Sample Median Research Articles

Ostracoda (Crustacea) and limnoecological characteristics of Lake Karamurat (Bolu, Turkey): Testing pseudorichness hypothesis

To investigate the relationship between ostracod occurrence patterns, community assemblage, and abiotic factors, we sampled five sites on lake Karamurat (Bolu, Turkey) and two nearby rheocrene springs. Thirteen ostracod taxa (10 from the lake, three from the springs) were collected. Species exhibited clear habitat preferences, and lake and spring ostracods showed clear differences in their monthly and seasonal occurrences. Darwinula stevensoni and Cypria ophtalmica were the dominant species for the lake and Psychrodromus cf. fontinalis and P. olivaceus were only reported from the springs. Ostracod Watch Model illustrated that a rare species, Notodromas monacha, was only found in May to August from the lake while two species (D. stevensoni, C. ophtalmica) were encountered from all year around. Common species also exhibited relatively high levels of ecological tolerances to multiple environmental variables. Canonical correspondence analyses explained about 91% of correlation between species and environmental variables and indicated that four variables (water temperature, dissolved oxygen, pH and electrical conductivity) most strongly influenced species occurrences. Also, binary data of sample medians showed significant (P < 0.01) differences between ostracod assemblages from 13 lakes and reservoirs compared to Lake Karamurat. A significant correlation was detected between Lake Karamurat and two other lakes (Abant and Yeniçağa) located in the same region. The Pseudorichness Ratio (noncosmopolitan/cosmopolitan species) of the lake was very low (Pr = 0.25), indicating dominancy of cosmopolitan species over noncosmopolitans. Conservation efforts should be considered to addressed increasing anthropogenic impacts to Lake Karamurat.

Occurrence, potential sources, and risk assessment of pharmaceuticals and personal care products in atmospheric particulate matter in Hanoi, Vietnam.

Pharmaceutical and personal care products (PCPPs) were recently recognized as emerging pollutants due to their potential for adverse health and environmental impacts. One potential route of exposure, atmospheric particulate matter (APM), for polar PPCP chemicals has to date received limited attention. This study screened for 190 polar PPCP chemicals in outdoor APM samples collected from two locations in Hanoi, Vietnam, and predictions of source and potential effects on human health are presented. Day and night, as well as dry and rainy seasonal samples, were taken, and samples screened by LC-TOF, using sequential window acquisition and all theoretical fragment ion spectra method. Eleven PPCP chemicals were detected above the LOD and in more than one sample. The ∑11PPCP chemicals ranged from 0.61 to 21.9ngm-3 (median 2.07ngm-3), with between 2 and 6 compounds identified in individual samples (median 4). The ∑11PPCP chemicals collected near a heavy traffic area was greater than that in a populated residential zone. Night concentrations were significantly greater than day in both dry and rainy seasons (p < 0.05). Butyl methoxydibenzoylmethane, benzophenone-3, acetaminophen, cotinine, and fluorescent brightener 71 were detected in > 50% of samples. These are typically found in sunscreens, cosmetics, antipyretics, tobacco, and dyes. The DIair, hazard quotient (HQ), and hazard index (HI) for adults and children at sampling sites were estimated. The HQ for both adults and children were orders of magnitude less than the risk or were close to or whichever. APM does appear to be a potential additional secondary exposure source of PPCP chemicals to the environment and more work is needed to identify if sources are local or ubiquitous and if there is a greater health risk.

Association of wearable device-measured vigorous intermittent lifestyle physical activity with mortality

Wearable devices can capture unexplored movement patterns such as brief bursts of vigorous intermittent lifestyle physical activity (VILPA) that is embedded into everyday life, rather than being done as leisure time exercise. Here, we examined the association of VILPA with all-cause, cardiovascular disease (CVD) and cancer mortality in 25,241 nonexercisers (mean age 61.8 years, 14,178 women/11,063 men) in the UK Biobank. Over an average follow-up of 6.9 years, during which 852 deaths occurred, VILPA was inversely associated with all three of these outcomes in a near-linear fashion. Compared with participants who engaged in no VILPA, participants who engaged in VILPA at the sample median VILPA frequency of 3 length-standardized bouts per day (lasting 1 or 2 min each) showed a 38%–40% reduction in all-cause and cancer mortality risk and a 48%–49% reduction in CVD mortality risk. Moreover, the sample median VILPA duration of 4.4 min per day was associated with a 26%–30% reduction in all-cause and cancer mortality risk and a 32%–34% reduction in CVD mortality risk. We obtained similar results when repeating the above analyses for vigorous physical activity (VPA) in 62,344 UK Biobank participants who exercised (1,552 deaths, 35,290 women/27,054 men). These results indicate that small amounts of vigorous nonexercise physical activity are associated with substantially lower mortality. VILPA in nonexercisers appears to elicit similar effects to VPA in exercisers, suggesting that VILPA may be a suitable physical activity target, especially in people not able or willing to exercise.

