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Introduction: We evaluated the comparative efficacy of six later-line (≥3) therapies for metastatic colorectal cancer (mCRC) over placebo. We applied a novel statistical method of reconstructing pseudo-patient-level data (pseudo-IPD) to inform a network meta-analysis of survival curves that considers shape in addition to scale parameters., Methods: A literature search yielded 10 phase II/III trials. We digitized all survival curves and applied a novel method incorporating curve coordinates, patients-at-risk, and events reported to generate pseudo-IPD. Using fitted random effects lognormal distributions, we estimated the survival proportions and HRs (95CrI) of progression-free (PFS) and overall survival (OS) over 12 months of follow-up., Results: Compared to placebo, in ascending order, 12-month OS HRs were 0.50 (95% CrI = 0.35, 0.69; PFS = 0.11 (95% CrI = 0.06, 0.14)) for TAS+bevacizumab; 0.71 (95% CrI = 0.51, 0.97; PFS = 0.26 (95% CrI = 0.16, 0.41)) for regorafenib; 0.75 (95% CrI = 0.61, 0.91; (PFS = 0.24 (95% CrI = 0.17, 0.31)) for TAS-102; 0.80 (95% CrI = 0.79, 0.90; PFS = 0.18 (95% CrI = 0.13, 0.24)) for fruquintinib; 0.83 (95% CrI = 0.50, 0.99; PFS = 0.42 (95% CrI = 0.20, 0.75)) for atezolizumab+cobimetinib; and 1.03 (95% CrI = 0.55, 1.65; PFS = 0.67 (95% CrI = 0.29, 1.01)) for atezolizumab., Conclusion: In this independent NMA of survival data, all later-line mCRC therapies but atezolizumab monotherapy exhibited superiority in 12-month PFS and OS over placebo. TAS+bevacizumab emerged as the most dominant option and may be the preferred choice, with fruquintinib, regorafenib, and TAS-102 monotherapy showing statistically significant but lower PFS and OS benefits., Registration: PROSPERO: CRD42022371953.

Lung cancer is the leading cause of global cancer-related mortality resulting in ∼ 1.8 million deaths annually. Systemic, molecular targeted, and immune therapies have provided significant improvements of survival outcomes for patients. However, drug resistance usually arises and there is an urgent need for novel therapy screening and personalized medicine. 3D patient-derived organoid (PDO) models have emerged as a more effective and efficient alternative for ex vivo drug screening than 2D cell culture and patient-derived xenograft (PDX) models. In this review, we performed an extensive search of lung cancer PDO-based ex vivo drug screening studies. Lung cancer PDOs were successfully established from fresh or bio-banked sections and/or biopsies, pleural effusions and PDX mouse models. PDOs were subject to ex vivo drug screening with chemotherapy, targeted therapy and/or immunotherapy. PDOs consistently recapitulated the genomic alterations and drug sensitivity of primary tumors. Although sample sizes of the previous studies were limited and some technical challenges remain, PDOs showed great promise in the screening of novel therapy drugs. With the technical advances of high throughput, tumor-on-chip, and combined microenvironment, the drug screening process using PDOs will enhance precision care of lung cancer patients., 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 Elsevier B.V. All rights reserved.)

