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Objectives: We sought to understand why some women with early-stage breast cancer decide to forgo or discontinue endocrine therapy (ET), and to identify factors that might lead to greater acceptance of, and long-term adherence to, this treatment., Methods: We conducted in-depth interviews with N = 53 stage I-III HR+ women who were either non-initiators of ET, initiators who discontinued or initiators who continued with variable daily patterns of adherence. An inductive content analysis was performed to explore the decision-making process of women prescribed ET., Results: Qualitative analyses revealed 55 themes that drove complex decision making. The initiators generally trusted their physicians and did little research before starting the medication. Non-initiators were more suspicious of the medical system, believing that ET presented more risks than benefits. Most discontinuers stopped ET because of side effects. Both non-initiators and discontinuers indicated that push-back from their physicians could have changed their decision. Stories and social support were important in decision making., Conclusions: Although ET can significantly reduce the risk of breast cancer recurrence, substantial barriers prevent many women from initiating or continuing it., Practice Implications: Physicians have powerful influence over patients' decisions to initiate ET and can be important levers for motivating patients to persist., Competing Interests: Declaration of Competing Interest The authors report no conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Cross-sectional studies have linked differences in white matter tissue properties to reading skills. However, past studies have reported a range of, sometimes conflicting, results. Some studies suggest that white matter properties act as individual-level traits predictive of reading skill, whereas others suggest that reading skill and white matter develop as a function of an individual's educational experience. In the present study, we tested two hypotheses: a) that diffusion properties of the white matter reflect stable brain characteristics that relate to stable individual differences in reading ability or b) that white matter is a dynamic system, linked with learning over time. To answer these questions, we examined the relationship between white matter and reading in a five-year longitudinal dataset and a series of large-scale, single-observation, cross-sectional datasets (N = 14,249 total participants). We find that gains in reading skill correspond to longitudinal changes in the white matter. However, in the cross-sectional datasets, we find no evidence for the hypothesis that individual differences in white matter predict reading skill. These findings highlight the link between dynamic processes in the white matter and learning., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The large and increasing burden of mental and substance use disorders, its association with social disadvantage and decreased economic output, and the substantial treatment gaps across country-income levels, are propelling mental health into the global spotlight. The inclusion of targets related to mental health and wellbeing in the UN's Sustainable Development Goals, as well as several national and global initiatives that formed during the past 5 years, signal an increasing momentum toward providing appropriate financing for global mental health. Drawing on the organisational and financial architecture of two successful global health scale-up efforts (the fight against HIV/AIDS and the improvement of maternal and child health) and the organisational models that have emerged to finance these and other global health initiatives, we propose a multi-sectoral and multi-organisational Partnership for Global Mental Health to serve two main functions. First is the mobilisation of funds, including raising, pooling, disbursing, and allocating. Second is stewardship, including supporting countries to use funds effectively, evaluate results, and hold stakeholders accountable. Such a partnership would necessarily involve stakeholders from the mental health field, civil society, donors, development agencies, and country-level stakeholders, organised into hubs responsible for financing, scale-up, and accountability., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Objective: Imaging of patients with multicystic dysplastic kidney (MCDK) has increased over the past three decades. This increased use of imaging has provided additional insights into the natural history of MCDK. The present study looked at this data for predictors of involution and associated anomalies., Methods and Materials: Institutional review board approval was obtained for this retrospective study. The University of Michigan Departments of Urology and Radiology records were searched to identify unilateral MCDK patients during 1980-2012. Available clinical, radiological and surgical records were reviewed, and pertinent data were recorded. The log-rank test and a Cox proportional regression analysis were performed to identify predictors of MCDK involution. Probability of involution over time was assessed using Kaplan-Meier methodology., Results: 301 unilateral MCDKs were identified; 195 (64.8%) were detected antenatally. Of the MCDKs found, 136 (45.2%) were in girls; 160 (53.2%) were right-sided. Mean size at baseline was 5.0 ± 0.2 cm (Mean ± SE). Associated abnormalities included: contralateral ureteropelvic junction obstruction (n = 10; 3.3%); contralateral ureterovesical junction obstruction/primary megaureter (n = 6; 2.0%); ipsilateral VUR (n = 21; 7.0%); contralateral VUR (n = 63; 20.1%); and renal fusion anomaly (n = 4; 1.3%). The cumulative probability of involution was: 9.8% at one year, 38.5% at five years, and 53.5% at ten years of age. Baseline MCDK size was the only significant predictor of involution at bivariate (p < 0.0001) and multivariate (p < 0.0001; HR 0.58 [95% CI: 0.49, 0.69]) analyses. No MCDK developed malignancy during the follow-up period., Conclusion: As many MCDKs eventually involute and the risk of associated malignancy appears to be very low, there is no absolute indication for nephrectomy. Based on the data and other recent studies, it is believed that pediatric MCDK patients with no other urologic abnormalities can safely tolerate more limited urological and radiological follow-up., (Copyright © 2014 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.)

