Significant Change In Trend Research Articles

Prediction of long-term future runoff under multi-source data assessment in a typical basin of the Yangtze River

Study regionThree Typical Basins of the Yangtze River (YRB), China Study focusMeteorological factors, such as precipitation, are key drivers of the hydrological system and critical inputs in hydrological modeling, and accurate meteorological data are essential to simulate hydrological processes. This study compares and evaluates the CN05.1, CMFD, and ERA5-L and meteorological forcing datasets in three typical basins of the Yangtze River and predicts the future runoff changes in the basin based on CMIP6 data. New hydrological insights for the regionThis study indicated that (1) the CN05.1 data exhibit the best applicability on the interannual and intra-annual scales in YRB, while ERA5-Land performs better in the upper reaches, and CMFD is more suitable for the middle and lower reaches. (2) Future runoff is projected to initially decrease and then increase, with the inflection and inflections points of runoff occurring earlier in the ssp585 scenario compared to the ssp245. The risk of spring flooding is increasing in CS and JZ river basin, and the risk of flooding is decreasing in the FH River Basin as the flood peaks are earlier. (3) Significant trend changes are anticipated in the future, with climate change contributing over 90 % of the runoff changes in the CS, while human factors will increasingly influence the JZ and FH basins.

Spatio-temporal land use/land cover change analysis and assessment of urban heat island in Ghana: A focus on the Greater Accra Region

The expansion of cities coupled with economic development over the years has transformed many locations into hotspots for massive urban populace. The Greater Accra Region which is the capital city of Ghana is no exception. The urban population growth rate in the region has expanded extensively at the expense of increasingly vegetation cover. As a result, there is an increasing need to investigate urban resilience, land use/land cover (LULC) change, and urban heat islands (UHI) dynamics in the region. The aim of this study is to analyze multi-spectral Landsat images of 2000 and 2020 to examine the LULC change and the UHI trend across the Greater Accra Region of Ghana. The results from the analysis show a significant change in the spatial trend of land surface temperature (LST) and UHI between the years 2000 and 2020. Spatial distribution of LST from 0 °C to 28 °C and 17 °C–33 °C in the years 2000 and 2020 respectively were observed. Urban areas dominated more than half of the study area in 2020, covering 85% (equivalent to 3160 sq. km), and reflecting a 20% increase from the year 2000–2020. During the same period, sparse and dense forested areas decreased by 10% (373 sq. km) and 4% (146 sq. km) with a 5% reduction in bare land (equivalent to 177 sq. km). The spatio-temporal analysis revealed a significant surge in the population of urban areas within the study area. The UHI areas also increased from 13.20% in 2000 to 18.20% in 2020. On the other hand, non-UHI areas decreased from 86.80% to 81.80% during the same period. The successful contribution of this research demonstrates the usefulness of spatial models as tools in generating LULC maps for assessing UHI to facilitate future sustainable city planning.

Key changes across valley floors in mountain areas affected by different levels of human impact: a case study of the Ochotnica river catchment in the Polish Carpathians

The goal of this paper was to present knowledge on changes in the morphodynamic structure of the Ochotnica River (Polish Carpathians) and transformations within its active river zone since the end of the 19th century. The study used a set of archival and contemporary cartographic materials and the results of three-fold field mapping of the morphodynamic structure of the riverbed. Direct and indirect human interference with the natural environment of the catchment and the fluvial system was taken into account in the analysis. Analysis of changes in the morphodynamic structure of the Ochotnica and its active river zone since the end of the 19th century indicated significant changes in the development trend of the riverbed. The contemporary structure of the Ochotnica is more complex than in the 1980s. There has been a fragmentation of the riverbed into sections with different morphodynamic sections. The proportion of erosive sections has increased, which explains the reduced in the width of the active river zone of the Ochotnica. The average width of the active river zone of the river between 1861 and 2022 has changed from 80 m to 18 m. Human impact has been identified as the main reason for the changes in the morphodynamic structure of the riverbed and its active river zone. Currently, only the unregulated sect ion is characterised by free lateral migration of the riverbed and the widest active river zone (∼ 28 m).

