., Methods: Secondary analysis from an open-label, prospective, multicenter cohort study among IBD patients with 2 or more CDI episodes was performed. Participants underwent a single FMT by colonoscopy (250 mL, healthy universal donor). Secondary IBD-related outcomes included rate of de novo IBD flares, worsening IBD, and IBD improvement-all based on Mayo or Harvey-Bradshaw index (HBI) scores. Stool samples were collected for microbiome and targeted metabolomic profiling., Results: Fifty patients enrolled in the study, among which 15 had Crohn's disease (mean HBI, 5.8 ± 3.4) and 35 had ulcerative colitis (mean partial Mayo score, 4.2 ± 2.1). Overall, 49 patients received treatment. Among the Crohn's disease cohort, 73.3% (11 of 15) had IBD improvement, and 4 (26.6%) had no disease activity change. Among the ulcerative colitis cohort, 62% (22 of 34) had IBD improvement, 29.4% (11 of 34) had no change, and 4% (1 of 34) experienced a de novo flare. Alpha diversity significantly increased post-FMT, and ulcerative colitis patients became more similar to the donor than Crohn's disease patients (P = 0.04)., Conclusion: This prospective trial assessing FMT in IBD-CDI patients suggests IBD outcomes are better than reported in retrospective studies., (© 2020 Crohn’s & Colitis Foundation. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Patients with degenerative hip and lumbar spine disorders requiring surgery in both locations is fairly common in clinical practice. We investigated if the order of total hip replacement (THR) and lumbar spinal stenosis surgery (LSSS) influences patient-reported outcomes (PROs). We used data from the Swedish Hip Arthroplasty Register (SHAR) and the Swedish Spine Register (Swespine), on patients operated with THR and LSSS in years 2002 to 2012. To increase the probability of having symptomatic disorders in both locations at the time of the first surgery, we only included patients with both LSSS and THR performed within 2 years. Linear and logistic regression analyses adjusted for age, sex, preoperative PROs, and time between surgeries were used to investigate the association between order of surgeries and the generic PRO measurements EQ-5D and EQ VAS. Eighty-four patients had THR prior to LSSS and 171 patients LSSS prior to THR. Linear regression showed that LSSS prior to THR was associated with higher EQ-5D index (B = 0.09, 95% confidence interval [CI] 0.03-0.16) and EQ VAS (B = 5.6, 95% CI 0.4-10.9) 1 year after the last surgery. Logistic regression showed that the odds ratio [OR] for not having any problems in the "pain" (OR = 3.0, 95% CI 1.5-6.3) and "anxiety/depression" (OR = 2.3, 95% CI 1.3-4.1) dimensions were higher for LSSS before THR. In our cohort, LSSS before THR was associated with better health-related quality of life outcomes compared to the reverse order. The results from our cohort can be helpful in a clinical situation where the physician gives advice to an individual patient when choosing the order of procedures. However, further studies are necessary in order to confirm these results in other cohorts. At present, standard of care remains that order of surgery should be individualized for each patient, with guidance from the operating surgeons., (© 2020 The Authors. Journal of Orthopaedic Research® published by Wiley Periodicals LLC on behalf of Orthopaedic Research Society.)

Background & Aims: Fecal microbiota transplantation (FMT) is recommended for recurrent Clostridioides difficile infection (CDI). FMT cures nearly 80% of patients with severe or fulminant CDI (SFCDI) when utilized in a sequential manner. We compared outcomes of hospitalized patients before and after implementation of an FMT program for SFCDI and investigated whether the changes could be directly attributed to the FMT program., Methods: We performed a retrospective analysis of characteristics and outcomes of patients hospitalized for SFCDI (430 hospitalizations) at a single center, from January 2009 through December 2016. We performed subgroup analyses of 199 patients with fulminant CDI and 110 patients with refractory SFCDI (no improvement after 5 or more days of maximal anti-CDI antibiotic therapy). We compared CDI-related mortality within 30 days of hospitalization, CDI-related colectomy, length of hospital stay, and readmission to the hospital within 30 days before (2009-2012) vs after (2013-2016) implementation of the inpatient FMT program., Results: CDI-related mortality and colectomy were lower after implementation of the FMT program. Overall, CDI-related mortality was 10.2% before the FMT program was implemented vs 4.4% after (P = .02). For patients with fulminant CDI, CDI-related mortality was 21.3% before the FMT program was implemented vs 9.1% after (P = .015). For patients with refractory SFCDI, CDI-related mortality was 43.2% before the FMT program vs 12.1% after (P < .001). The FMT program significantly reduced CDI-related colectomy in patients with SFCDI (6.8% before vs 2.7% after; P = .041), in patients with fulminant CDI (15.7% before vs 5.5% after; P = .017), and patients with refractory SFCDI (31.8% vs 7.6%; P = .001). The effect of FMT program implementation on CDI-related mortality remained significant for patients with refractory SFCDI after we accounted for the underlying secular trend (odds ratio, 0.09 for level change; P = .023)., Conclusions: An FMT program significantly decreased CDI-related mortality among patients hospitalized with refractory SFCDI., (Copyright © 2020 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Purpose: To determine the biology, recurrence rate, metastatic patterns and survival times in primary triple-negative breast cancer (TNBC) with focus on the comparison between younger and elderly patients., Methods: Patients with primary TNBC stage I-IV diagnosed from 2007 to 2015 were identified and information on tumor biology, stage, treatment, recurrences and death recorded., Results: A total of 524 patients, median age 60 years (range 24-94) with a median follow-up of 55 months (range 0-129) were identified. Stage was similar in younger (< 40 years) (n = 58) and older (> 74 years) (n = 96) patients (p = 0.37). A statistically significant difference was found concerning histopathologic grade (p = 0.006) and Ki67 (median 80% versus 70%; p = 0.002) but not for LVI (p = 0.9) with more aggressive tumors among younger patients. Adjuvant/neoadjuvant chemotherapy was more frequently given to younger compared with older patients (96% versus 12%; p = 0.0005). Only brain (p = 0.016) and liver (p = 0.047) metastases were more often registered among younger patients while other locations were similar. Shorter survival times, recurrence-free survival (RFS), distant disease-free survival (DDFS) and breast cancer-specific survival (BCSS) were found in the older group, although not after adjusting for adjuvant/neoadjuvant chemotherapy. Most deaths (68%) in the older group were caused by TNBC. When comparing patients > 75 years (n = 92) with ≤ 75 years (n = 432), a worse outcome among older was also observed: RFS (p = 0.00012), DDFS (p = 0.00041), BCSS (p < 0.0001) and survival following distant metastasis (p = 0.0064) CONCLUSIONS: Primary TNBC in younger patients is more often of poor differentiation grade and highly proliferative compared with older patients. The majority of older patients still have grade III tumors with a Ki67 > 60% and outcome is poor. Few older patients in our study were treated with chemotherapy both in adjuvant and palliative setting, underlining the need for more prospective trials and treatment options suitable for this patient population.