Association of umbilical cord blood lead with neonatal behavior at varying levels of exposure

BACKGROUND: In the light of the ongoing debate about lowering the cut-off for acceptable blood lead level to <5 μg/dL from the currently recommended level of <10 μg/dL, we considered whether prenatal exposure to varying levels of lead is associated with similar or disparate effects on neonatal behavior. METHODS: Using Brazelton's Neonatal Behavioral Assessment Scale (NBAS), an epidemiological approach and robust statistical techniques like multivariate linear regression, logistic regression, Poisson regression and structural equations modeling analyses we estimated the simultaneous indirect effects of umbilical cord blood lead (CBL) levels and other neonatal covariates on the NBAS clusters. RESULTS: We observed that when analyzed in all study subjects, the CBL levels independently and strongly influenced autonomic stability and abnormal reflexes clusters. However, when the analysis was restricted to neonates with CBL <10 μg/dL, CBL levels strongly influenced the range of state, motor and autonomic stability clusters. Abnormal walking reflex was consistently associated with an increased CBL level irrespective of the cut-off for CBL, however, only at the lower cut-offs were the predominantly behavioral effects of CBL discernible. CONCLUSION: Our results further endorse the need to be cognizant of the detrimental effects of blood lead on neonates even at a low-dose prenatal exposure

Considering the totality of evidence: Combining real-world data with clinical trial results to better inform decision-making

Clinical trials are the key mechanism for testing efficacy of cancer therapy. While results from clinical trials have high internal validity, generalizability is limited due to strict criteria for inclusion and exclusion (i.e., eligibility criteria). Indeed, eligibility criteria are designed to protect the safety of trial participants by excluding those expected to have low efficacy or high toxicity from the treatment under investigation. However, if overly restrictive, eligibility criteria can also result in narrow populations that do not reflect the general population treated in routine practice. Recent analyses of cancer clinical trial data have shown that eligibility criteria have become increasingly restrictive, ranging from 16 to 32 exclusion criteria per trial, over time. Therefore, it is not surprising that <5% of US adult patients with cancer participate in clinical trials, and those who do are often younger and healthier than patients seen in clinical practice. These differences raise serious concern that the “efficacy” of cancer therapies reported in published clinical trials provides incomplete evidence of their “effectiveness” when administered to patients in routine care

CPO and quantitative textural analyses within sheath folds

Acknowledgments This has been a multi-national collaboration from authors based in Europe, North America, Australia and India. Erasmus funding to GIA in 2018 enabled a visit to Catania leading to discussion and initiation of this project. The authors are grateful to Amarnath Dandapat for preparation of superpolished rock thin sections at the Department of Geology and Geophysics (IIT Kharagpur, India). Niloy Bhowmik is thanked for assistance with SEM-EBSD data generation in the Central Research Facility (IIT Kharagpur, India). E.F. thanks Sibio Carmelo for thin sections preparation at the University of Turin (Italy). Authors are grateful to ANSTO laboratory personnel for the preparation of specimens (funded proposals: P9835 with the title “Sheath fold texture characterisation”, principal scientist: E.F.; co-proposers: G.I.A. and V.L.; DB6749 with the title “Texture analysis of rocks”, principal scientist: V.L.; co-proposer: E.F.; DB9606 with the title “A pilot experiment for texture characterisation in a sheath fold”, principal scientist: E.F..; co-proposers: G.I.A. and V.L.). L.N. and R.G. report that this publication has been assigned the NRCan contribution number 20230109. Many thanks to Richard D. Law and an anonymous reviewer for their careful revision that substantially improved the original version of the manuscript. We also thanks Dr. T.K. Cawood from the Geological Survey of Canada for her useful comments on the drafted manuscript. The editorial handling by Fabrizio Agosta is greatly appreciated.Peer reviewedPublisher PD

A simple method to combine multiple molecular biomarkers for dichotomous diagnostic classification