Background: The use of bone marrow-derived mesenchymal stromal cells (MSCs) as a cellular therapy for various diseases, such as graft-versus-host disease, diabetes, ischemic cardiomyopathy and Crohn's disease, has produced promising results in early-phase clinical trials. However, for widespread application and use in later phase studies, manufacture of these cells must be cost-effective, safe and reproducible. Current methods of manufacturing in flasks or cell factories are labor-intensive, involve a large number of open procedures and require prolonged culture times., Methods: We evaluated the Quantum Cell Expansion System for the expansion of large numbers of MSCs from unprocessed bone marrow in a functionally closed system and compared the results with a flask-based method currently in clinical trials., Results: After only two passages, we were able to expand a mean of 6.6 × 10(8) MSCs from 25 mL of bone marrow reproducibly. The mean expansion time was 21 days, and cells obtained were able to differentiate into all three lineages: chondrocytes, osteoblasts and adipocytes. The Quantum was able to generate the target cell number of 2.0 × 10(8) cells in an average of 9 fewer days and in half the number of passages required during flask-based expansion. We estimated that the Quantum would involve 133 open procedures versus 54,400 in flasks when manufacturing for a clinical trial. Quantum-expanded MSCs infused into an ischemic stroke rat model were therapeutically active., Conclusions: The Quantum is a novel method of generating high numbers of MSCs in less time and at lower passages when compared with flasks. In the Quantum, the risk of contamination is substantially reduced because of the substantial decrease in open procedures., (Copyright © 2014 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Vaccination has been among the greatest contributors to the past century's dramatic improvements in health and life expectancy. Recent advances in vaccinology have resulted in new vaccines that will likely lead to substantial future health gains. However, the high cost of these new vaccines, such as the human papillomavirus (HPV) vaccine, poses an obstacle to their widespread adoption in many countries. Economic evaluation can help to determine if investment in vaccine introduction is worthwhile. However, existing economic evaluations usually focus on a narrow set of vaccination-mediated benefits-most notably avoided medical-care costs-and fail to account for several categories of potentially important gains. We consider three sources of such benefit and discuss them with respect to HPV vaccination: (i) outcome-related productivity gains, (ii) behaviour-related productivity gains, and (iii) externalities. We also highlight that HPV vaccination protects against more than just cervical cancer and that these other health gains should be taken into account. Failing to account for these broader benefits of HPV vaccination could result in substantial underestimation of the value of HPV vaccination, thereby leading to ill-founded decisions regarding its introduction into national immunization programmes., (© 2012 The Authors. Clinical Microbiology and Infection © 2012 European Society of Clinical Microbiology and Infectious Diseases.)