The association between long‐term PM2.5 exposure and late‐life amyloid burden in the Atherosclerosis Risk in Communities (ARIC) study cohort

AbstractBackgroundA number of studies show an association between long‐term exposure to ambient particulate matter ≤ 2.5 um (PM2.5) and late‐life cognitive impairment. Mechanistic models suggest that PM2.5 may influence cognitive health through promotion of Alzheimer’s disease, which is characterized by brain amyloid accumulation. However, the association between long‐term PM2.5 exposure and brain amyloid deposition remains poorly characterized in epidemiological studies.MethodWe used data from the Atherosclerosis Risk in Communities (ARIC) study cohort. We used a chemical transport model with data fusion to estimate mean PM2.5 concentrations (ug/m3) in 36‐, 12‐, 4‐, and 1‐km grid cells in ARIC study areas. We linked the concentrations to geocoded participant addresses and calculated mean PM2.5 concentrations from 2000 to 2007. We estimated amyloid deposition using florbetapir amyloid positron emission tomography (PET) scans in 346 ARIC‐PET participants with normal cognition or mild cognitive impairment in 2011‐2014. We defined amyloid positivity as a global cortical standardized uptake value ratio (SUVR) ≥ the sample median of 1.2. We used logistic regression models to quantify the association between amyloid positivity and mean 2000‐2007 PM2.5 concentration after adjusting for potential confounders. We additionally explored effect measure modification by APOE e4 allele status and tested whether effect estimates were consistent using alternate PM2.5 exposure methods.ResultAfter restricting to participants with non‐missing exposure and confounder data and excluding one participant with dementia, the analytic sample included 279 participants. At the time of amyloid‐PET scans, their mean age was 78 years, 56% were female, 42% were Black, and 26% had mild cognitive impairment. After adjusting for age, sex, education, and race‐study center, we found no significant association between brain amyloid positivity and long‐term mean PM2.5 exposure. We also found no evidence of effect measure modification by APOE e4 allele status. Results were consistent when we used alternate PM2.5 estimation methods.ConclusionOur findings suggest that ambient PM2.5 may induce neurotoxic effects through non‐amyloid, potentially vascular pathways, though we note the small sample size may have made us underpowered to detect a significant association.

Standard error estimation in meta-analysis of studies reporting medians.

We consider the setting of an aggregate data meta-analysis of a continuous outcome of interest. When the distribution of the outcome is skewed, it is often the case that some primary studies report the sample mean and standard deviation of the outcome and other studies report the sample median along with the first and third quartiles and/or minimum and maximum values. To perform meta-analysis in this context, a number of approaches have recently been developed to impute the sample mean and standard deviation from studies reporting medians. Then, standard meta-analytic approaches with inverse-variance weighting are applied based on the (imputed) study-specific sample means and standard deviations. In this article, we illustrate how this common practice can severely underestimate the within-study standard errors, which results in poor coverage for the pooled mean in common effect meta-analyses and overestimation of between-study heterogeneity in random effects meta-analyses. We propose a straightforward bootstrap approach to estimate the standard errors of the imputed sample means. Our simulation study illustrates how the proposed approach can improve the estimation of the within-study standard errors and consequently improve coverage for the pooled mean in common effect meta-analyses and estimation of between-study heterogeneity in random effects meta-analyses. Moreover, we apply the proposed approach in a meta-analysis to identify risk factors of a severe course of COVID-19.

Understanding Oral Prep Interest Among South African Adolescents: The Role of Perceived Parental Support and PrEP Stigma.

We examined oral PrEP interest among adolescents and its association with perceived parental support and PrEP stigma. Cross-sectional data were collected during baseline procedures of the "Our Family Our Future" intervention trial in South Africa. Adolescents (14-16 years) at elevated risk for acquiring HIV and their parents or caregivers were dyadically enrolled from 2018 to 2021. There were 879 complete adolescent-parent dyads. Among adolescents, 27% had heard about PrEP, 67% reported they would want to use PrEP, and 58% thought their parent would want them to use PrEP. Among parents, 33% had heard about PrEP and 85% reported they would want their adolescent to use PrEP. Adolescents who thought their parent would want them to use PrEP were more likely to be interested in PrEP than adolescents who thought their parent would not want them to use PrEP (adjusted prevalence ratio (aPR) = 2.11, 95% CI 1.82, 2.44). Further, adolescents with higher average PrEP stigma scores above the adolescent sample median were less likely to be interested in PrEP than adolescents with lower average PrEP stigma scores (aPR = 0.81, 95% CI 0.72, 0.91). In conclusion, parents were more supportive of their adolescent taking PrEP than adolescents perceived they would be, and perceptions of low parental support and greater PrEP stigma were associated with reduced PrEP interest among adolescents. Interventions should aim to improve adolescent-parent communication around sexual health and effective HIV prevention tools.

