Nevin Manimala

J Manag Care Spec Pharm. 2023 Sep 11:1-12. doi: 10.18553/jmcp.2023.23045. Online ahead of print.

ABSTRACT

BACKGROUND: Research conducted in 2017 by Runyan et al concerning the current and future management of oncology drugs in the United States formed the basis for this research. The authors concluded that despite the high cost of oncology drugs, US payers relied on traditional management tools to manage the category, although these tools were ineffective at controlling costs. Innovative tools were not common in 2017. OBJECTIVE: To compare findings from the 2017 research with findings from a 2022 payer survey to understand how payer management of oncology drugs changed over 5 years. The study evaluates changing trends in oncology drug management. METHODS: The survey that informed the publication by Runyan et al in 2017 was reviewed, updated, and completed by 21 pharmacy and medical directors across 18 organizations representing 121.9 million covered lives. Both surveys included questions about management tools being employed in oncology and challenges to managing oncology. They used case studies in non-small cell lung cancer and chronic lymphocytic leukemia. These disease areas were chosen again in 2022 because they were included in the 2017 survey and because of the increase in competition in both categories from 2017 to 2022. The payer sample was designed to match the 2017 sample. The research was fielded from March to May 2022. The results were analyzed in Microsoft Excel; basic statistical analysis was conducted. Payers’ responses for each question were weighted by the number of reported covered lives at their organization so that the organization’s site was represented. RESULTS: On average, payers rated the management priority of oncology as a 5.3 and the budget impact as a 6.3 on a scale of 1 to 7, where 1 was low and 7 was high. Traditional tools remain dominant in this therapeutic area. However, there has been an increase in use of innovative tools. Pathways of care are trending upward since the initial survey in 2017. The Institute for Clinical and Economic Review (ICER) also influences payers’ decision-making in oncology more than it did 5 years ago. Despite these shifts, most payers allow for unrestricted access of targeted therapies in non-small cell lung cancer and chronic lymphocytic leukemia, in line with each drug’s US Food and Drug Administration-approved label. CONCLUSIONS: The increased use of pathways of care, shifting financial risk to providers, and the influence of ICER should continue to be monitored. Future research should focus on the role of pathways of care, comprehensive, evidence-based treatment protocols, in influencing prescribing decisions of hematologists and oncologists. DISCLOSURES: The authors work for Envision Pharma Group (formerly Two Labs), a company that provides consulting services to the pharmaceutical and biotech industries. As such, clients in these industries pay Envision Pharma Group for their services. This study was funded independently by Envision Pharma Group.

PMID:37695273 | DOI:10.18553/jmcp.2023.23045

Sci Total Environ. 2023 Sep 8:166915. doi: 10.1016/j.scitotenv.2023.166915. Online ahead of print.

ABSTRACT

Ground hardening in urban areas increases the risk of thermal enrichment in surface rainwater runoff. Moreover, the thermal pollution from rainwater runoff has become an important problem that damages the urban aquatic environment. Current studies have focused mainly on the potential hazard caused by runoff thermal pollution to aquatic microorganisms. However, there are few studies on the efficacy of controlling runoff thermal load through low-impact development (LID) and renovation in urban areas. The effects of LID modification were evaluated by monitoring the characteristics of the runoff thermal load on each underlying surface in the study area and conducting laboratory-scale bioretention experiments. The results showed that the initial thermal effect of each underlying surface was significant after the start of rainfall, based on the thermal load. Ceramic granules are remarkable bioretention fillers. Their average heat load and volume reduction rates are 55.6 % and 32.7 %, respectively. After LID modification, the thermal load of surface runoff in the study area decreased to 73.42 % under similar rainfall conditions. After the secondary treatment of the bioretention facility, the total thermal load of the outflow facility was 31.40 % of that before renovation. The peak thermal load reduced by 69.15 % and was delayed for 10 min. The control effect differed statistically.

PMID:37690765 | DOI:10.1016/j.scitotenv.2023.166915

Chem Biol Interact. 2023 Sep 8:110699. doi: 10.1016/j.cbi.2023.110699. Online ahead of print.