Regional Disparities and Trends in Venous Thromboembolism Mortality in Spain (1999–2022)

AimThis study aims to analyze trends in venous thromboembolism (VTE) mortality in the Spanish Autonomous Communities (ACs) from 1999 to 2022, with a focus on identifying regional disparities and informing targeted public health interventions. MethodsAge-standardized mortality rates (ASMRs) were calculated using the European standard population as a reference. Joinpoint regression analysis was employed to identify significant changes in mortality trends, and geographical analysis was conducted using Bayesian inference to assess regional variations in mortality risk. ResultsFrom 1999 to 2022, Spain recorded 59,515 VTE-related deaths, with a higher proportion in women (59.4%) compared to men (40.6%). On a nationwide scale, VTE ASMRs showed a general decline for both men and women, with rates decreasing from 11.0 to 5.1 per 100,000 in men and from 9.2 to 4.4 per 100,000 in women. However, this decline was not uniform across all regions or demographic groups. Notably, mortality rates among younger individuals, particularly men, increased during the study period, highlighting the need for targeted interventions. Analysis revealed significant regional disparities, with higher mortality risks observed in Extremadura, Aragon, Navarre, and Andalusia, particularly for women. ConclusionsThis study provides valuable insights into the complex landscape of VTE mortality in Spain. While the overall decline in mortality is encouraging, persistent regional disparities and rising rates among younger individuals underscore the need for ongoing surveillance and targeted interventions.

Temporal trends in suicide ideation and attempt among youth in juvenile detention, 2016-2021.

Data from the general population of youth show increases in suicide ideation and attempt in recent years, with rates of increase differing across sex and racial/ethnic groups. This study assessed trends in suicide ideation and attempt from 2016 to 2021 in youth in juvenile detention, across sex, age, and racial/ethnic groups. We leveraged state-wide suicide screening data of all detained youth (n = 53,769) from 2016 to 2021. We analyzed data for periods defined by statistically significant changes in trends of lifetime suicide attempt, past 6-month suicide attempt, and current suicide ideation. The prevalence of lifetime, but not past six-month, attempts increased, whereas the prevalence of current suicide ideation decreased annually from 2016 to 2021. Overall trends were qualified by distinct patterns among subgroups: rates of lifetime attempt increased among male, adolescent, and Black youth, while rates of current ideation decreased among male, adolescent, and White and Hispanic youth. These data document increasing rates of lifetime suicide attempts in detained youth from 2016 to 2021, especially among male and Black adolescents, concomitant with decreasing rates of current suicide ideation. Suicide prevention approaches for detained youth may need to prioritize variables besides or in addition to suicide ideation.

Impact of the COVID-19 pandemic on initiation of antihypertensive drugs in Sweden: an interrupted time series study

ObjectivesAntihypertensives reduce the risk of myocardial infarction and stroke. Restrictions during the COVID-19 pandemic limited access to healthcare, which may have had a negative impact on drug prescribing. This study...

Hypoxia cycle in shallow lakes during winter (ice-covered to melting period): Stable and decay, hypoxia, and recovery phases

This study investigates hypoxic processes beneath lake ice and explores the interactions between water environmental factors and dissolved oxygen (DO) during winter, aiming to systematically assess the influence of winter climate changes on lake ecosystems through environmental variables (physical, chemical, and biological characteristics of water). A complete hypoxic cycle in a high-altitude shallow lake was recorded using high-frequency monitoring technology, and based on a predetermined hypoxic threshold (DO<2 mg/L), it was divided into three phases: stable and decay phase, hypoxic phase, and recovery phase. Significant trend changes of environmental variables under different levels of DO were analyzed for each phase using the Mann-Kendall non-parametric test. On the basis of evaluating the overall trend of the time series, a GAM multi-factor optimization model integrating interactive effects was constructed to explore the response mechanism of environmental variables to hypoxic processes. The optimized model showed excellent explanatory performance with R2 values of 0.833 for the stable and decay phase and 0.932 for the recovery phase, with AIC values of 1554.72 and 721.03, respectively. The trend test combined with model analysis indicates that: (1) the decay of DO under the ice is primarily affected by the increase in EC, BGA, and EC*Temp, (2) the phytoplankton biomass in shallow lakes during winter has a definite contribution to the occurrence of oxygen deficiency, and (3) the water body experiences rapid reoxygenation after the ice layer breaks, but the DO level is restricted by the increase in temperature. This study highlights the ecosystem characteristics of shallow ice-covered lakes in cold arid regions, advancing our understanding of the response relationship between hypoxic aquatic environments under ice and environmental factors.