Prevalence of Vitamin C Deficiency and Bleeding at a Tertiary Care Center: Mayo Clinic Florida (MCF) Experience

Background: Ascorbic acid (AA, vitamin C) deficiency is easily overlooked in the differential of patients with bruising and bleeding. While studies suggest that the incidence may be declining in the U.S in recent years, we recognized this entity clinically in the work-up of patients with unexplained bleeding or nutritional deficiencies. We analyzed AA testing and deficiency at a single institution to determine its relative incidence and associated clinical phenotype across moderate and severe deficiency. Methods: We performed a retrospective review of MCF patients from January 1, 2018 through December 31, 2019 who underwent AA testing in a CLIA-certified standard of care laboratory following IRB approval. Deficiency was defined as an AA level ≤0.3 mg/dL. Patients were evaluated with a systematic EMR review including demographic information, presence of associated symptoms (i.e., clinical bleeding or "easy bruising or bleeding" reported on the electronic review of systems), and markers of malnutrition/malabsorption. History of hematologic disorder (e.g. sickle cell disease, thalassemia, hematologic malignancy); hematologic complications of renal disease, liver disease, solid tumor, or scleroderma; multivitamin or proton pump inhibitor use; and associated gastrointestinal (GI) disorders (i.e. inflammatory bowel disease) and gastric bypass surgery were included. Continuous variables were summarized with the sample median and range and categorical variables with number and percentage of patients. The proportion of patients with AA deficiency was estimated along with a 95% confidence interval (CI). AA deficient patient characteristics were compared according to AA level (i.e., 0.1 mg/dL vs. 0.2 or 0.3 mg/dL) using a Kruskal-Wallis rank sum test or Fisher's exact test. P-values <0.05 were considered statistically significant. All tests were two-sided. Statistical analysis was performed using R Statistical Software. Results: We identified 1,124 patients who underwent AA testing over 24 months, and n=245 (21.8%, 95% CI: 19.5% - 24.3%) were deficient. Of those, n=23 (9.4 %) reported symptoms of mucocutaneous bleeding (predominantly ecchymosis, easy bruising or epistaxis) and n=19 (7.8%) had GI or genitourinary (GU) bleeding. There were 42 bleeding events among 39 patients (15.9%), 3 of whom had combined mucocutaneous and GU bleeding. 100 of the deficient patients (40.8%) were taking an oral multivitamin. 171 patients (69.8%) underwent prior bariatric surgery. 79 of these (46.2%) were AA deficient before surgery. Patients were analyzed according to the degree of AA deficiency (i.e., 0.1 mg/dL vs. 0.2 mg/dL or 0.3 mg/dL, respectively) to determine the clinical characteristics associated with profound deficiency; Table 1. Significant associations were observed for ethnicity (Hispanic or Latino: 1.8% vs. 2.2% vs. 10.0%, p=0.036), reported marijuana or illicit drug use (5.2% vs. 10.9% vs. 2.2%, p=0.049), and history of underlying hematologic diagnosis, specifically predisposition to "iron overload" (19% vs. 23.9% vs. 9.5%, p=0.039). Eating disorder/restrictive diet, alcohol, gastric bypass surgery, PPI use, degree of hematologic abnormality on CBC, and other markers of nutritional deficiency were not associated with the degree of AA deficiency. Conclusion: AA deficiency is surprisingly common but underappreciated in current practice. Nearly 22% of patients tested were deficient despite 41% of them reporting multivitamin use, and they often endorsed bleeding symptoms. We identified clinically relevant characteristics associated with the degree of AA deficiency, including drug use, hematologic disorder, and ethnicity. We found no association with risk factors like eating disorders, PPI use, and gastric bypass. While the etiology of bleeding dysfunction in this population may be multifactorial, AA deficiency likely contributes and represents a reversible cause. AA deficiency is easily confirmed and should be considered in the work-up of unexplained or easy bruising/bleeding in the absence of other clear etiologies. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

T-Cell Receptor Amino Acid Sequence Selected By Cytotoxic T Cells Specific to HTLV-1 in HLA-A02:01-Positive ATL Patients

Purpose: Adult T cell leukemia/lymphoma (ATL) is an aggressive peripheral malignancy of T cells caused by human T cell lymphotropic virus type-1 (HTLV-1). Its prognosis remains very poor. Tax is the most important regulatory protein for HTLV-1, which is associated with the proliferation of host cells. Tax has been considered as an important target antigen for CD8+cytotoxic T cells (CTLs). We aimed to reveal such a unique sequence of complementarity-determining region 3 (CDR3) of the T cell receptor (TCR)-α and-β chain of HLA-A*02:01-restricted Tax11-19-specific CTLs (Tax-CTL). Methods: We serially analyzed Tax-CTLs from ATL patients with HLA-A*02:01 who had received allogeneic hematopoietic cell transplantation (all-HCT), chemotherapies alone, or had not ever received any treatment. Tax-CTLs were defined as a living CD3+CD8+Tax-tetramer+cells. After sorting Tax-CTLs directly from an actual patient sample into a PCR tube, TCR-α and -β chains of individual CTL clones were determined by the next-generation sequence (NGS) method with SMARTer technology. In addition, we cultured and established individual Tax-CTL clones from a sorted single cell, and finally evaluated the cytotoxicity of Tax-CTLs by calcein-acetoxymethyl (AM)-based cytotoxicity assay. Results: Peripheral blood samples were obtained from 7 patients (Pt-1,-2,-3,-4,-5,-6 and -7). Pt-1 had received allo-HCT and the samples were available 270 days, 1 year, 3 years, 5 years and 7 years after allo-HCT. Samples before treatment were available in the other 5 patient (acute ATL Pt-2,-3, and -6; chronic ATL, Pt-4; HTLV-1 asymptomatic charrier, Pt-5), while the samples after treatment were available in 1 patient (acute ATL Pt-7). Tax-specific CTLs were detected in 0.03-0.58% of total peripheral blood mononuclear cells, and 144-1000 cells per sample (median; 250 cells) were sorted and analyzed for TCR determination. Of them, 2 to 30 Tax-specific CTL clones were identified for each patient. Tax-specific CTLs seemed oligoclonal, and their usage of BV and BJ genes were restricted in TCR-BV28(30.5%), -BV6-5(33.3%), and -BJ2-1(30.5%), while their usage of AV and AJ genes were restricted in TCR-AV12-2(54.5%) and -AJ24(24.2%) gene families. The length of amino acids (AA) in TCR-α and TCR-β CDR3 of all Tax-CTLs clones seemed to be symmetrically distributed, and the most frequently observed AA length was 13 in TCR-α, and 15 in TCR-β. The unique motifs of "DSWGK" in TCR-α and "LAGG" in TCR-β at CDR3 were observed in almost all ATL patients. The 'DSWGK' motif was observed in 0-81.7% (median; 55.5%), and the 'LAGG' motif was observed in 5.2%-80.3% (median; 48%). Pt-2 didn't have any clones with 'DSWGK' motif in TCR-α, whereas regarding 'LAGG' motif in TCR-β, all patients had it in this study. We established Tax11-19-specific CTL clones from a single cell of Pt-4, which showed killing activities against Tax-peptide-pulsed HLA-A2+ T2 cell lines. Conclusion: These methods and results can help us to better understand immunity against ATL, leading to future studies on the clinical application of adoptive T-cell therapies in the future.

