Technical Review Panel for the Pension Insurance Modeling System (PIMS)

In April of 2013, the Pension Research Council of the Wharton School at the University of Pennsylvania convened a Technical Review Panel, comprising ten experts whose task it was to review the Pension Benefit Guaranty Corporation’s (PBGC) Pension Insurance Modeling System (PIMS), including inputs, outputs, and model assumptions. The review was intended to provide a formal evaluation of the technical adequacy of the model by outside experts. Each expert participating on the Technical Panel was asked to review background material (see References) and focus on a particular aspect of the PIMS model. The list of panelists and topics was developed by the Council in discussion with the Social Security Administration (SSA). This report and the appended papers herein from our Technical Panel comprise the Final Report under this project. The Panel’s key findings may be summarized as follows: (1) The PIMS models are an important and valuable tool in modeling the Agency’s liability risk. To the best of our knowledge, there is no other model that can do a comparable job. (2) Nevertheless, some improvements could be integrated in the Agency’s approach to modeling. Those deserving highest priority attention in the experts’ view are the following: (a) Incorporating systematic mortality risk (i.e., treat mortality and longevity as stochastic variables); (b) Including new asset classes increasingly found in defined benefit plan portfolios (e.g., commercial real estate, private equity funds, infrastructure, hedge funds, and others); (c) Developing a more complex model for the term structure of interest rates; and (d) Incorporating an option value approach to pricing the insurance provided. (3) The Agency could also do more to communicate the range of uncertainty and potential for problems associated with the PBGC’s financial status. This could include additional information including the Conditional Value at Risk (CVaR), and perhaps an ‘intermediate,’ ‘optimistic,’ and ‘pessimistic’ set of projected outcomes, as well as the expected ‘date of exhaustion’ for assets backing pension benefits insured by the PBGC.Social Security Administrationhttp://deepblue.lib.umich.edu/bitstream/2027.42/102265/1/wp290.pd

The Therapeutic Potential of Mangosteen Pericarp as an Adjunctive Therapy for Bipolar Disorder and Schizophrenia

New treatments are urgently needed for serious mental illnesses including bipolar disorder and schizophrenia. This review proposes that Garcinia mangostana Linn. (mangosteen) pericarp is a possible adjunctive therapeutic agent for these disorders. Research to date demonstrates that neurobiological properties of the mangosteen pericarp are well aligned with the current understanding of the pathophysiology of bipolar disorder and schizophrenia. Mangosteen pericarp has antioxidant, putative neuroprotective, anti-inflammatory, and putative mitochondrial enhancing properties, with animal studies demonstrating favorable pharmacotherapeutic benefits with respect to these disorders. This review summarizes evidence of its properties and supports the case for future studies to assess the utility of mangosteen pericarp as an adjunctive treatment option for mood and psychotic disorders

The impact of digital health technologies on tuberculosis treatment : a systematic review

Digital technologies are increasingly harnessed to support treatment of persons with tuberculosis (TB). Since in-person directly observed treatment (DOT) can be resource intensive and challenging to implement, these technologies may have the potential to improve adherence and clinical outcomes. We reviewed the effect of these technologies on TB treatment adherence and patient outcomes. We searched several bibliographical databases for studies reporting the effect of digital interventions, including short message service (SMS), video-observed therapy (VOT) and medication monitors (MMs), to support treatment for active TB. Only studies with a control group and which reported effect estimates were included. Four trials showed no statistically significant effect on treatment completion when SMS was added to standard care. Two observational studies of VOT reported comparable treatment completion rates when compared with in-person DOT. MMs increased the probability of cure (RR 2.3, 95% CI 1.6-3.4) in one observational study, and one trial reported a statistically significant reduction in missed treatment doses relative to standard care (adjusted means ratio 0.58, 95% CI 0.42-0.79). Evidence of the effect of digital technologies to improve TB care remains limited. More studies of better quality are needed to determine how such technologies can enhance programme performance

TCF7L1 Regulates <i>LGR5</i> Expression in Colorectal Cancer Cells

Mutations in components of the Wnt/β-catenin signaling pathway drive colorectal cancer (CRC), in part, by deregulating expression of genes controlled by the T-cell factor (TCF) family of transcription factors. TCFs contain a conserved DNA binding domain that mediates association with TCF binding elements (TBEs) within Wnt-responsive DNA elements (WREs). Intestinal stem cell marker, leucine-rich-repeat containing G-protein-coupled receptor 5 (LGR5), is a Wnt target gene that has been implicated in CRC stem cell plasticity. However, the WREs at the LGR5 gene locus and how TCF factors directly regulate LGR5 gene expression in CRC have not been fully defined. Here, we report that TCF family member, TCF7L1, plays a significant role in regulating LGR5 expression in CRC cells. We demonstrate that TCF7L1 binds to a novel promoter-proximal WRE through association with a consensus TBE at the LGR5 locus to repress LGR5 expression. Using CRISPR activation and interference (CRISPRa/i) technologies to direct epigenetic modulation, we demonstrate that this WRE is a critical regulator of LGR5 expression and spheroid formation capacity of CRC cells. Furthermore, we found that restoring LGR5 expression rescues the TCF7L1-mediated reduction in spheroid formation efficiency. These results demonstrate a role for TCF7L1 in repressing LGR5 gene expression to govern the spheroid formation potential of CRC cells