Introduction: Deciding on the optimal second-line (2L) treatment for metastatic clear-cell renal cell carcinoma (ccRCC) remains challenging due to the limited information comparing each of the available options and the influence of the newly expanding first-line (1L) agents., Patients and Methods: We identified phase II/III randomized controlled trials (RCTs) evaluating 2L treatments in metastatic ccRCC. This Network Meta-analysis (NMA) evaluates the overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and severe adverse events (SAE). We used normal likelihood model to incorporate log hazard ratios (HRs), odds ratios (OR), and 95%-confidence-intervals (CI). Treatment p-scores were used for ranking. Data was analyzed in a fixed-effects model using the netmeta package in R v.1.5-0., Results: All therapies demonstrated some benefits over placebo. Lenvatinib + everolimus ranked first for OS (HR = 0.44; 95%CI = 0.24-0.82; p-score = 0.92), PFS (HR = 0.13; 95%CI = 0.07-0.24, p-score = 0.98), and ORR (OR = 35.95; 95%CI = 11.55-111.87; p-score = 0.93) compared to placebo, though with a higher SAE (OR = 5.27; p-score = 0.23). Cabozantinib ranked second for OS (HR = 0.57, p-score = 0.80), PFS (HR = 0.19; p-score = 0.86), and ORR (OR = 27.24, p-score = 0.84). Nivolumab was third for ORR (p-score = 0.79), fourth for OS (p-score = 0.69), fifth for PFS (p-score = 0.61), and last for SAE (p-score = 0.83). Lenvatinib monotherapy ranked worst SAE (OR = 5.89, p-score = 0.17) and third for OS and PFS. The latest drug, tivozanib, was sixth for PFS, OS, and ORR. The NMA matrix revealed no differential OS benefit between cabozantinib, lenvatinib + everolimus, and nivolumab. Other regimens had no significant OS benefit when compared to placebo., Conclusion: Based on OS and PFS, the lenvtatinib + everolimus combination yielded superior, followed by cabozantinib and Lenvatinib monotherapies; all were limited by a worse SAE profile. Nivolumab and pazopanib had the lowest odds of SAEs., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: While various interventions have been conducted to decrease cervical cancer's burden in Nigeria, no study has examined the trends in cervical cancer screening uptake over time. The present study sought to fill this gap in knowledge using data collected at Jos University Teaching Hospital (JUTH) in Nigeria., Methods: Data collected continuously between 2006 and 2016 were analyzed to identify trends in screening uptake, changes in risk factors for cervical cancer, and to identify factors for women screened at Jos University Teaching Hospital (JUTH) in Jos, Nigeria. Categorical analyses and logistic regression models were used to describe patient characteristics by year, and to identify factors associated with repeated screening uptake., Results: A total of 14,088 women who were screened between 2006 and 2016 were included in the database; 2,800 women had more than one screening visit. Overall, screening uptake differed significantly by year. On average women were first screened at age 38. About 2% of women screened were women living with HIV. Most women (86%) had normal pap smear at first screening, with the greatest decreased risk of abnormalities observed between 2011 and 2014. Odds of a follow-up screening after a normal result decreased significantly between 2008 and 2016 compared to women screened in 2006 and 2007. Finally, women living with HIV had increased odds of follow-up screening after having a normal pap smear., Conclusions: These findings contribute to our understanding of the potential social and health system barriers to cervical cancer control in Nigeria. The findings may assist policy makers to design interventions to increase access and compliance to recommended screening schedules in this vulnerable population., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: Ebola virus disease (EVD) continues to be a major public health threat globally, particularly in the low-and-middle-income countries (LMICs) of Africa. The social and economic burdens of EVD are substantial and have triggered extensive research into prevention and control. We aim to highlight the impact and economic implications, identify research gaps, and offer recommendations for future economic studies pertaining to EVD., Method: We conducted a comprehensive librarian-led search in PubMed/Medline, Embase, Google Scholar, EconLit and Scopus for economic evaluations of EVD. After study selection and data extraction, findings on the impact and economics of EVD were synthesized using a narrative approach, while identifying gaps, and recommending critical areas for future EVD economic studies., Results: The economic evaluations focused on the burden of illness, vaccine cost-effectiveness, willingness-to-pay for a vaccine, EVD funding, and preparedness costs. The estimated economic impact of the 2014 EVD outbreak in Guinea, Liberia, and Sierra Leone across studies ranged from $30 billion to $50 billion. Facility construction and modification emerged as significant cost drivers for preparedness. The EVD vaccine demonstrated cost-effectiveness in a dynamic transmission model; resulting in an incremental cost-effectiveness ratio of about $96 per additional disability adjusted life year averted. Individuals exhibited greater willingness to be vaccinated if it incurred no personal cost, with a minority willing to pay about $1 for the vaccine., Conclusions: The severe impact of EVD puts pressure on governments and the international community for better resource utilization and re-allocation. Several technical and methodological issues related to economic evaluation of EVD remain to be addressed, especially for LMICs. We recommend conducting cost-of-sequelae and cost-of-distribution analyses in addition to adapting existing economic analytical methods to EVD. Characteristics of the affected regions should be considered to provide evidence-based economic plans and economic-evaluation of mitigations that enhance resource allocation for prevention and treatment.

Introduction: A climate survey was piloted to obtain an understanding of the perceptions and personal experiences of faculty for intentional planning of future meaningful, effective, and sustainable diversity, equity, and inclusion (DEI) efforts at a college of pharmacy., Methods: A 48-item, four section, online survey was developed and administered to 69 faculty between October and November 2021. Likert-like five-point scales and free-text items were included to determine an overall assessment of climate, as well as perceptions and/or personal experiences for each domain of DEI, and demographics., Results: Thirty-nine (57%) faculty completed the survey. For climate, every attribute had at least one respondent that observed someone make an insensitive or disparaging remark "rarely," "occasionally," and "frequently." The response pattern was similar for personal experience with insensitive remarks. For participation in diversity activities, "awareness without participation" was selected by 56% of respondents. For perceptions of diversity, "fairly" or "very" was selected by 38% to 54% of respondents. For equity, "attainable for some" to "not attainable" was identified for 15% to 26% of respondents., Conclusions: These pilot climate survey results inform climate improvement as it relates to DEI and informs survey instrument refinement., Competing Interests: Conflict of interest None., (Copyright © 2023. Published by Elsevier Inc.)