Vκ*MYC Mouse Model Recapitulates Key Genomic Defining Events in Multiple Myeloma

Background: The Vk*MYC transgenic model of multiple myeloma (MM) is based on the sporadic AID-induced activation of MYC in a single germinal center (GC) B-cell, in a mouse strain (C57Bl6) that spontaneously develops monoclonal gammopathy. With age, Vk*MYC mice universally develop a progressive expansion of class-switched, somatically hypermutated, monoclonal plasma cells. Myeloma defining events occur only after long latency, suggesting that additional mutations are required to induce malignancy. Here, we interrogated the genomic landscape of Vk*MYC MM to capture somatic mutations selected during progression. Methods: We interrogated whole genome (WGS) and exome sequencing (WES) from 55 purified plasma cell (PC) from Vκ*MYC transgenic mice tumors. Additional 27 and 12 Vκ*MYC mice were investigated with array comparative genomic hybridization (aCGH) and mate-pair low coverage WGS, respectively. Our analysis included 34 individual de novo tumors from aged Vk*MYC mice, 37 individual tumors from recipient mice transplanted with tumor cell lines established from de novo donors, and 13 tumors selected to propagate in vitro. Results: Tumor mutational burden was lowest in de novo samples (median 2.3 mutations/Mb, range 0.3-4.3 mutations/Mb) and highest in in vitro samples (median 5.8 mutations/Mb, range 1.2-12.7 mutations/Mb), similar to that of human MGUS and MM, respectively. To identify genes affected by nonsynonymous mutations more frequently than expected by chance (i.e., driver genes under positive selection), we ran dndscv. A total of 11 significant driver genes were detected, 7 of which are known driver genes in human MM: Dusp2, Trp53, Nfkbia, Pim1, Tent5c (Fam46c), Hist1h1c, Hist1h1e. Driver genes not previously described in MM were: Apobec3, Pten, Cd74, Cd79b. Additional nonsynonymous mutations were detected in driver genes frequently altered in MM including Kras, Nras, Dis3, as well as histone modifiers and NF-kB regulators. Differential mutation analysis revealed bi-allelic inactivation of Trp53 and Pten were more frequent in in vitro samples compared to de novo and transplanted tumor, in line with the almost universal p53 inactivation reported in human MM cell lines. As in human hyperdiploid MM, GISTIC and molecular time analyses revealed evidence of simultaneous multi-gain events of chromosomes 1, 9, 11, and 15. As reported previously, we observed frequent deletion of chromosome 5. There were numerous recurrent focal CNAs involving oncodrivers. These included focal deletion of tumor suppressors genes Cdkn2a, Cdkn2b, Cdh11, Ncor1, Rb1, Trp53, Kdm6a and Pten, as well as amplification of oncogenes Mdm4, Mcl1, and Kras. We detected several structural variants and complex events throughout the Vκ*MYC genome, similar to human MM. Importantly, we found chromothripsis in five (14%) cases. Additionally, in three Vκ*MYC mice we detected chromosomal translocations involving the immunoglobulin heavy or light chain loci that partnered and induced overexpression of MM associated genes such as Irf4, Map3k14 and Pou2af1. Overall, mutations activating the NF-kB and STAT3 pathways were the most common events, each present in more than half MM. Overall, the genomic landscape of the Vκ*MYC model resembles hyperdiploid MM in humans, with MYC translocations and enrichment of events affecting the NF-κB pathway. Finally, analysis of mutational signatures uncovered similar signatures present in human MM, including aging, APOBEC, and poly-eta in the GC, among others. In particular, APOBEC mutational activity was detected in more than half of Vκ*MYC MM, further supporting the similarities with human MM where APOBEC mutational activity is detectable in 80-90% of human MM and progressive precursor, but it is undetectable in the stable precursor conditions. Conclusions: Overall, these data reveal a progressive accumulation of genomic events from de novo, to transplant, to in vitro tumors that mimic the natural progression from newly diagnosed, to relapsed disease, to cell lines noted in human MM. Thus, our results highlight how the transformation pathways to malignant PC are conserved between mice and men. Given the long lead time between precursor diagnosis and malignant transformation to MM that limit the ability to investigate the earliest phases of tumorigenesis in human MM, the Vκ*MYC transgenic mouse model of human MM represents a unique opportunity to overcome this temporal limitation.