ABSTRACT

Parabens have been used for decades as preservatives in food, drugs and cosmetics. The majority however, were banned in 2009 and 2014 leaving only methyl-, ethyl-, propyl-, and butyl-derivates available for subsequent use. Methyl- and propylparaben have been extensively tested in vivo, with no resulting evidence for developmental and reproductive toxicity (DART). In contrast, ethylparaben has not yet been tested for DART in animal experiments, and it is currently debated if additional animal studies are warranted. In order to perform a comparison of the four currently approved parabens, we used a previously established in vitro test based on human induced pluripotent stem cells (iPSC) that are exposed to test substances during their differentiation to neuroectodermal cells. EC₅₀ values for cytotoxicity were 906 μM, 698 μM, 216 μM and 63 μM for methyl-, ethyl-, propyl- and butylparaben, respectively, demonstrating that cytotoxicity increases with increasing alkyl chain length. Genome-wide analysis demonstrated that FDR-adjusted significant gene expression changes occurred only at cytotoxic or close to cytotoxic concentrations, for example 1720 differentially expressed genes (DEG) at 1000 μM ethylparaben, 1 DEG at 316 μM, and no DEG at 100 μM or lower concentrations. The highest concentration of ethylparaben that did not induce any cytotoxicity nor DEG was 1670-fold above the highest published concentrations reported in biomonitoring studies (60 nM ethylparaben in cord blood). In conclusion, cytotoxicity and gene expression alterations of ethylparaben occurred at concentrations of approximately three orders of magnitude above human blood concentrations; moreover, the substance fitted well into a scenario where toxicity increases with the alkyl chain length, and gene expression changes only occur at cytotoxic or close to cytotoxic concentrations. Therefore, no evidence was obtained suggesting that in vivo DART with ethylparaben would lead to different results as the methyl- or propyl derivates.

PMID:37690743 | DOI:10.1016/j.cbi.2023.110699

J Dairy Sci. 2023 Sep 8:S0022-0302(23)00626-4. doi: 10.3168/jds.2023-23478. Online ahead of print.

ABSTRACT

A 305-d lactation followed by a 60-d dry period has traditionally been considered economically optimal, yet dairy cows in modern intensive dairy systems are frequently dried off while still producing significant quantities of milk. Managing cows for an extended lactation has reported production, welfare and economic benefits, but not all cows are suitable for an extended lactation. Implementation of an extended lactation strategy on-farm could benefit from use of a decision support system, based on a mathematical lactation model, that can identify suitable cows during early lactation that have a high likelihood of producing above a target milk yield (MY) at 305 d in milk (DIM). Therefore, our objectives were 1) to compare the suitability of 3 commonly used lactation models for modeling extended lactations (Dijkstra, Wood, and Wilmink) in primiparous and multiparous cows under a variety of lactation lengths, and 2) to determine the amount of early lactation daily MY data needed to accurately forecast MY at d 305 by using the most suitable model and determine if this is sufficient for identifying cows suitable for an extended lactation before the end of a typical voluntary waiting period (50 to 90 d). Daily MY data from 467 individual Holstein-Friesian lactations (DIM >305 d; 379 ± 65 d lactation length [mean ± SD]) were fitted by the 3 lactation models using a nonlinear regression procedure. The parameter estimates of these models, lactation characteristics (peak yield, time to peak yield, and persistency), and goodness-of-fit were compared between parity and different lactation lengths. The models had similar performance and differences between parity groups were consistent with previous literature. Then, data from only the first i DIM for each individual lactation, where i was incremented by 30 d from 30 to 150 DIM and by 50 d from 150 to 300 DIM, were fitted by each model to forecast MY at d 305. The Dijkstra model was selected for further analysis as it had superior goodness-of-fit statistics for i = 30 and 60. The data set was fit twice by the Dijkstra model, with parameter bounds either unconstrained or constrained. The quality of predictions of MY at d 305 improved with increasing data availability for both models and assisting the model fitting procedure with more biologically relevant constraints on parameters improved the predictions, but neither was reliable enough for practical use on-farm due to the high uncertainty of forecasted predictions. Using 90 d of data, the constrained model correctly classified 66% of lactations as being above or below a target MY at d 305 of 25 kg/d, with a probability threshold of 0.95. The proportion of correct classifications became smaller at lower targets of MY at d 305 and became greater when using more lactation days. Overall, further work is required to develop a model that can forecast late lactation MY with sufficient accuracy for practical use. We envisage that a hybridized machine learning and mechanistic model that incorporates additional historical and genetic information with early lactation MY could produce meaningful lactation curve forecasts.