BACKGROUND: In spite of the recognized diagnostic potential of biomarkers, the quest for squelching noise and wringing in information from a given set of biomarkers continues. Here, we suggest a statistical algorithm that – assuming each molecular biomarker to be a diagnostic test – enriches the diagnostic performance of an optimized set of independent biomarkers employing established statistical techniques. We validated the proposed algorithm using several simulation datasets in addition to four publicly available real datasets that compared i) subjects having cancer with those without; ii) subjects with two different cancers; iii) subjects with two different types of one cancer; and iv) subjects with same cancer resulting in differential time to metastasis. RESULTS: Our algorithm comprises of three steps: estimating the area under the receiver operating characteristic curve for each biomarker, identifying a subset of biomarkers using linear regression and combining the chosen biomarkers using linear discriminant function analysis. Combining these established statistical methods that are available in most statistical packages, we observed that the diagnostic accuracy of our approach was 100%, 99.94%, 96.67% and 93.92% for the real datasets used in the study. These estimates were comparable to or better than the ones previously reported using alternative methods. In a synthetic dataset, we also observed that all the biomarkers chosen by our algorithm were indeed truly differentially expressed. CONCLUSION: The proposed algorithm can be used for accurate diagnosis in the setting of dichotomous classification of disease states

Cost-effectiveness of pembrolizumab as second-line therapy for the treatment of locally advanced or metastatic urothelial carcinoma in Sweden

Background: Urothelial carcinoma (UC) is the most common subtype of bladder cancer. The randomized phase 3 KEYNOTE-045 trial showed that pembrolizumab, used as second-line therapy significantly prolonged overall survival with fewer treatment-related adverse events than chemotherapy for advanced UC. Pembro- lizumab has been approved by the European Medicines Agency for the treatment of locally advanced or metastatic UC in adults who have received platinum-contain- ing chemotherapy. Many European countries use cost-effectiveness analysis to inform reimbursement decisions. Objective: To assess the cost-effectiveness of pembrolizumab as second-line ther- apy for the treatment of advanced UC from a Swedish health care perspective. Design, setting, and participants: We developed a partitioned-survival model to assess the costs and effectiveness of pembrolizumab compared with vinflunine (base case), paclitaxel, or docetaxel monotherapy in patients with advanced UC over a 15-yr time horizon. We obtained Kaplan-Meier estimates for survival end- points, adverse events, and utility data from KEYNOTE-045. Outcome measurements and statistical analysis: We performed parametric extra- polations to estimate overall and progression-free survival beyond the clinical trial period. Swedish costs and utility weights were used to estimate total costs, quality- adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICERs). We performed deterministic and probabilistic sensitivity analyses to assess the ro- bustness of the model results. Results and limitations: In the base-case analysis, pembrolizumab resulted in a mean survival gain of 1.66 years (1.38 QALYs) at an incremental cost of s69 852 and an ICER of s50 529/QALY gained versus vinflunine monotherapy. ICERs for other chemotherapies were s81 356/QALY for pembrolizumab versus paclitaxel or doc- etaxel monotherapy, and s71924/QALY for pembrolizumab versus paclitaxel, docetaxel, or vinflunine monotherapy. Long-term follow-up from KEYNOTE-045 and real-world data are needed to validate the extrapolations

Association of CCR2-CCR5 Haplotypes and CCL3L1 Copy Number with Kawasaki Disease, Coronary Artery Lesions, and IVIG Responses in Japanese Children

BACKGROUND: The etiology of Kawasaki Disease (KD) is enigmatic, although an infectious cause is suspected. Polymorphisms in CC chemokine receptor 5 (CCR5) and/or its potent ligand CCL3L1 influence KD susceptibility in US, European and Korean populations. However, the influence of these variations on KD susceptibility, coronary artery lesions (CAL) and response to intravenous immunoglobulin (IVIG) in Japanese children, who have the highest incidence of KD, is unknown. METHODOLOGY/PRINCIPAL FINDINGS: We used unconditional logistic regression analyses to determine the associations of the copy number of the CCL3L1 gene-containing duplication and CCR2-CCR5 haplotypes in 133 Japanese KD cases [33 with CAL and 25 with resistance to IVIG] and 312 Japanese controls without a history of KD. We observed that the deviation from the population average of four CCL3L1 copies (i.e., <or>four copies) was associated with an increased risk of KD and IVIG resistance (adjusted odds ratio (OR)=2.25, p=0.004 and OR=6.26, p=0.089, respectively). Heterozygosity for the CCR5 HHF*2 haplotype was associated with a reduced risk of both IVIG resistance (OR=0.21, p=0.026) and CAL development (OR=0.44, p=0.071). CONCLUSIONS/SIGNIFICANCE: The CCL3L1-CCR5 axis may play an important role in KD pathogenesis. In addition to clinical and laboratory parameters, genetic markers may also predict risk of CAL and resistance to IVIG

A prospective cohort study of postoperative complications in the management of perforated peptic ulcer