Oppression, systemic bias, and racism have unfortunately long been part of the human experience. This paper is a review of basic elements of the Indian caste system, understanding its impact on the daily lives of different caste members, the role of colonialism in perpetuating the caste system, the Indian reservation system for mitigating disadvantages created by the caste system, and how categorization and labels can affect individual identity. This paper then discusses the global relevance of the caste system and its impact on mental health and psychological functioning. In India, the caste system is a comprehensive, systematized, and institutionalized form of oppression of members of the lower castes, particularly the Dalits. Formalized during the British colonial period, the caste system brings together two related Indian concepts of varna and jāti to create four social orders and multiple subunits. Sitting outside the traditional four orders are the Dalits, who experience social, economic, and religious discrimination due to an inherited status related to traditionally polluting occupations. Since the caste system extends beyond India to other South Asian countries, as well as to communities around the world that are home to the Indian diaspora, the inequities created by the caste system are a global issue. India's affirmative action system provides important insights to policy makers, as well as researchers in the social sciences for how to counteract the effects of systematized oppression. Collectively, this can aid in a better understanding of the effects of discrimination and oppression on identity, self-esteem, and mental health, and how we can develop more targeted policies and procedures in our own local contexts., 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. The handling editor SF declared a past co-authorship with the author VG., (Copyright © 2023 Goghari and Kusi.)

Introduction: Cervical cancer is the fourth most diagnosed cancer among women globally, with much of the burden being carried by women in limited-resource settings often worsened by the high prevalence of HIV. Furthermore, the COVID-19 pandemic disrupted organized screening efforts and HIV management regimens worldwide, and the impact of these disruptions have not been examined in these settings. The purpose of this paper is to describe whether uptake of cervical cancer screening and HIV management changed before, during, and since the COVID-19 pandemic in North-Central Nigeria., Methods: Longitudinal healthcare administration data for women who obtained care between January 2018 and December 2021 were abstracted from the AIDS Prevention Initiative Nigeria (APIN) clinic at Jos University Teaching Hospital. Patient demographics, pap smear outcomes, and HIV management indicators such as viral load and treatment regimen were abstracted and assessed using descriptive and regression analyses. All analyses were conducted comparing two years prior to the COVID-19 pandemic, the four quarters in 2020, and the year following COVID-19 restrictions., Results: We included 2304 women in the study, most of whom were between 44 and 47 years of age, were married, and had completed secondary education. About 85% of women were treated with first line highly active retroviral therapy (HAART). Additionally, 84% of women screened using pap smear had normal results. The average age of women who sought care at APIN was significantly lower in Quarter 3, 2020 (p = 0.015) compared to the other periods examined in this study. Conversely, the average viral load for women who sought care during that period was significantly higher in adjusted models (p < 0.0001). Finally, we determined that the average viral load at each clinic visit was significantly associated with the period in which women sought care., Conclusions: Overall, we found that COVID-19 pandemic mitigation efforts significantly influenced women's ability to obtain cervical cancer screening and routine HIV management at APIN clinic. This study buttresses the challenges in accessing routine and preventive care during the COVID-19 pandemic, especially in low-resource settings. Further research is needed to determine how these disruptions to care may influence long-term health in this and similar at-risk populations., (© 2023. The Author(s).)