We describe a child of Middle Eastern descent by first-cousin coupling with idiopathic neurogenic bladder and high-grade vesicoureteral reflux at 1 year of age, whose characteristic facial grimace led to the diagnosis of Ochoa (urofacial) syndrome at age 5 years. We used homozygosity mapping, exome capture and paired-end sequencing to identify the disease causing mutation in the proband. We reviewed the literature with respect to the urologic manifestations of Ochoa syndrome. A large region of marker homozygosity was observed at 10q24, consistent with known autosomal recessive inheritance, family consanguinity and previous genetic mapping in other families with Ochoa syndrome. A homozygous mutation was identified in the proband in HPSE2: c.1374&#95;1378delTGTGC, a deletion of 5 nucleotides in exon 10 that is predicted to lead to a frameshift followed by replacement of 132 C-terminal amino acids with 153 novel amino acids (p.Ala458Alafsdel132ins153). This mutation is novel relative to very recently published mutations in HPSE2 in other families. Early intervention and recognition of Ochoa syndrome with control of risk factors and close surveillance will decrease complications and renal failure., (Copyright © 2011 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.)

Alemtuzumab is a monoclonal antibody that depletes T and B cells and is used as induction therapy for renal transplant recipients. Without long-term calcineurin inhibitor (CNI) therapy, alemtuzumab-treated patients have a propensity to develop alloantibody and may undergo antibody-mediated rejection (AMR). In pursuit of a mechanistic explanation, we analyzed peripheral B cells and serum of these patients for BAFF (Blys) and BAFF-R, factors known to be integral for B-cell activation, survival, and homeostasis. Serum BAFF levels of 22/24 alemtuzumab-treated patients were above normal range, with average levels of 1967 pg/mL compared to 775 pg/mL in healthy controls (p = 0.006). BAFF remained elevated 2 years posttransplant in 78% of these patients. BAFF-R on CD19(+) B cells was significantly downregulated, suggesting ligand/receptor engagement. BAFF mRNA expression was increased 2-7-fold in CD14(+) cells of depleted patients, possibly linking monocytes to the BAFF dysregulation. Addition of recombinant BAFF to mixed lymphocyte cultures increased B-cell activation to alloantigen, as measured by CD25 and CD69 coexpression on CD19(+) cells. Of note, addition of sirolimus (SRL) augmented BAFF-enhanced B-cell activation whereas CNIs blocked it. These data suggest associations between BAFF/BAFF-R and AMR in alemtuzumab-treated patients.

Alemtuzumab induction with 60 days of tacrolimus treatment and continuous sirolimus treatment prevented acute rejection in nine of 10 consecutive renal allograft recipients. All patients are alive with a functioning kidney graft at 27-39 months of follow-up. Extensive immune monitoring was performed in all patients. Alloantibody detection, cytokine kinetics assay (CKA), and trans vivo delayed-type hypersensitivity (DTH) assay were performed every 6 months showing correlation with clinical evolution. Despite alloantibody presence in five patients, eight patients remain without the need for specific treatment and only sirolimus monotherapy in decreasing dosage. Four patients take only 1 mg sirolimus daily with levels of 3-4 ng/mL. One patient showed clinical signs of rejection at month 9 post-transplant, with slow increase in serum creatinine and histological signs of mixed cellular (endarteritis) and humoral rejection (C4d positivity in peritubular capillaries and donor-specific antibody (DSA)). In summary, the addition of tacrolimus therapy for 2 months to a steroid-free, alemtuzumab induction and sirolimus maintenance protocol limited the previously shown acute rejection development. Nevertheless, alloantibody was present in serum and/or C4d present on 1-year biopsy in half the patients. The combination of CKA and DSA monitoring or the performance of transvivo DTH correlated with immune status of the patients.