Assessing the quality of immunization data from administrative data in Enugu State, South-East Nigeria: A cross-sectional study.

Studies evaluating immunization data quality and its determinants in low- and middle-income countries are scarce. Therefore, this study assessed the accuracy of routine immunization data and its associated factors in Enugu State, South-East Nigeria. This was a descriptive cross-sectional, mixed-method study. A multi-stage sampling technique was used to select 60 out of 180 primary health facilities in six local government areas (LGAs). Routine data on Bacillus Calmette Guerin (BCG), pentavalent vaccine dose3 (Penta3), and Measles2 vaccinations in tallied registers, facility reports, and District Health Information System II (DHIS2) in 2020 were abstracted using a questionnaire. The dependent variables were the accuracy ratios of the facility and DHIS2 reports. We collected data on the independent variables including LGAs, type of location, facility type, tool availability, tool use, frequency of supervision, defaulter tracing, and vaccine tracking. Additionally, semi-structured, in-depth interviews were conducted with 35 purposively selected actors on factors affecting the data quality. The proportions of facilities with normal, under-, or over-reporting were summarized in percentages. The median accuracy ratios and interquartile range (IQR) were also reported. Differences in median accuracy ratios were tested using the independent sample median test. We tested the predictive model using a generalized linear model. Statistical significance was set at P < 0.05. The qualitative data were analyzed using content analysis. The accuracy of facility reports ranged from 38% to 68% (normal), 17-30% (under-reporting), and 15-35% (over-reporting) of health facilities. In DHIS2, the accuracy ranged from 5% to 10% (normal), 37-42% (under-reporting), and 53-63% (over-reporting) of health facilities. The median (IQR) accuracy ratios of facility reports were 100.0% (98.3-103.2%), 100.0% (98.5-103.6%), and 100.0% (81.6-110.2%) for BCG, Penta3, and Measles2, respectively. The median (IQR) accuracy ratios of DHIS2 reports were 83.6% (43.3-192.7%), 88.4% (37.8-200.8%), and 46.2% (10.7-202.7%) for BCG, Penta3, and Measles2, correspondingly. No facility characteristic predicted the accuracy of routine immunization reports. Reasons for inaccurate data include untimely recording, wrong counting, delayed reporting, infrequent supervision, lack of data audits, resource constraints, and high workload. Routine immunization data are not always accurate in Enugu state. Continuous efforts to improve the data monitoring system, supervision, data audits, funding, and staffing are warranted.

CSF IL-8 Associated with Response to Gene Therapy in a Case Series of Spinal Muscular Atrophy

Gene therapies have greatly changed the outlook in spinal muscular atrophy (SMA), and this disorder provides a rare opportunity to study longitudinal biomarker changes correlated with reduced disease burden and improved clinical outcomes. Recent work suggests clinical response to correlate with declining cerebrospinal fluid (CSF) levels of the neurodegenerative marker neurofilament light chain (NfL) in children receiving serial anti-sense oligonucleotide therapy. However, change in CSF NfL levels is no longer a practical biomarker as more children undergo single-dose gene replacement therapy. Here we leverage serial CSF samples (median of 4 per child) collected in 13 children with SMA undergoing anti-sense oligonucleotide therapy to characterize the longitudinal profiles of NfL as well as inflammatory and neuronal proteins. In contrast to neurodegeneration in adults, we found NfL levels to first decrease following initiation of treatment but then increase upon further treatment and improved motor functions. We then examined additional CSF inflammatory and neuronal markers for linear association with motor function during SMA treatment. We identified longitudinal IL-8 levels to inversely correlate with motor functions determined by clinical examination (F(1, 47) = 12.903, p = 0.001) or electromyography in the abductor pollicis brevis muscle (p = 0.064). In keeping with this, lower baseline IL-8 levels were associated with better longitudinal outcomes, even though this difference diminished over 2 years in the younger group. We thus propose CSF IL-8 as a biomarker for baseline function and short-term treatment response in SMA, and a candidate biomarker for future treatment trials in other neurodegenerative disorders.

The sample median as an estimator of population mean true willingness to pay under valuation uncertainty: a synthesis and analysis of the literature

ABSTRACT This paper reviews the contingent valuation literature on hypothetical bias and valuation uncertainty, with special emphasis on measures of central tendency suitable for applied welfare analysis. In a theoretical scenario without valuation uncertainty, sample mean willingness to pay (WTP) is an estimator of population mean true WTP, the appropriate welfare measure. It is proposed here that this may not hold under valuation uncertainty. In this case, mean true WTP should be bounded by mean hypothetical WTP and mean actual WTP (in turn, mean actual WTP should exceed mean certain WTP). Based on a theoretical model and a review of existing empirical studies, median hypothetical WTP was found to be an estimator of mean true WTP. It is therefore proposed that contingent valuation researchers should consider using the sample hypothetical median as an estimator of population mean true WTP when supporting data on the degree of valuation uncertainty are absent. This could be a straightforward approach, e.g. in a low income country context, where the possibility of financing elaborate research designs accounting for valuation uncertainty is limited. It can also prove useful to revisit existing contingent valuation studies with these findings in mind.