Transcriptome Analyses Identify Deregulated <i>MYC</i> in Early Onset Colorectal Cancer

Despite a global decrease in colorectal cancer (CRC) incidence, the prevalence of early-onset colorectal cancer (EOCRC), or those occurring in individuals before the age of 50, has steadily increased over the past several decades. When compared to later onset colorectal cancer (LOCRC) in individuals over 50, our understanding of the genetic and molecular underpinnings of EOCRCs is limited. Here, we conducted transcriptomic analyses of patient-matched normal colonic segments and tumors to identify gene expression programs involved in carcinogenesis. Amongst differentially expressed genes, we found increased expression of the c-MYC proto-oncogene (MYC) and its downstream targets in tumor samples. We identified tumors with high and low differential MYC expression and found patients with high-MYC tumors were older and overweight or obese. We also detected elevated expression of the PVT1 long-non-coding RNA (lncRNA) in most tumors and found gains in copy number for both MYC and PVT1 gene loci in 35% of tumors evaluated. Our transcriptome analyses indicate that EOCRC can be sub-classified into groups based on differential MYC expression and suggest that deregulated MYC contributes to CRCs that develop in younger patients

The influence of childhood trauma on the treatment outcomes of pharmacological and/or psychological interventions for adolescents and adults with bipolar disorder: A systematic review and meta-analysis

[Objective] The influence of childhood trauma on the treatment outcomes of pharmacological and/or psychological interventions for adolescents and adults with bipolar disorder was systematically reviewed.[Methods] Randomised and non-randomised studies of interventions for bipolar disorder that included an assessment of childhood trauma were eligible. MEDLINE Complete, Embase, PsycINFO, and the Cochrane Central Register of Controlled Trials were searched. Two independent reviewers completed the screening and extraction process. Two independent reviewers assessed the risk of bias in the included studies using the Cochrane Collaboration's Risk of Bias tool and the Newcastle-Ottawa Scale. Alongside a narrative synthesis, random-effects meta-analyses were performed.[Results] Twelve studies (1175 participants) were included. The narrative review highlighted differential treatment outcomes among individuals with a history of childhood trauma. The meta-analyses suggested that childhood trauma was unrelated to treatment response (five studies, 426 participants; odds ratio 0.58, 95% CI 0.27–1.25, p = .164) but may be associated with greater improvement in global functioning (three studies, 210 participants; Hedge's g 0.65, 95% CI 0.04–1.26, p = .037).[Limitations] The impact of childhood trauma on the effectiveness of specific pharmacological/psychological interventions could not be explored due to the small body of research identified.[Conclusion] The overall quality of the extant evidence is low, which precludes definitive comment on the role of childhood trauma in the treatment of bipolar disorder. Additional research that uses large and representative samples is required to ascertain whether a history of childhood trauma affects the treatment outcomes of interventions for individuals with bipolar disorder.ALW is supported by a Deakin University Centre of Research Excellence in Psychiatric Treatment Postgraduate Research Scholarship. AJ is supported by a Deakin University Research Training Program Scholarship. SER is supported by an Australian Government Research Training Program Scholarship. WM is currently funded by an Alfred Deakin Postdoctoral Research Fellowship and a Multiple Sclerosis Research Australia early-career fellowship. OMD is supported by a NHMRC R.D. Wright Biomedical Career Development Fellowship (APP1145634). SMC is supported by a NHMRC Senior Research Fellowship (APP1136344). MB is supported by a NHMRC Senior Principal Research Fellowship (APP1156072).Peer reviewe

A systematic review of nutraceuticals for the treatment of bipolar disorder: Une revue systématique des nutraceutiques pour le traitement du trouble bipolaire

BACKGROUND: Certain nutrient supplements (nutraceuticals) may target neurobiological pathways perturbed in bipolar disorder (BD) such as inflammation, oxidative stress, and mitochondrial dysfunction. Nutraceuticals thus may have a potential role as adjunctive treatments for BD. METHODS: A search of Embase via embase.com, PubMed via PubMed, Cumulated index to nursing and allied health literature (CINAHL) Complete via EBSCO, and Cochrane Central Register of Controlled Clinical Trials via cochranelibrary.com was conducted to identify published randomized controlled trials assessing the efficacy of nutraceuticals on mood symptomatology in adults with BD. Search terms for BD, nutraceuticals, and clinical trials (total search terms = 75) were used to search from inception to February 20, 2020. The Cochrane Collaboration’s tool for assessing the risk of bias in randomized trials was used to assess the risk of bias. RESULTS: A total of 1,712 studies were identified through the search. After rigorous screening, 22 studies were included in the review. There was large variability across the studies with 15 different nutraceutical agents assessed and as such insufficient homogeneity for a meta-analysis to be conducted (I (2) > 50%). Studies revealed promising, albeit conflicting, evidence for omega-3 fatty acids and N-acetylcysteine. Isolated positive results were reported for coenzyme Q10. CONCLUSION: Given nutraceuticals are tolerable and accessible, they may be useful as potential adjunctive treatments for BD. Nutraceuticals targeting neuroinflammation or mitochondrial activity may have the most potential for the depressive phase. However, further studies are required to determine efficacy