To address the results of calcineurin inhibitor (CNI) withdrawal after alemtuzumab induction relative to CNI continuation, we performed a pilot randomized clinical trial in renal allograft recipients on CNI, a mycophenolic acid derivative and steroids after the first 2 months posttransplantation. Forty patients were randomized to taper off CNI or to maintain it, and followed for at least 1 year. Four patients in the withdrawal group were treated for acute rejection while no patient received antirejection treatment in the control group. Two control patients withdrew CNI due to nephrotoxicity. Estimated GFR was similar in both groups after 1 year. Flow cytometry of CD4(+)CD25(+)CTLA-4(+)FoxP3(+) regulatory T cells (Treg) demonstrated a significant increase in Treg percentages in the peripheral blood of alemtuzumab-treated patients on CNI early postransplant. Furthermore, the increased Treg percentages in the withdrawal cohort were unchanged at month 6 postenrollment, whereas they decreased significantly in those patients maintained on CNI. Patients withdrawn from CNI after alemtuzumab trend toward a higher rejection rate, but most patients can be weaned from a CNI using this regimen. With the exception of maintaining increased Treg levels, the benefits are not appreciable in this short follow-up, and a larger randomized trial is justified.

Campath-1H (Alemtuzumab) is an effective immunodepletion agent used in renal transplantation. To evaluate its influence on T lymphocytes during repletion, we analyzed peripheral blood from Campath-1H-treated renal allograft recipients for the presence of FOXP3(+) regulatory T (Treg) cells. Flow cytometry demonstrated that CD4(+)CD25(+)FOXP3(+) lymphocytes increased significantly within the CD4(+) T-cell population, skewing Treg/Teff (T effector) ratios for up to several years. In contrast, Treg levels in patients treated with anti-CD25 (Basiliximab) and maintained on CsA demonstrated a sustained decrease. The increase in Tregs in Campath-1H treated patients developed independent of maintenance immunosuppression. Importantly, the increase in Tregs was not fully explained by their homeostatic proliferation, increased thymic output, or Treg sparing, suggesting de novo generation/expansion. Consistent with this, in vitro stimulation of PBMCs with Campath-1H, with or without anti-CD3, activation led to an increase in CD4(+)CD25(+)FOXP3(+) cells that had suppressive capabilities. Together, these data suggest that Campath-1H promotes an increase in peripheral Tregs and may act as an intrinsic generator of Tregs in vivo.

Objectives: To determine the safety and efficacy of electroporation with bleomycin in patients with advanced squamous cell carcinoma of the head and neck., Methods: Two open-label, multicenter, single-arm Phase II studies of intratumour electroporation therapy. Sixty-two patients with 86 squamous cell carcinoma tumours of the head and neck were enrolled. Twenty-five patients were treated with bleomycin alone. Fifty-four patients (17 initially treated with bleomycin alone) were treated with electroporation and bleomycin therapy. Local tumour response was measured., Results: In the bleomycin alone group, one tumour showed a partial response and 36 tumours showed no response to treatment. In the bleomycin with electroporation groups, 17 tumours showed complete response, 22 tumours showed partial response and 30 failed to achieve more than a 50% reduction in tumour size (no response). Bleomycin with electroporation had a significantly (p<0.001) greater number of patients showing a partial or complete response to the therapy when compared to bleomycin alone. Thirteen adverse events were reported which included five episodes of local bleeding, six local infections, one local tongue swelling and one cardiac arrhythmia., Conclusions: Fifty-seven percent of squamous cell carcinomas of the head and neck demonstrated a partial or complete response to intratumour electroporation with bleomycin suggesting that further work investigating its use as a treatment for local control of these lesions should be pursued.