BACKGROUND: With dwindling rates of postoperative mortality in perforated peptic ulcer that is attributable to H(2)-receptor blocker usage, there is a need to shift the focus towards the prevention of postoperative morbidity. Further, the simultaneous contribution of several putative clinical predictors to this postoperative morbidity is not fully appreciated. Our objective was to assess the predictors of the risk, rate and number of postoperative complications in surgically treated patients of perforated peptic ulcer. METHODS: In a prospective cohort study of 96 subjects presenting as perforated peptic ulcer and treated using Graham's omentoplatsy patch or gastrojejunostomy (with total truncal vagotomy), we assessed the association of clinical predictors with three domains of postoperative complications: the risk of developing a complication, the rate of developing the first complication and the risk of developing higher number of complications. We used multiple regression methods – logistic regression, Cox proportional hazards regression and Poisson regression, respectively – to examine the association of the predictors with these three domains. RESULTS: We observed that the risk of developing a postoperative complication was significantly influenced by the presence of a concomitant medical illness [odds ratio (OR) = 8.9, p = 0.001], abdominal distension (3.8, 0.048) and a need of blood transfusion (OR = 8.2, p = 0.027). Using Poisson regression, it was observed that the risk for a higher number of complications was influenced by the same three factors [relative risk (RR) = 2.6, p = 0.015; RR = 4.6, p < 0.001; and RR = 2.4, p = 0.002; respectively]. However, the rate of development of complications was influenced by a history suggestive of shock [relative hazards (RH) = 3.4, p = 0.002] and A(- )blood group (RH = 4.7, p = 0.04). CONCLUSION: Abdominal distension, presence of a concomitant medical illness and a history suggestive of shock at the time of admission warrant a closer and alacritous postoperative management in patients of perforated peptic ulcer

Evaluation of chemiluminescence, toluidine blue and histopathology for detection of high risk oral precancerous lesions: A cross-sectional study

<p>Abstract</p> <p>Background</p> <p>Early detection holds the key to an effective control of cancers in general and of oral cancers in particular. However, screening procedures for oral cancer are not straightforward due to procedural requirements as well as feasibility issues, especially in resource-limited countries.</p> <p>Methods</p> <p>We conducted a cross-sectional study to compare the performance of chemiluminescence, toluidine blue and histopathology for detection of high-risk precancerous oral lesions. We evaluated 99 lesions from 55 patients who underwent chemiluminescence and toluidine blue tests along with biopsy and histopathological examination. We studied inter-as well as intra-rater agreement in the histopathological evaluation and then using latent class modeling, we estimated the operating characteristics of these tests in the absence of a reference standard test.</p> <p>Results</p> <p>There was a weak inter-rater agreement (kappa < 0.15) as well as a weak intra-rater reproducibility (Pearson's r = 0.28, intra-class correlation rho = 0.03) in the histopathological evaluation of potentially high-risk precancerous lesions. When compared to histopathology, chemiluminescence and toluidine blue retention had a sensitivity of 1.00 and 0.59, respectively and a specificity of 0.01 and 0.79, respectively. However, latent class analysis indicated a low sensitivity (0.37) and high specificity (0.90) of histopathological evaluation. Toluidine blue had a near perfect high sensitivity and specificity for detection of high-risk lesions.</p> <p>Conclusion</p> <p>In our study, there was variability in the histopathological evaluation of oral precancerous lesions. Our results indicate that toluidine blue retention test may be better suited than chemiluminescence to detect high-risk oral precancerous lesions in a high-prevalence and low-resource setting like India.</p

The Use of Herbal Medications and Dietary Supplements by People with Mental Illness

This study examined the relationship between herbal medication and dietary supplement (HMDS) use and mental health characteristics. Data are drawn from a national household survey of the United States’ civilian, non-institutionalized population (N = 9,585). Psychiatric medication and HMDS use, psychiatric diagnoses and treatment needs, utilization and satisfaction were assessed. Compared to non-users, HMDS users were more likely to perceive themselves as having mental health needs, to have received mental health and primary care treatment, and to be dissatisfied with their overall healthcare. Psychiatric medication use was not related to HMDS use, and in multivariate analyses, HMDS use was associated with perceived mental health needs. Differences in use of specific HMDS between those with and without a psychiatric disorder were also examined. The use of HMDS warrants particular attention in persons with perceived mental health problems as these individuals may be turning to HMDS use for treatment of their symptoms