Tumor-associated macrophages (TAMs) are integral to the development of complex tumor microenvironments (TMEs) and can execute disparate cellular programs in response to extracellular cues. However, upstream signaling processes underpinning this phenotypic plasticity remain to be elucidated. Here, we report that concordant AXL-STAT3 signaling in TAMs is triggered by lung cancer cells or cancer-associated fibroblasts in the cytokine milieu. This paracrine action drives TAM differentiation toward a tumor-promoting "M2-like" phenotype with upregulation of CD163 and putative mesenchymal markers, contributing to TAM heterogeneity and diverse cellular functions. One of the upregulated markers, CD44, mediated by AXL-IL-11-pSTAT3 signaling cascade, enhances macrophage ability to interact with endothelial cells and facilitate formation of primitive vascular networks. We also found that AXL-STAT3 inhibition can impede the recruitment of TAMs in a xenograft mouse model, thereby suppressing tumor growth. These findings suggest the potential application of AXL-STAT3-related markers to quantitatively assess metastatic potential and inform therapeutic strategies in lung cancer., Competing Interests: Declaration of interests S.W. is principal investigator at Sumitomo Dainippon Pharma Oncology., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The combinations of BRAF + MEK inhibitors-encorafenib (ENC) + binimetinib (BIN), cobimetinib (COB) + vemurafenib (VEM), and dabrafenib (DAB) + trametinib (TRA)-are recommended for the treatment of BRAF-mutated advanced melanoma., Objective: To assess the cost-effectiveness and cost-utility of ENC + BIN versus COB + VEM versus DAB + TRA from a US payer perspective., Methods: A Markov model was constructed to simulate a hypothetical cohort over a time horizon of 10 years. The overall survival (OS) and progression-free survival (PFS) curves were independently digitized from a randomized controlled trial for ENC + BIN and fitted using R software. Published and indirectly estimated hazard ratios were used to fit OS and PFS curves for COB + VEM and DAB + TRA. Costs, life-year gains, and quality-adjusted life years (QALYs) associated with the 3 treatment combinations were estimated. A base case analysis and probabilistic sensitivity analysis (PSA) were conducted to estimate the incremental cost-utility ratio (ICUR). A discount rate of 3.5% was applied on cost and outcomes., Results: The ENC + BIN versus COB + VEM comparison was associated with an ICUR of $656 233 per QALY gained. The ENC + BIN versus DAB + TRA comparison was associated with an ICUR of $3 135 269 per QALY gained. The DAB + TRA combination dominated COB + VEM. The base case analysis estimates were confirmed by the PSA estimates. ENC + BIN was the most cost-effective combination at a high willingness-to-pay (WTP) threshold of $573 000 per QALY and $1.5 million/QALY when compared to COB + VEM and DAB + TRA, respectively., Conclusion and Relevance: Given current prices and acceptable WTP thresholds, our study suggests that DAB + TRA is the optimum treatment. In this study, ENC + BIN was cost-effective only at a very high WTP per QALY threshold.

Purpose: Comorbidities can further challenge prognosis and general wellbeing of cancer patients. This study aimed to assess the association between comorbidities and perceived health status (PHS) of US persons with cancer., Methods: This cross-sectional study used 2019 Medical Expenditure Panel Survey (MEPS) data and included individuals who were alive throughout the year, aged 18 to 84 years, and had diagnosis for cancer. Using adjusted logistic regression models, we estimated the association of comorbidities (no, few [1/2], and more [3 or more] comorbidities) with PHS. Analyses accounted for the complex design of MEPS., Results: The dataset included 28,512 participants, 1739 of which were eligible for the study. Of these, 11.16% (95% CI 9.64, 12.59%); 41.73% (95% CI 39.21, 43.96%); and 47.10% (95% CI 44.86, 49.73%) reported having no, few, and more comorbidities, respectively. While breast (N = 356), prostate (N = 276), and melanoma (N = 273) were the most common cancers, hypertension (88.3%), hypercholesterolemia (49.5%), and arthritis (48%) were the most prevalent comorbidities. Adjusted logistic regression showed that, compared with those with no comorbidities, persons with few and more comorbidities had 1.58 (95% CI = 0.79, 3.15) and 2.27 (95% CI = 1.19, 4.32) times greater odds of poor PHS. Younger or male patients, those with less formal education, low-income, pain, functional limitation, or poor perception of mental health were more likely to regard their health as poor., Conclusion: About 88% of persons with history of cancer in the USA aged 18-84 years reported at least one comorbidity. Having more comorbidities, along with several other variables, was associated with poor PHS. Comorbidities management must be given special consideration to improve the prognosis and general wellbeing of persons with cancer., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Brain networks involved in language, attentional and response processes are detectable by fMRI during lexical decision (LD). Here, we investigated possible abnormalities in the functional networks involved in LD in patients with bipolar disorder (BD)., Methods: fMRI and behavioural data were compared between BD (n = 25) and control (n = 21), with groups matched for age and sex. The functional brain networks involved in LD were extracted by manipulating the "word-likeness" of LD stimuli and using a multidimensional analysis method., Results: Attentional, response and language processes were captured in separate function-specific brain networks (default mode network, response network, linguistic processing network, respectively) in the BD and control groups, replicating the results of our previous study in an independent group of healthy adults. Behaviourally, the BD group showed higher performance than the control group in the LD task. Activity in the default mode network (DMN) and the linguistic processing network (LPN) did not differ between the groups, but the BD group had higher activation than the control group in the response network (RESP)., Limitations: Due to the small sample, the study is underpowered, capable of only detecting large effects., Conclusions: The results suggest that BD may be associated with sustained activity in the RESP network, which might contribute to psychomotor dysfunction in BD. Future studies should investigate the possible link between altered RESP activation and psychomotor disturbances in BD, as well as the basis for altered RESP activity in BD., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Using real-world data, this retrospective cross-sectional study aimed to analyze the association between patient-physician communication and self-reported mental health from cancer patients using publicly available 2019 Medical Expenditure Panel Survey (MEPS) household component data. Four adjusted logistic regression models were conducted to analyze the association between patient-physician communication and self-perceived mental health among United States adult cancer patients, with each model assessing different aspects of patient-physician communication: being respected (respect), being listened to (listen), spending enough time (time), and being explained (explain). The main finding from this study was that only the time model showed a statistical significance, where patients who reported that their physician always spent enough time perceived their mental health as good. Other covariates that showed statistical significance with self-perceived mental health in cancer patients included age, income level, physical limitation, and limitation from pain. In conclusion, there were generally no statistically significant associations between patient-physician communication and mental health among cancer patients.