Objective: To assess lifetime and current psychiatric disorders at least 1 year after traumatic brain injury (TBI) in children and adolescents., Method: Forty-six youths who sustained a TBI between the ages of 6 through 15 years were evaluated at least 1 year post-TBI to identify the presence of lifetime and/or novel psychiatric disorders. Semistructured interviews of the parent and child and standardized parent self-report rating instruments were used., Results: Attention-deficit/hyperactivity disorder and depressive disorders were the most common lifetime and novel diagnoses. A wide variety and high rate of novel psychiatric disorders were identified; 74% of these disorders persisted in 48% of the injured children. Internalizing disorders were more likely to resolve than externalizing disorders. Both interviews and parent ratings were sensitive to current externalizing behaviors; interviews more often detected internalizing disorders, whereas parent ratings also identified cognitive difficulties., Conclusions: Findings were generally consistent with previous research demonstrating the high rate of novel psychiatric disorders following pediatric TBI. Psychiatric interviews were sensitive in identifying both lifetime and novel disorders.

We describe a case of Caroli's disease associated with a choledochal cyst and autosomal recessive polycystic kidney disease in a child whose diagnosis was confirmed with magnetic resonance cholangiopancreatography (MRCP), after initial abnormalities were seen by ultrasonography. Invasive procedures such as liver biopsy or endoscopic retrograde cholangiopancreatography (ERCP) were, therefore, not necessary. Recent radiological advances in the diagnosis of Caroli's disease with particular emphasis on MRCP are discussed.

NPM (nucleophosmin/B23) is a nucleolar phosphoprotein abundant in tumor cells. It dissociates from nucleoli of cells after treatments with various anticancer drugs. To determine the domain of NPM responsible for nucleolar binding, the N- and C-terminal halves of NPM were fused to GFP (green fluorescent protein) and introduced into HeLa cells. The N-terminal half (aa 1-150) of NPM (GFP-NPM(N)) was found localized in the nucleoli. A stable transformant of GFP-NPM(N) in HeLa cells was prepared and tested for association to nucleoli after anticancer drug treatments. GFP-NPM(N) dissociates from nucleoli after treatments with daunomycin, actinomycin D, camptothecin, and toyocamycin. The dissociation is time- and dose-dependent, and correlates with the cytotoxicity induced by the drugs. These results indicate that a stable transformant of GFP-NPM(N) in HeLa cells may be useful for the screening of anticancer drugs., (Copyright 1999 Academic Press.)

Prostaglandin E2 (PGE2) is a potent mediator generated in immune tissues by cyclooxygenation of arachidonic acid. PGE2 affects T cell functions through four homologous G protein-coupled receptors termed EP1R, EP2R, EP3R, and EP4R that differ in tissue distribution and signaling. Antigen-evoked secretion of interferon-gamma (IFN-gamma) by sperm whale myoglobin-specific Th1 cells of DBA/2 mouse I-Ed-restricted clones, that express EP3Rs and EP4Rs, was enhanced a maximum of 3-fold by 10(-10) to 10(-8) M PGE2 and 2.5-fold each for the EP1R/EP3R-directed agonist sulprostone (10(-8) and 10(-7) M) and for the EP4R/EP3R/EP2R agonist misoprostol (10(-9) M). Neither PGE2 nor the synthetic analogs affected secretion of IFN-gamma by PMA plus ionomycin-stimulated clones of Th1 cells. Antigen-evoked secretion of IFN-gamma by influenza hemagglutinin-specific mouse lymph node Th1 cells, that also express EP3Rs and EP4Rs, was increased a maximum of 12-fold by 10(-9) to 10(-8) M PGE2, 14-fold by 10(-9) M sulprostone, and 10-fold by 10(-9) M misoprostol. Production of IFN-gamma by either type of Th1 cell was not affected significantly by 10(-6) M PGE2 alone. The generation of IFN-gamma by antigen-stimulated Th1 cells thus is significantly enhanced by physiologically relevant concentrations of PGE2., (Copyright 1999 Academic Press.)