Revealing the Diversity and Complexity behind Long-Term Income Inequality in Latin America: 1920–2011

This paper analyzes and documents a new long-term income inequality series for Argentina, Brazil, Chile, Colombia, Mexico, and Venezuela based on dynamic social tables with four occupational groups. This enables the calculation of comparable Overall (four groups) and Labor Ginis (three groups) with their between- and within-group components. The main findings are the absence of a unique inequality pattern over time; country outcomes characterized by trajectory diversity and level divergence during industrialization and by commonality and convergence post-1980; the occurrence of inequality-leveling episodes with different timing and length; and significant changes in trends, but also evidence indicating persistence. The income-inequality dataset is included as supplementary material.

Metric Stability of One Month Handgrip Maximal and Explosive Isometric Strength Measured by Classic and Impulse Contractions

Abstract The aim of this study is to determine the metric stability of the one-month handgrip test (HGT) in order to define the contractile characteristics of the biological variation of maximal isometric strength (F max) and maximal isometric rate of force development (RFD max) of the handgrip in two different testing regimes (classic and impulse). The study was conducted with a total of 16 participants (11 men and 5 women). Testing was performed using an isometric handgrip probe with a standardized test protocol and equipment sports medical solutions (SMS). The results of F max showed a low relative standard error of the mean (RS = 1.33 %), a high value of inter-class correlation (ICC = 0.996), and no statistically significant change in trend (p &gt; 0.05) during the testing period. Therefore, can conclude that the HGT procedure in classic mode can be used as a stable parameter in a human subject sample. However, the RFD max results showed a low RS (2.13 %) and a high ICC value (0.996), but a statistically significant change of trend (p &lt; 0.05) during the measurement period. The regression constant (RCO) trend was 42.629 N/s, which can be attributed to learning or to the adaptive effects of the test procedure, which triggered similar adaptation processes as the training. In general, it can be concluded that the handgrip can be used to sensitively measure the effects of different long-term health improvements, or the effects of different medical/health exercises, rehabilitation programs, effects of medication applications, or dietary supplements for F max. However, further research should be conducted for the RFD max considering the metric stability parameters.

Use of Hydrochlorothiazide in the United States Following Label Update About Skin Cancer Risk.

On August 20, 2020, the United States (U.S.) Food and Drug Administration (FDA) issued a Drug Safety Communication (DSC) along with labeling updates to inform the public about a small increased risk of non-melanoma skin cancer (NMSC) associated with hydrochlorothiazide (HCTZ) use. This study aims to assess whether the DSC impacted HCTZ use in the U.S. We conducted a trend analysis in the Sentinel Distributed Database using national healthcare administrative data from January 2017 to November 2022. We identified two cohorts each month: An overall cohort of all enrollees and a skin cancer cohort of those with a history of NMSC. For each cohort, we plotted the monthly proportion of patients receiving HCTZ-containing products among those receiving any thiazide diuretics. We performed interrupted time series analyses to quantify the impact of the DSC on these monthly proportions. Secondary analyses were conducted on the proportion of HCTZ users among patients receiving any antihypertensives. In the overall cohort, the DSC was only associated with a statistically significant but clinically negligible trend change of monthly HCTZ proportion within this cohort (0.018%; 95% CI, 0.012%-0.025%). Similar results were observed in the skin cancer cohort. The secondary analysis found no significant level change or trend change in the monthly proportion of HCTZ use among antihypertensive users. We did not observe significant changes in HCTZ use following the DSC about its NMSC risk, among the overall population and those with a history of NMSC. Our findings were in accordance with the DSC recommendation.