Background: There are limited data on the psychometric properties of instruments evaluating professional identity (PI) among student pharmacists., Objectives: This study analyzed the psychometric properties of an instrument to assess student pharmacists' perception of their PI., Methods: Data from a cross-sectional survey were used to establish validity and reliability evidence of student pharmacists' perception of PI using Rasch analysis. Linear regression was conducted to evaluate the association of students' characteristics with their perceived PI. Analyses were conducted in WINSTEPS (SWREG, Minnetonka, MN) and SAS (SAS, Cary, NC)., Results: The analysis included 118 student pharmacists. Primary analysis suggested inadequate scale functionality; thus, some response categories were merged. With modified item anchors and the removal of the most misfitting item, the data fit the model as measured by student and item infit and outfit mean-squared values. The item-person map showed appropriate distribution of item difficulty, identifying medicine adviser and entrepreneur being the easiest and hardest items to agree with, respectively. Students' abilities initially mismatched with item difficulty and exhibited a ceiling effect, requiring addition of items reflecting students' higher perceptions of PIs. Although students' reliability coefficient (RC) and separation index were 0.98 and 1.73, respectively, RC of the items was 0.94. Students who reported receiving formal PI training were 0.3 times more likely to have high perception of PI than those who did not report training., Conclusion: The instrument exhibited fair validity and reliability evidence for assessing the perception of PI among student pharmacists. Additional items to fill identified item gaps are needed to improve the instrument's content validity., (Copyright © 2022 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

Background: Historically marginalized youth are at risk for daily substance use. Daily use may be associated with social and environmental factors., Methods: In March 2018, we surveyed primarily Latino adolescents ages 14-18 who lived on the US-Mexico border and assessed associations between daily substance use, neighborhood stress, border community and immigration stress, and family support., Results: Of 443 surveyed adolescents, 41 (9%) reported daily use. Those who used daily were more likely to be older, identify as male, and reported lower social support and higher neighborhood and border community stress compared to those who did not use daily. Perceived neighborhood stress (OR = 1.95, 95% CI 1.37-2.80) and border community and immigration stress (OR = 1.55, 95% CI 1.12-2.02) were associated with increased odds of daily substance use., Discussion: Latino adolescents who live near the US-Mexico border experience unique socioenvironmental stress which is associated with daily substance use., Competing Interests: Conflict of Interest Statement: The authors declare that there are no conflicts of interest.

The epigenome delineates lineage-specific transcriptional programs and restricts cell plasticity to prevent non-physiological cell fate transitions. Although cell diversification fosters tumor evolution and therapy resistance, upstream mechanisms that regulate the stability and plasticity of the cancer epigenome remain elusive. Here we show that 2-hydroxyglutarate (2HG) not only suppresses DNA repair but also mediates the high-plasticity chromatin landscape. A combination of single-cell epigenomics and multi-omics approaches demonstrates that 2HG disarranges otherwise well-preserved stable nucleosome positioning and promotes cell-to-cell variability. 2HG induces loss of motif accessibility to the luminal-defining transcriptional factors FOXA1, FOXP1, and GATA3 and a shift from luminal to basal-like gene expression. Breast tumors with high 2HG exhibit enhanced heterogeneity with undifferentiated epigenomic signatures linked to adverse prognosis. Further, ascorbate-2-phosphate (A2P) eradicates heterogeneity and impairs growth of high 2HG-producing breast cancer cells. These findings suggest 2HG as a key determinant of cancer plasticity and provide a rational strategy to counteract tumor cell evolution., Competing Interests: Declaration of interests The authors declare no competing interests., (Published by Elsevier Inc.)