Development of cerebral inhibitory processes among individuals with Down syndrome (DS) may be delayed at an early age. In support of this hypothesis, sensory-evoked potentials (EPs) and event-related brain potentials (ERPs) have previously delineated altered habituation to stimuli among infants with DS. The purpose of the current study was to provide extended experience with visual stimuli among 6-month-old infants with and without DS (nDS) to determine if altered ERP and behavioral response decrements would be evident even after repeated presentations of stimuli. An 80/20% oddball paradigm was employed. Infants with DS and nDS were matched according to age and gender. Infants with DS demonstrated significantly larger Nc areas, Nc peak amplitudes, Nc2 areas and, inversely, significantly smaller peak Pb amplitudes when compared to infants nDS. Contrasts of the two study groups were most robust within ERP measures from frontal (Fz) and parietal (Pz) recording sites. Infants with DS also demonstrated a significantly slower decrement of most ERP components with repetitive stimulus experience. Most noteworthy was the observation of little or no decrement of ERP components at Fz among infants with DS. Both infants with DS and nDS demonstrated significantly larger Nc peak amplitudes, Nc areas, Nc2 areas, Pb peak amplitudes and NSW areas to rare stimuli. While significant probability and experiential trends were observed in visual fixation measures across both study groups, there were no significant differences of visual attention between infants with DS or nDS. These data demonstrate the value of ERPs within the study of atypical cognitive development during infancy and support the concept of altered inhibitory processes in the brain of infants with DS.

Objective: To evaluate whether children with borderline disorder (also referred to as multiple complex developmental disorder) (BD/MCDD) and comorbid attention-deficit hyperactivity disorder (ADHD) demonstrate evidence of abnormal attention and/or auditory processing impairments as indexed by both behavioral and physiological measures., Method: Three groups of children were compared in two different experiments on behavioral rating scales (Conners Parent Rating Scale and Child Behavior Checklist), behavioral accuracy to auditory and visual target detection tasks, selected neuropsychological tests, and brain physiology (event-related potentials) collected during auditory and visual target detection tasks., Results: The results demonstrate that children with BD/MCDD differ from children with ADHD in the (1) prevalence of internalizing and externalizing behaviors, (2) neuropsychological deficits related to auditory processing, and (3) event-related potential brain physiology associated with auditory cognitive target attention tasks., Conclusion: Some of the pervasive pathology described in children with BD/MCDD may be due to biological vulnerabilities, particularly problems with auditory processing. Auditory processing impairments in such children deserves special attention with respect to both understanding their behavioral symptoms and developing a comprehensive treatment plan.

A pharmaco-economic study of the administration of adjunctive therapy in patients with chronic epilepsy is described. A decision-analytic model has been used, which represents the consequences of treatment over a 1-year time period, when one of three drugs is used first. The cost-effectiveness ratio for clobazam, lamotrigine and vigabatrin have been calculated. The expected cost per patient of treatment over the 1-year period was up to 50% higher with vigabatrin and lamotrigine compared with clobazam, with a cost-effectiveness ratio around 40% higher.

Alterations in renal perfusion have been shown in a variety of liver diseases. We have examined the possibility that the syndrome is due to a renal vascular hypersensitivity to noradrenalin (NA). Isolated perfused kidneys and segments of rabbit femoral artery were used. Potentiation of the pressor effects of injected NA occurred in all (five artery and five kidney) preparations when jaundiced baboon plasma was perfused. These changes were significant (P less than 0.05) in nine out of the ten experiments. Controls to which normal baboon plasma was administered showed no such change. No correlation was found between the degree of NA potentiation and the plasma concentrations of bilirubin (total and conjugated), serum glutamic oxaloacetic transaminase, blood urea nitrogen, serum glutamic pyruvic transaminase, alkaline phosphatase, Na+ ions or K+ ions in the jaundiced plasma. Plasma renin levels were not significantly changed. When arteris were perfused with Krebtentiation of NA was found. Perfusion of sodium taurocholate or sodium deoxycholate (400 mug/ml) yielded no potentiation. Thus, the altered renal perfusion associated with jaundice may be attributed to a potentiated pressor response to NA which may be caused by an increased level of cholesterol carried on the beta-lipoprotein.