PMID:37690727 | DOI:10.3168/jds.2023-23478

J Dairy Sci. 2023 Sep 8:S0022-0302(23)00641-0. doi: 10.3168/jds.2023-23874. Online ahead of print.

ABSTRACT

We determined the effects of altering the ratio of palmitic (C16:0) and stearic (C18:0) acids in supplemental fatty acid (FA) blends on production responses of mid-lactation dairy cows. Twenty-four multiparous Holstein cows (mean ± standard deviation; 47.1 ± 5.8 kg of milk yield, 109 ± 23 DIM) were randomly assigned to treatment sequences in a replicated 4 × 4 Latin square design with 21-d periods. Treatments were a non-FA supplemented control diet (CON), and 3 diets incorporating 1.5% dry matter (DM) FA supplement blends containing 30% C16:0 + 50% C18:0 (L-PA), 50% C16:0 + 30% C18:0 (M-PA), and 80% C16:0 + 10% C18:0 (H-PA). Additionally, the FA blends were balanced to contain 10% oleic acid (cis-9 C18:1). The FA blends replaced soyhulls in the CON diet. Diets were formulated to contain (% DM) 31.0% neutral detergent fiber, 27.0% starch, and 16.9% crude protein. The statistical model included the random effect of cow within square and the fixed effects of period, treatment, and their interaction. Pre-planned contrasts included CON vs. overall effect of FA supplementation (FAT) and the linear and quadratic effects of increasing C16:0 in FA blends. Overall FAT had no effect on dry matter intake but increasing C16:0 linearly increased dry matter intake. Compared with CON, overall FAT increased yields of milk, 3.5% fat corrected milk, energy corrected milk, and milk fat, but did not affect milk protein yield. Increasing C16:0 linearly increased milk fat yield and tended to linearly increase the yields of 3.5% fat corrected milk and energy corrected milk. FAT decreased the yield of de novo milk FA, but increased yields of mixed and preformed milk FA compared with CON. Increasing C16:0 in FA treatments did not affect the yield of de novo milk FA, linearly increased the yield of mixed and decreased the yield of preformed milk FA. In summary, feeding FA supplements containing C16:0 and C18:0 increased milk production responses with no effect on DMI compared with a non-FA supplemented control diet. Mid-lactation cows producing ∼40-50 kg/d of milk yield responded best to increasing supplemental C16:0 in FA supplements, demonstrating that FA supplements higher in C16:0, and limiting C18:0, improves production responses.

PMID:37690714 | DOI:10.3168/jds.2023-23874

Behav Brain Res. 2023 Sep 8:114659. doi: 10.1016/j.bbr.2023.114659. Online ahead of print.

ABSTRACT

Learning to discriminate between environmental visual stimuli is essential to make right decisions and guide appropriate behaviors. Moreover, impairments in visual discrimination learning are observed in several neuropsychiatric disorders. Visual discrimination learning requires perception and memory processing, in which the hippocampus critically involved. To understand the molecular mechanisms underpinning hippocampus function in visual discrimination learning, we examined the hippocampal gene expression profiles of Sprague-Dawley rats with different cognitive performance (high cognition group vs. low cognition group) in the modified visual discrimination learning task, using high-throughput RNA sequencing technology. Compared with the low cognition group, bioinformatics analysis indicated that 319 genes were differentially expressed in the high cognition group with statistical significance, of which 253 genes were down-regulated and 66 genes were up-regulated. The functional enrichment analysis showed that protein translation and energy metabolism were up-regulated pathways, while transforming growth factor beta receptor signaling pathway, bone morphogenetic protein signaling pathway, apoptosis, inflammation response, transport, and glycosaminoglycan metabolism were down-regulated pathways, which were related to good cognitive performance in the visual discrimination learning task. Taken together, our finding reveals the differential gene expression and enrichment biological pathways related to cognitive performance differences in visual discrimination learning of rats, which provides us direct insight into the molecular mechanisms of hippocampus function in visual discrimination learning and may contribute to developing potential treatment strategies for neuropsychiatric disorders accompanied with cognitive impairments.