Background: Although adherence to imatinib is critical for attaining treatment responses in chronic myeloid leukemia, there is evidence of varying adherence among patients. Our aim was to model and determine the margin of tolerance, if any, required to ensure treatment responses among patients prescribed imatinib before treatment response is at risk., Method: We performed post hoc analyses of the ADAGIO study conducted in Belgium on 169 evaluable patients (Blood 2009). Applying Kaplan-Meier methods using adherence instead of the conventional time variable, we modeled the likelihood of complete cytogenetic (CCyR), complete hematological (CHR), major molecular (MMR) and optimal (OR) response as a function of 90-day pill count adherence., Results: Analyses showed that ∼100 % adherence of prescribed dose is associated with probabilities of 0.84 for CHR, 0.83 for CCyR, 0.82 for OR, and 0.77 for MMR; compared to, 0.37 (CHR and CCyR), 0.35 (OR), and 0.39 (MMR) at 90 % adherence. Increasing intake of imatinib from 90 % to 100 % of the prescribed dose increased the likelihood of the various treatment responses by 1.95-2.35-fold., Conclusion: There is virtually no margin for nonadherence, if the objective is to optimize the likelihood of treatment response, and a minimal margin to avoid impaired treatment response., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

White matter pathology likely contributes to the pathogenesis of bipolar disorder (BD). Most studies of white matter in BD have used diffusion tensor imaging (DTI), but the advent of more advanced multi-shell diffusion MRI imaging offers the possibility to investigate other aspects of white matter microstructure. Diffusion kurtosis imaging (DKI) extends the DTI model and provides additional measures related to diffusion restriction. Here, we investigated white matter in BD by applying whole-brain voxel-based analysis (VBA) and a network-based connectivity approach using constrained spherical deconvolution tractography to assess differences in DKI and DTI metrics between BD (n = 25) and controls (n = 24). The VBA showed lower mean kurtosis in the corona radiata and posterior association fibers in BD. Regional differences in connectivity were indicated by lower mean kurtosis and kurtosis anisotropy in streamlines traversing the temporal and occipital lobes, and lower mean axial kurtosis in the right cerebellar, thalamo-subcortical pathways in BD. Significant differences were not seen in DTI metrics following FDR-correction. The DKI findings indicate altered connectivity across cortical, subcortical and cerebellar areas in BD. DKI is sensitive to different microstructural properties and is a useful complementary technique to DTI to more fully investigate white matter in BD., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objectives: To demonstrate how medical purchasing power parities (mPPP) may harmonize economic evaluations from different jurisdictions and enable comparisons across jurisdictions., Methods: We describe the use of mPPPs and illustrate this with an example of economic evaluations of nab-paclitaxel with gemcitabine (Nab-P + Gem) versus gemcitabine monotherapy in the setting of metastatic pancreatic cancer. Following a literature search, we extracted data from cost-effectiveness studies on these treatments performed in various countries. mPPPs from the Organization for Economic Co-operation and Development were used to convert reported costs in the jurisdiction of origins to US dollars for the most current year using two possible pathways: (1) reported costs first adjusted by mPPP then adjusted by exchange index; and (2) reported costs first adjusted by exchange index then adjusted by mPPP., Results: Despite many of the pharmaco-economic evaluations sharing similar assumptions and inputs, even after mPPP conversion, residual heterogeneity was attributable to perspectives, discount rate, outcomes, and costs, among others; including in studies conducted in the same jurisdiction., Conclusion: Despite the methodological challenges and heterogeneity within and across jurisdictions, we demonstrated that mPPP offers a way to compare economic evaluations across jurisdictions.

Background: With the increasing occurrence of infectious diseases in lower-and-middle-income countries (LMICs), emergency preparedness is essential for rapid response and mitigation. Economic evaluations of mitigation technologies and strategies have been recommended for inclusion in emergency preparedness plans. We aimed to perform an economic evaluation using dynamic transition modeling of ebola virus disease (EVD) vaccination in a hypothetical community of 1,000 persons in the Democratic Republic of Congo (DRC)., Method: Using a modified SEIR (Susceptible, Exposed, Infectious, Recovered, with Death added [SEIR-D]) model that accounted for death and epidemiological data from an EVD outbreak in the DRC, we modeled the transmission of EVD in a hypothetical population of 1,000. With our model, we estimated the cost-effectiveness of an EVD vaccine and an EVD vaccination intervention., Results: The results showed vaccinating 50% of the population at risk prevented 670 cases, 538 deaths, and 22,022 disability-adjusted life years (DALYs). The vaccine was found to be cost-effective with an incremental cost-effectiveness ratio (ICER) of $95.63 per DALY averted. We also determined the minimum required vaccination coverage for cost-effectiveness to be 40%. Sensitivity analysis showed our model to be fairly robust, assuring relatively consistent results even with variations in such input parameters as cost of screening, as well as transmission, infection, incubation, and case fatality rates., Conclusion: EVD vaccination in our hypothetical population was found to be cost-effective from the payer perspective. Our model presents an efficient and reliable approach for conducting economic evaluations of infectious disease interventions as part of an emergency preparedness plan.