Molecular epidemiology of SARS-CoV-2 in healthcare workers and identification of viral genomic correlates of transmissibility and vaccine break through infection: A retrospective observational study from a cancer hospital in eastern India

PurposeDespite COVID vaccination with ChAdOx1 ncov-19 (COVISHIELD®) (ChAdOx1 ncov-19) a large number of healthcare workers (HCWs) were getting infected in wave-2 of the pandemic in a cancer hospital of India. It was important therefore to determine the genotypes responsible for vaccine breakthrough infections. Methods & ObjectivesRetrospective observational study of HCWs. Whole genome sequencing of SARS CoV-2 using Illumina NovaSeq was done. Mutations from both waves were compared to identify genomic correlates of transmissibility and vaccine breakthrough infections. ResultsVaccine breakthrough infections were seen in 127 HCWs out of 1806 fully vaccinated staff (7.03%). Median number of HCWs infected per day in wave-1 was 0.92 versus 3.25 in wave-2. Majority of wave-1 samples belonged to B.1 and B.1.1 lineage. Variant of concern- Delta variant (90%), and variant of interest- Kappa variant (10%), was seen in only wave-2 samples. Total mutation observed in wave-2 samples (median ​= ​44) was 1.8 times than wave-1 sample (median ​= ​24). Spike protein in wave-2 samples had 13 non-synonymous mutation as compared to 8 seen in wave-1 samples. E484Q-vaccine escape mutant was detected in five samples of wave-2; T478K – highly infectious mutation was seen in 31 samples of wave-2. We identified a novelcoding disruptive in-frame deletion (c.467_472delAGTTCA, p. Glu156_Arg158delinsGly) in the Spike protein. This mutation was seen only in wave-2 (78%, n ​= ​39) samples. ConclusionThe circulating virus strains in wave-2 infections demonstrated a greater degree of infectivity. There was a significant change in the genotypes observed in wave-1 and wave-2 infections along with almost twice the number of mutations. We noted that vaccine breakthrough infections (although mostly mild).

Super-polynomial accuracy of one dimensional randomized nets using the median of means

Letffbe analytic on[0,1][0,1]with|f(k)(1/2)|⩽Aαkk!|f^{(k)}(1/2)|\leqslant A\alpha ^kk!for some constantsAAandα&gt;2\alpha &gt;2and allk⩾1k\geqslant 1. We show that the median estimate ofμ=∫01f(x)dx\mu =\int _0^1f(x)\,\mathrm {d} xunder random linear scrambling withn=2mn=2^mpoints converges at the rateO(n−clog⁡(n))O(n^{-c\log (n)})for anyc&gt;3log⁡(2)/π2≈0.21c&gt; 3\log (2)/\pi ^2\approx 0.21. We also get a super-polynomial convergence rate for the sample median of2k−12k-1random linearly scrambled estimates, whenk/mk/mis bounded away from zero. Whenffhas app’th derivative that satisfies aλ\lambda-Hölder condition then the median of means has errorO(n−(p+λ)+ϵ)O( n^{-(p+\lambda )+\epsilon })for anyϵ&gt;0\epsilon &gt;0, ifk→∞k\to \inftyasm→∞m\to \infty. The proof techniques use methods from analytic combinatorics that have not previously been applied to quasi-Monte Carlo methods, most notably an asymptotic expression from Hardy and Ramanujan on the number of partitions of a natural number.

UHPLC-ESI-MS/MS assay for quantification of endocannabinoids in cerebrospinal fluid using surrogate calibrant and surrogate matrix approaches

Endocannabinoids are endogenous lipids with the main function recognized to act as neuromodulators through their cannabinoid receptors. Dysregulation of the endocannabinoid system is implicated in various pathologies, such as inflammatory and neurodegenerative diseases. In this study we describe a sensitive UHPLC-MS/MS method for the analysis of trace levels of 7 endocannabinoids in cerebrospinal fluid samples. The analytes covered comprised 1- and 2-arachidonoylglycerol 1- and 2-AG (which were analysed as sum due to their interconversion), 2-arachidonylglycerol ether 2-AGE, anandamide AEA, N-linoleoyl ethanolamide LEA, N-palmitoyl ethanolamide PEA and N-oleoyl ethanolamide OEA. Analytes were extracted from the biofluid by a simple monophasic procedure involving protein precipitation with acetonitrile (MeCN). The analytical method is based on chromatographic separation of the analytes with solid-core (core-shell, superficially porous) particle column Cortecs C18+ . Gradient elution with changing proportion of water and acetonitrile and constant concentration of formic acid provided reasonable separation of analytes, close elution of analytes and their internal standards and minimized matrix effects in biological samples. For specific detection of the endocannabinoids a triple-quadrupole tandem mass spectrometer with electrospray ionisation (ESI) and selected reaction monitoring (SRM) mode was used, and it provided good assay selectivity. The developed method required a minute volume of the biological samples (50 µL) and achieved excellent sensitivity (the lower limit of detection was between 4.15 and 30.18 pM of the biological sample). Linear calibration was achieved in the range from 25 to 10,545 pM for AEA, 90–3802 pM for 1-AG, 90–724 pM for 2-AG, 12–5226 pM for LEA, 33–13,942 for OEA, 34–23,850 pM for 2-AGE, 72–30,190 for PEA and 10–4218 for AEA-d4 in CSF. The method was validated and revealed relative errors in the range of − 14.7 to + 12.3% at LLOQ and − 14.1 to + 14.2% for the remaining validation range. Precisions were in the acceptable range (< 20% RSD at LLOQ, and <15% for the remaining levels) as well. It was finally used to quantify endocannabinoids in human cerebrospinal fluid obtained from 118 donors. Accurate quantification of endogenous compounds in biological samples was achieved by using two different principal approaches (surrogate matrix for AEA, 2-AG, OEA, 2-AGE, LEA and PEA, and surrogate calibrant for AEA only) and they were evaluated by use of the Passing-Bablok regression. Concentrations (median) of CSF samples of patients suffering from CNS infection and controls were found to be around 160 pM for 1- and 2-AG, 86 pM for AEA, 62 for 2-AGE, 58 for LEA, 93 pM for PEA, and 83 pM for OEA.