Global, regional, and national trends in the burden of breast cancer among individuals aged 70 years and older from 1990 to 2021: an analysis based on the global burden of disease study 2021

BackgroundBreast cancer poses a substantial health challenge for the world’s over-70 population. However, data on the impact and epidemiology of breast cancer in this age group are limited. We aimed to evaluate global, regional, and national breast cancer trends among those aged 70 and older between 1990 and 2021.MethodsIn this trend analysis based on the 2021 Global Burden of Diseases (GBD), we report on the incidence rates and Global Burden of Diseases (GBD) disability-adjusted life years (DALYs) counts, as well as the incidence rates per 100,000 individuals and average annual percentage changes (AAPCs) for breast cancer among individuals aged 70 and above at the global, regional, and national levels. We analyzed these global trends by age, sex, and socio-developmental index (SDI). Joinpoint regression elucidates pivotal trend shifts.ResultsFrom 1990 to 2021, the global incidence of breast cancer in the over-70 population modestly increased from 104 to 107 per 100,000, with significant trend changes in 1995, 2005, and 2018. Regionally, High-income North America had the highest incidence in 2021, while North Africa and the Middle East saw the steepest rise in incidence and DALYs. The only decrease was in the High SDI quintile. The 70–74 age group experienced the largest increase globally, with rates rising from 86.3 to 90 per 100,000 (AAPC 0.27).ConclusionFrom 1990 to 2021, global breast cancer incidence in the over-70 population saw a slight uptick, contrasted by a significant reduction in DALYs, likely due to progress in endocrine and targeted therapies. This underscores the critical need for enhanced screening and personalized treatments for older patients.

Chronic low-grade inflammation associated with higher risk and earlier onset of cardiometabolic multimorbidity in middle-aged and older adults: a population-based cohort study.

Evidence regarding the role of chronic low-grade inflammation in the progression of cardiometabolic diseases (CMDs) and cardiometabolic multimorbidity (CMM) is currently limited. This prospective cohort study, utilising data from the UK Biobank, included 273,804 adults aged 40-69years initially free of CMD at baseline. CMM was defined as the coexistence of two or more CMDs, such as coronary artery disease, type 2 diabetes mellitus, hypertension and stroke. The aggregated inflammation score (INFLA-score), incorporating C-reactive protein, white blood cell count, platelet count and granulocyte-to-lymphocyte ratio, quantified chronic low-grade inflammation. Absolute risks (ARs), hazard ratios (HRs) and 95% confidence intervals (CIs) assessed the association of increased INFLA-score with the risk of CMMs and CMDs. The accelerated failure time model explored the effect of INFLA-score on the time to CMM onset, and a restricted cubic spline characterised the dose-dependent relationship between INFLA-score and CMM risk. After a median follow-up of 166.37months, 13,755 cases of CMM were identified. In quartiles with increasing INFLA-score levels, CMM ARs were 4.41%, 4.49%, 5.04% and 6.01%, respectively; HR increased by 2%, 15% and 36%, respectively, compared to the lowest quartile. The INFLA-score and CMM risk relationship was nonlinear (P for nonlinear < 0.001), exhibiting a significant risk trend change at a score of 9. For INFLA-score < 9, CMM risk increased by 1.9% for each 1-point increase; for INFLA-score ≥ 9, the risk increased by 5.9% for each 1-point increase. Additionally, a higher INFLA-score was associated with an earlier onset of CMM (P < 0.001). Compared to the first INFLA-score quartile, the AFT model revealed adjusted median times to CMM occurrence were 2.92, 6.10 and 13.19months earlier in the second, third and fourth quartile groups, respectively. Chronic low-grade inflammation is associated with a higher risk of cardiometabolic multimorbidity and earlier onset among middle-aged and older adults. Monitoring and screening the INFLA-score in adults without CMDs may improve early prevention of CMM.

The association between introduction of the micro-axial flow pump Impella in hospitals and in-hospital mortality in patients treated with extracorporeal membrane oxygenation: interrupted time-series analyses.