Among single-cell analysis technologies, single-cell RNA-seq (scRNA-seq) has been one of the front runners in technical inventions. Since its induction, scRNA-seq has been well received and undergone many fast-paced technical improvements in cDNA synthesis and amplification, processing and alignment of next generation sequencing reads, differentially expressed gene calling, cell clustering, subpopulation identification, and developmental trajectory prediction. scRNA-seq has been exponentially applied to study global transcriptional profiles in all cell types in humans and animal models, healthy or with diseases, including cancer. Accumulative novel subtypes and rare subpopulations have been discovered as potential underlying mechanisms of stochasticity, differentiation, proliferation, tumorigenesis, and aging. scRNA-seq has gradually revealed the uncharted territory of cellular heterogeneity in transcriptomes and developed novel therapeutic approaches for biomedical applications. This review of the advancement of scRNA-seq methods provides an exploratory guide of the quickly evolving technical landscape and insights of focused features and strengths in each prominent area of progress., Competing Interests: Conflicts of interest All authors declared that there are no conflicts of interest.

The interplay between glycolysis and mitochondrial oxidative phosphorylation (OXPHOS) is central to maintain energy homeostasis. It remains to be determined whether there is a mechanism governing metabolic fluxes based on substrate availability in microenvironments. Here we show that menin is a key transcription factor regulating the expression of OXPHOS and glycolytic genes in cancer cells and primary tumors with poor prognosis. A group of menin-associated proteins (MAPs), including KMT2A, MED12, WAPL, and GATA3, is found to restrain menin's full function in this transcription regulation. shRNA knockdowns of menin and MAPs result in reduced ATP production with proportional alterations of cellular energy generated through glycolysis and OXPHOS. When shRNA knockdown cells are exposed to metabolic stress, the dual functionality can clearly be distinguished among these metabolic regulators. A MAP can negatively counteract the regulatory mode of menin for OXPHOS while the same protein positively influences glycolysis. A close-proximity interaction between menin and MAPs allows transcriptional regulation for metabolic adjustment. This coordinate regulation by menin and MAPs is necessary for cells to rapidly adapt to fluctuating microenvironments and to maintain essential metabolic functions.

Background: Chromothripsis is an event of genomic instability leading to complex chromosomal alterations in cancer. Frequent long-range chromatin interactions between transcription factors (TFs) and targets may promote extensive translocations and copy-number alterations in proximal contact regions through inappropriate DNA stitching. Although studies have proposed models to explain the initiation of chromothripsis, few discussed how TFs influence this process for tumor progression., Methods: This study focused on genomic alterations in amplification associated regions within chromosome 17. Inter-/intra-chromosomal rearrangements were analyzed using whole genome sequencing data of breast tumors in the Cancer Genome Atlas (TCGA) cohort. Common ERα binding sites were defined based on MCF-7, T47D, and MDA-MB-134 breast cancer cell lines using univariate K-means clustering methods. Nanopore sequencing technology was applied to validate frequent rearrangements detected between ATC loci on 17q23 and an ERα hub on 20q13. The efficacy of pharmacological inhibition of a potentially druggable target gene on 17q23 was evaluated using breast cancer cell lines and patient-derived circulating breast tumor cells., Results: There are five adjoining regions from 17q11.1 to 17q24.1 being hotspots of chromothripsis. Inter-/intra-chromosomal rearrangements of these regions occurred more frequently in ERα-positive tumors than in ERα-negative tumors. In addition, the locations of the rearrangements were often mapped within or close to dense ERα binding sites localized on these five 17q regions or other chromosomes. This chromothriptic event was linked to concordant upregulation of 96 loci that predominantly regulate cell-cycle machineries in advanced luminal tumors. Genome-editing analysis confirmed that an ERα hub localized on 20q13 coordinately regulates a subset of these loci localized on 17q23 through long-range chromosome interactions. One of these loci, Tousled Like Kinase 2 (TLK2) known to participate in DNA damage checkpoint control, is an actionable target using phenothiazine antipsychotics (PTZs). The antiproliferative effect of PTZs was prominent in high TLK2-expressing cells, compared to low expressing cells., Conclusion: This study demonstrates a new approach for identifying tumorigenic drivers from genomic regions highly susceptible to ERα-related chromothripsis. We found a group of luminal breast tumors displaying 17q-related chromothripsis for which antipsychotics can be repurposed as treatment adjuncts.