Improving the robustness of spectral estimation to loud transients with a truncated order statistics filter

Underwater acoustic recordings often include loud transients from human or natural sources. The transients cause a positive bias for Welch's average periodogram spectral estimator when estimating the power spectral density of the background environment. Estimators based on single order statistics (e.g., the sample median) avoid the bias caused by outliers at the cost of a higher variance than the sample mean. Schwock and Abadi (2021) showed that, for exponential random variables, the estimator based on the 80th sample percentile has the lowest variance among any unbiased estimator based on a single order statistics. This work tests a hybrid approach between Welch's and order statistics estimators by performing a weighted sum of the quietest subset of ordered samples of the periodograms. By discarding the loudest samples of the periodogram, the truncated linear order statistics filter (TLOSF) reduces the bias caused by loud transients. By combining multiple order statistics into the estimate, the TLOSF achieves a lower variance than the 80th percentile estimator. The TLOSF reduced the MSE by 1dB compared to Schwock &amp; Abadi's 80th percentile estimator for a mixture combining an exponential distribution with 1% outliers 23 dB above the background. On periodograms of shallow water hydrophone recordings, the TLOSF yielded a lower output power in the frequency bins where both the Welch's and 80th percentile estimators had a positive bias due to loud transients. [Work supported by ONR Code 321US.]

What influences demand for cigars among African American adult cigar smokers? Results from a hypothetical purchase task.

African Americans (AA) have historically been targeted by the tobacco industry and have the highest rates of current cigar use among racial/ethnic groups in the U.S. Yet, there is limited evidence on other factors influencing cigar use. Amongst a sample of 78 AA current cigar (any type) smokers, log-linear regression models examined correlates of cigar demand obtained from a validated behavioral economic purchase task. Mean intensity, or cigar demand when free, was 6.68 cigars (standard deviation [SD]: 8.17), while mean breakpoint, or the highest price a participant was willing to pay, was $4.62 (SD: 3.88). Mean maximum daily expenditure, Omax was $15.20 (SD: 25.73) and Pmax, the price at Omax was $5.25 (SD: 3.95). Participants aged 21 to 30 years compared to those aged 18 to 20 years, those with higher levels of dependence, and females compared to males, had a significantly higher intensity. Participants with cannabis use above the sample median in the last 30 days (4 + days) had significantly higher intensity and Omax than those below the median. Further, participants with a high school education or more had a significantly lower intensity, breakpoint, and Omax than those with less than high school education. Individuals with income below the federal poverty line (FPL) also had a significantly lower breakpoint and Omax than those above. Finally, tobacco harm perceptions were inversely associated with Pmax. Stricter policies on cigar products, such as higher taxes and product-specific harm messaging, may have an immediate and sustained impact on health disparities related to cigar use. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Microplastic pollution in sediments of tropical shallow lakes

Forty-eight tropical shallow lakes (depth ≤ 4 m) across a climatic gradient were assessed for microplastic (MPs; <5 mm) pollution based on MPs concentrations in archive samples from lake shore sediments. The MPs were classified by type (fragments or fibres), colour (yellow, black, red, green, blue, white, and transparent), size (0.55 to 4.93 mm), and polymer (polyester, polyethylene, chlorinated polyethylene, and polyamide). Sediments were predominantly medium sand, and all samples (144) contained MPs, consisting of 24 % fragments (6.3 ± 11.3 MPs·300 g−1) and 76 % fibres (21.25 ± 12.7 MPs·300 g−1). The lake climate (humid, transitional, or semi-arid), type of surrounding land use (urban, semi-arid, or rural), and distance from the shoreline (0, 5 or 10 m) did not explain the differences in MPs concentrations, partially refuting the initial hypothesis. The only significant difference was between the sample medians for the number of fragments based on the region (H = 7.586; p = 0.0481). The number of fragments in the lakes in the humid region was greater than that in the semi-arid region (p < 0.05). Poor sanitation, sewage effluents, and solid wastes reaching and accumulating in the lakes may be the primary and transversal conditioning factors for this small difference among diverse environments. Freshwater lakes are investigated in all continents, and the present study contributes to the first record of MPs in shallow lake sediments in eastern South America. The 48 shallow lakes assessed showed a relatively low concentration of MPs compared to other lake contaminants reported in the international literature. This information coincides with public policies issued, regarding the control and reduction of plastics and MPs in Brazil, and the study region.