PMID:37690703 | DOI:10.1016/j.bbr.2023.114659

Environ Res. 2023 Sep 8:117085. doi: 10.1016/j.envres.2023.117085. Online ahead of print.

ABSTRACT

This study was carried out to evaluate and analyze the fluctuations in groundwater for certain trace metals (Fe, Mn, Cu, Zn, Al, Cd, Cr, Pb, As, and Se) in Taizhou City over three years (2020-2022), evaluate the potential human health risks due to the consumption of groundwater. To quantify the spatiotemporal changes in groundwater trace metals, the heavy metal pollution index (HPI) and heavy metal evaluation index (HEI) were utilized. Furthermore, multivariate statistical methods were utilized to distinguish the sources of trace elements. Deterministic health risk assessment and Monte Carlo health risk simulation methods were employed to evaluate human health risks associated with exposure to trace metals. The results indicate that areas with higher pollution are in the south-central region, with low HPI increasing from 50% to 75% and low HEI from 68.75% to 81.25%, reflecting improved water quality. Correlation matrix analysis and principal component analysis (PCA) pinpointed anthropogenic sources as major trace metal contributors. Cr and As concentrations were associated with farming activities, Cd and Pb concentrations showed links to local industries such as e-waste recycling and shipbuilding. Furthermore, Cu levels in groundwater was influenced by the combined effects of industry, agriculture, and urban sewage discharge. Based on the hazard quotient (HQ) and hazard index (HI) calculations, the majority of groundwater samples did not exceed the reference values, indicating acceptable noncarcinogenic risks for both adults and children. However, the analysis of carcinogenic risk (CR) and uncertainty revealed an overall decreasing trend in carcinogenic risk, with Cr and Cd possessing the highest potential for causing carcinogenic risks. The sensitivities were 46.3%, 53.3%, and 70.3% for Cr, and 18.8%, 27.6%, and 9.3% for Cd.

PMID:37690628 | DOI:10.1016/j.envres.2023.117085

Photodiagnosis Photodyn Ther. 2023 Sep 7:103772. doi: 10.1016/j.pdpdt.2023.103772. Online ahead of print.

ABSTRACT

PURPOSE: To determine alterations of the choroidal thickness (CT) and the choroidal vascularity index (CVI) in patients with glomerular hyperfiltration, a marker of early diabetic nephropathy (DN).

METHODS: Twenty-two patients with type 2 diabetes (T2D) with glomerular hyperfiltration (early DN group) and 28 patients with T2D without DN (NDN group) were included in the study. Patients with diabetic retinopathy were excluded. Parameters including subfoveal CT, the subfoveal choroidal vascularity index (CVI), and total CVI were measured using spectral-domain enhanced depth imaging optical coherence tomography method.

RESULTS: The early DN group included 22 patients and the NDN group comprised 28 patients. The groups were similar in terms of age and sex (p>0.05). The CT values were statistically significantly lower in the early DN group than in the NDN group (p < 0.001). There was no significant difference between the early DN group and the NDN group in terms of total and subfoveal CVI (p>0.05).

CONCLUSION: The choroidal thickness decreased in patients with T2D with glomerular hyperfiltration, but there were no differences in CVI when they were compared with patients with T2D without DN.

PMID:37690616 | DOI:10.1016/j.pdpdt.2023.103772

J Obstet Gynaecol Can. 2023 Sep 8:102215. doi: 10.1016/j.jogc.2023.102215. Online ahead of print.

ABSTRACT

OBJECTIVE: The purpose of this study was to measure the proportion of non-vaccination for pertussis in mothers in Canada who had been advised by their prenatal care provider to get vaccinated, and to identify socio-demographic factors and beliefs associated with non-vaccination.

METHODS: The Survey on Vaccination during Pregnancy (part of childhood National Immunization Coverage Survey) included biological mothers of children born from September 2018 to March 2019. This analysis was restricted to 2,657 mothers who had been advised by their prenatal care provider to get vaccinated against pertussis during pregnancy and knew whether or not they had been vaccinated.