What Is Known and Objective: Hypertension and hyperlipidaemia have high prevalence among diabetics and increase patients' risk of cardiovascular diseases, ultimately affecting prognosis negatively. Medicine claims data have gained prominence in the study of drug-related events and outcomes. There is paucity of publications on the time-to-onset of treatment for these conditions among South African diabetics using secondary data. This study aims to determine the time-to-onset of treatment for hypertension and hyperlipidaemia among diabetics using a South African medicine claims data., Methods: Survival analysis was conducted using retrospective data of patients enrolled continuously with a Pharmaceutical Benefit Management (PBM) company in South Africa from 1 January 2008 to 31 December 2016. We identified patients based on International Classification of Diseases, Tenth Revision (ICD-10) diagnoses codes for type 2 diabetes mellitus (E11) who were receiving antidiabetic medication according to the National Pharmaceutical Product Index (NAPPI) codes provided by the Monthly Index of Medical Specialities (MIMS) classification code 19.1 (N = 2996). Among these patients, we then selected those who had ICD-10 codes for hypertension (I10, I11, I12, I13, I15, O10 and O11) who were receiving antihypertensive medications, and those who had hyperlipidaemia (E78.5), who received antihyperlipidaemics during the study period. Data were extracted using SAS ® system version 9.4 classification codes. The Kaplan-Meier approach, used to compare the survival experience of patients who commenced treatment for hypertension and hyperlipidaemia, was conducted using IBM ® SPSS ® version 25. The time to the commencement of treatment of hypertension and hyperlipidaemia among the diabetics were measured in days. With 2008 serving as the index year, we followed up on patients until 31 December 2016., Results and Discussion: A total of 494 patients with an average age of 53.5 (SD 11.1) years were included in the study, 34.8% of whom were females. Prevalence of hyperlipidaemia and hypertension among patients were 35.0% and 45.6%, respectively. Average time-to-onset of treatment for hyperlipidaemia was 2684.4 (SD 42.2) days compared to 2434.2 (SD 47.6) days for hypertension. There was no statistically significant difference in age and sex among patients who started treatment for either of these conditions during the study (P = 0.404; Cohen's d = 0.132 for hyperlipidaemia and P = 0.644, Cohen's d = 0.059 for hypertension)., What Is New and Conclusion: Within an average of 6 years after an index period of 1 year free of disease, diabetics may commence treatment for hyperlipidaemia, hypertension or both. With all significant data appropriately captured, medicine claims data can be effectively used in survival analysis to determine time-to-onset of treatment for hyperlipidaemia and hypertension among diabetics., (© 2019 John Wiley & Sons Ltd.)

Introduction The Nepal earthquake of 2015 was a major disaster that exacted an enormous toll on human lives and caused extensive damage to the infrastructure of the region. Similar to other developing countries, Nepal has a network of community health workers (CHWs; known as female community health volunteers [FCHVs]) that was in place prior to the earthquake and continues to function to improve maternal and child health. These FCHVs and other community members were responsible, by default, for providing the first wave of assistance after the earthquake. Hypothesis/Problem Community health workers such as FCHVs could be used to provide formal relief services in the event of an emergency, but there is a paucity of evidence-based literature on how to best utilize them in disaster risk reduction, preparedness, and response. Data are needed to further characterize the roles that this cadre has played in past disasters and what strategies can be implemented to better incorporate them into future emergency management., Methods: In March 2016, key-informant interviews, FCHV interviews, and focus group discussions (FGDs) were conducted in Nepali health facilities using semi-structured guides. The audio-recorded data were obtained with the assistance of a translator (Nepali-English), transcribed verbatim in English, and coded by two independent researchers (manually and with NVivo 11 Pro software [QSR International; Melbourne, Australia])., Results: Across seven different regions, 14 interviews with FCHVs, two FGDs with community women, and three key-informant interviews were conducted. Four major themes emerged around the topic of FCHVs and the 2015 earthquake: (1) community care and rapport between FCHVs and local residents; (2) emergency response of FCHVs in the immediate aftermath of the earthquake; (3) training requested to improve the FCHVs' ability to manage disasters; and (4) interaction with relief organizations and how to create collaborations that provide aid relief more effectively., Conclusions: The FCHVs in Nepal provided multiple services to their communities in the aftermath of the earthquake, largely without any specific training or instruction. Proper preparation, in addition to improved collaboration with aid agencies, could increase the capacity of FCHVs to respond in the event of a future disaster. The information gained from this study of the FCHV experience in the Nepal earthquake could be used to inform risk reduction and emergency management policies for CHWs in various settings worldwide. Fredricks K , Dinh H , Kusi M , Yogal C , Karmacharya BM , Burke TF , Nelson BD . Community health workers and disasters: lessons learned from the 2015 earthquake in Nepal. Prehosp Disaster Med. 2017;32(6):604-609.