Abstract A40: Evaluation of the tumor microenvironment in mycosis fungoides using the PanCancer IO 360™ assay and nCounter® platform

Abstract BACKGROUND: Alterations in the tumor microenvironment (TME) can result in a “T-cell inflamed” TME, which is characterized by activation of the PD1/PD-L1 pathway, immunosuppression, and production of anergic, “exhausted” CD8(+)-T-cells. Similar alterations in the TME of Mycosis Fungoides (MF) have been linked to disease progression. However, the relationship between progression and the TME in MF remains incompletely understood. We aimed to further study the TME in MF using the PanCancer IO 360™ 750-gene expression panel and nCounter® platform (Nanostring; Seattle, WA). DESIGN: Clinical and laboratory data from the electronic medical record were reviewed in combination with microscopic review of biopsies from 27 patients to confirm diagnosis of MF and assign samples as “low-grade” (patch/plaque; n=8) or “high-grade” (tumor/large cell transformation, n=19). Patients were also classified as having “limited stage” (TNMB1 &amp;lt;1B, n=8) or “advanced stage” (TNMB1 &amp;gt;1B, n=19) disease. All patients received prior, heterogenous treatment, but no patients received prior anti-PD1 therapy. RNA was extracted from formalin-fixed, paraffin-embedded (FFPE), punch biopsy sections and analyzed per manufacturer’s instructions. Gene expression scores (log2) and a “tissue inflammation score” (TIS) were calculated for each sample. A TIS of &amp;gt;5 has been associated with the presence of a “T-cell inflamed” microenvironment. Samples scores were compared by histologic group and disease stage as described above. RESULTS: Twenty-nine of 30 samples had sufficient RNA integrity for analysis. TIS was &amp;gt;5 in 26/30 samples (median, 7.6; range, 4.3-9.3). No significant differences in TIS were identified between low-grade/limited-stage and high-grade/advanced-stage samples. High-grade samples had significantly increased expression of PD1 and higher amounts of exhausted CD8(+)-cells than low-grade samples (p= 0.015, 0.027). Low-grade samples showed significantly higher expression of ARG1, B7-H3, and genes associated with tissue hypoxia. Expression of genes associated with tumor proliferation was higher in high-grade lesions (p= 0.0019). Limited stage samples showed higher levels of endothelial cells, mast cells, and T-regulatory cells (p=0.033, 0.024, 0.004,) than advanced stage samples. Proliferation, PD1, and exhausted CD8 scores trended higher in advanced stage disease but did not reach statistical significance. CONCLUSION: Our findings indicate that the IO 360™ panel provides comprehensive analysis of the TME in MF. Most samples showed a TIS of &amp;gt;5, suggesting a T-cell inflamed TME in MF. Increased PD1 and exhausted CD8(+) cells were found in high-grade lesions, supporting a role for this pathway in progression. Increased expression of factors associated with angiogenesis (endothelial cells, ARG1) and immunosuppression (B7-H3, tissue hypoxia, mast cells, T-regulatory cells) suggest these mechanisms may play a role in early stages of disease. These findings highlight the complex and dynamic nature of the TME during MF progression, and the need for further study. Citation Format: Stanton Miller, Akshat Patel, Kiran A Kumar, Farrukh Awan, Heather W Goff, Travis Vandergriff, Marisa Juntilla, Franklin Fuda, Weina Chen, Jesse M Jaso. Evaluation of the tumor microenvironment in mycosis fungoides using the PanCancer IO 360™ assay and nCounter® platform [abstract]. In: Proceedings of the Third AACR International Meeting: Advances in Malignant Lymphoma: Maximizing the Basic-Translational Interface for Clinical Application; 2022 Jun 23-26; Boston, MA. Philadelphia (PA): AACR; Blood Cancer Discov 2022;3(5_Suppl):Abstract nr A40.

Non-asymptotic analysis and inference for an outlyingness induced winsorized mean

Robust estimation of a mean vector, a topic regarded as obsolete in the traditional robust statistics community, has recently surged in machine learning literature in the last decade. The latest focus is on the sub-Gaussian performance and computability of the estimators in a non-asymptotic setting. Numerous traditional robust estimators are computationally intractable, which partly contributes to the renewal of the interest in the robust mean estimation. Robust centrality estimators, however, include the trimmed mean and the sample median. The latter has the best robustness but suffers a low efficiency drawback. Trimmed mean and median of means, achieving sub-Gaussian performance have been proposed and studied in the literature. This article investigates the robustness of leading sub-Gaussian estimators of mean and reveals that none of them can resist greater than \(25\%\) contamination in data and consequently introduces an outlyingness induced winsorized mean which has the best possible robustness (can resist up to \(50\%\) contamination without breakdown) meanwhile achieving high efficiency. Furthermore, it has a sub-Gaussian performance for uncontaminated samples and a bounded estimation error for contaminated samples at a given confidence level in a finite sample setting. It can be computed in linear time.