RESULTS: Of those who had been advised to get vaccinated against pertussis, 21% were not. This rate varied across provinces and territories, ranging from 9% in Prince Edward Island to 32% in Newfoundland and Labrador. Factors independently associated with pertussis non-vaccination included lower household income, having had past live births, and having received prenatal care from an obstetrician-gynecologist or a midwife compared to a family doctor. The risk of pertussis non-vaccination despite prenatal care advice was higher for those who disagreed that the baby will be at greater risk of pertussis if the mother does not get vaccinated. It was also higher for those who disagreed with statements regarding perceived benefits for vaccination. Conversely, disagreement with statements on perceived barriers were negatively associated with pertussis non-vaccination.

CONCLUSION: These findings highlight the underlying factors associated with non-vaccination against pertussis despite prenatal care provider recommendation. Some inaccurate beliefs about pertussis and vaccination during pregnancy persist, leading to non-vaccination.

PMID:37690611 | DOI:10.1016/j.jogc.2023.102215

Orthop Traumatol Surg Res. 2023 Sep 8:103682. doi: 10.1016/j.otsr.2023.103682. Online ahead of print.

ABSTRACT

INTRODUCTION: Over the past decades, numerous structural changes in implants, medical treatments, and surgical technics have been made for Malignant Bone Tumors (MBT) around the knee. However, the overall care improvement is still unclear. The method is crucial when analyzing outcomes in surveys involving tumors, and a thorough assessment of the mortality is mandatory because death acts as competing event. The aims of this study were 1) a comprehensive and longitudinal assessment of the revisions with an extensive follow-up and adequate methods 2) a complete mortality review to consider competing risks.

HYPOTHESIS: The hypothesis was that some prosthesis’s structural improvements were made while the surgical toll increased as well as an improvement of mortality was also expected.

MATERIAL AND METHODS: Analyses were performed on 248 patients with MBT (mean follow-up was 8.7 years, surgeries between 1972 and 2017). Three prosthesis models were successively used over time: 120 Guepar (older model), 42 Tornier, and 86 Stanmore (more recent model). The primary outcome was the assessment of revisions sorted out according to Henderson: type-1 soft-tissue failures or instability, type-2 aseptic loosening, type-3 structural failures, type-4 periprosthetic infections, type-5 tumoral progression. Death and amputations were considered as competing events. An extensive assessment of mortality was performed by merging the dataset with the French register of Deaths (INSEE). Cumulative probabilities were computed at 2, 5, 10, and 15 years and compared with Gray’s tests.

RESULTS: The overall 5-year survival was, 80% (95% CI: 73-87) for Guepar, 69% (95% CI: 56-84) for Tornier, and 71% (95% CI: 62-82) for Stanmore (p = 0.4). The 5-year cumulative risks for type-1 were 5% (95% CI: 1-9), 9% (95% CI: 0-18), and 17% (95% CI: 9-25) for Guepar, Tornier, and Stanmore, respectively (p =0.01). The 15-year cumulative risks for type-2 were 22% (95% CI: 15-39), 8% (95% CI: 0-17) and 8% (95% CI: 2-14) for Guepar, Tornier, and Stanmore, respectively (p = 0.10). Ten patients had an implant failure, nine Guepar, and one Tornier. The 5-year cumulative risks for type-4 were 7% (95% CI: 2-12), 19% (95% CI: 7-31), and 12% (95% CI: 5-18) for Guepar, Tornier, and Stanmore, respectively (p = 0.08). There were 29 tumoral progressions; the 15-year risks were 16% (95% CI: 2-22), 2% (95% CI: 0-7%), and 12% (95% CI: 4-19%) for Guepar, Tornier, and Stanmore, respectively (p= 0.08). No difference whatsoever was found between the proximal tibial and distal femur.

CONCLUSION: There were some improvements in prosthesis design (forged steel instead of cast steel) and probably also in cemented stem fixation, but not in prosthetic joint infection and local recurrence over forty years. The overall mortality did not change significantly over the last 40 years amongst this specific cohort of patients who benefited from a hinge reconstruction prosthesis.

LEVEL OF EVIDENCE: III; comparative case series with sensibility analysis.

PMID:37690605 | DOI:10.1016/j.otsr.2023.103682