The micro-axial flow pump Impella, a new mechanical circulatory device for cardiogenic shock, is still only available in a limited number of hospitals, due to the facility certification requirements and insufficient evidence of the benefit of introducing Impella in hospitals. This study aimed to evaluate the impact of introducing Impella in hospitals on in-hospital mortality of patients treated with extracorporeal membrane oxygenation (ECMO). Using a nationwide Japanese inpatient database, we identified patients who received ECMO during hospitalization between 1 April 2014 and 31 March 2021. A hospital-level propensity score-matched cohort was created matching hospitals that introduced Impella (exposure group) to those that did not introduce Impella (control group). The inclusion period in each hospital was divided into two time periods according to the time of Impella introduction in the exposure group and the corresponding hospital in the control group (before and after exposure). The primary outcome was in-hospital mortality. Uncontrolled and controlled interrupted time-series analyses involved before-after exposure comparison and exposure-control comparison. Out of 34,379 eligible patients, we created a matched cohort of 8351 patients from 86 hospitals with Impella introduction (exposure group) and 7230 patients from 86 hospitals without Impella introduction (control group). In-hospital mortality before and after exposure was 62.5% and 59.3, respectively, in the exposure group; and 66.8% and 63.7%, respectively, in the control group. Uncontrolled interrupted time-series analysis showed no significant level change or trend change in the before-after exposure comparison in both the exposure and the control groups. Controlled interrupted time-series analysis also showed no significant level change (-0.01%; 95% confidence intervals -5.36% to + 5.33%) or trend change (+ 0.10%, -0.30% to + 0.40%) after exposure in the exposure-control comparison. This nationwide inpatient database study showed no association between Impella introduction in hospitals and in-hospital mortality of patients who underwent ECMO. Because this study confined itself to analze of the impact of the introduction of Impella solely at the hospital level, further detailed studies are warranted to assess its efficacy at the patient level.

Trends in Vaccination Coverage among Children Aged 2-6 Years in Tennessee Counties, 2017-2023.

Background/Objectives: This study examines trends in county-level vaccination coverage before, during, and after the COVID-19 pandemic among children aged 2-3 and 4-6 years in Tennessee, with a focus on rurality; Methods: Data from the Tennessee Immunization Information System (January 2017 to September 2023) were analyzed for vaccination coverage in children in both age groups. The study categorized the COVID-19 pandemic into three periods: pre-pandemic (P1: January 2017 to December 2019), stay-at-home (P2: January 2020 to May 2021), and reopening (P3: June 2021 to September 2023). Vaccination trends were stratified by vaccine type, rurality, sex, race and ethnicity; Results: During P1, there were no significant changes in trends of vaccination coverage percentages in both rural and urban counties for both age groups. However, vaccination coverage declined significantly during P2 and P3 compared to P1 for most vaccines, except for influenza, which initially increased but later declined. Rural counties experienced a more pronounced decline compared to urban counties during P2 and P3 for both age groups. Within rural and urban counties, vaccination coverage was higher among white children compared to black children, and among non-Hispanic compared to Hispanic children. There were higher coverage percentages in age group 4-6 for all vaccines, except for influenza, compared to 2-3 year group; Conclusions: The COVID-19 pandemic has exacerbated disparities in childhood vaccination coverage, particularly in rural areas. These findings highlight the need for targeted public health interventions to address barriers to vaccination and ensure equitable access to vaccines for all children.

Trends in COPD severe exacerbations, and all-cause and respiratory mortality, before and after implementation of newer long-acting bronchodilators in a large population-based cohort

BackgroundLittle is known about the trends in morbidity and mortality at the population level that followed the introduction of newer once-daily long-acting bronchodilators for COPD. The purpose of the study was to evaluate whether the availability of new bronchodilators was associated with changes in the temporal trends in severe COPD exacerbations and mortality between 2007 and 2018 in the older population with COPD; and whether this association was homogeneous across sex and socioeconomic status classes.MethodsWe used an interrupted time-series and three segments multivariate autoregressive models to evaluate the adjusted changes in slopes (i.e., trend effect) in monthly severe exacerbation and mortality rates after 03/2013 and 02/2015 compared to the tiotropium period (04/2007 to 02/2013). Cohorts of individuals > 65 years with COPD were created from the nationally representative database of the Quebec Integrated Chronic Disease Surveillance System in the province of Quebec, Canada. Whether these trends were similar for men and women and across different socioeconomic status classes was also assessed.ResultsThere were 130,750 hospitalizations for severe exacerbation and 104,460 deaths, including 24,457 (23.4%) respiratory-related deaths, over the study period (928,934 person-years). Significant changes in trends were seen after 03/2013 for all-cause mortality (-1.14%/month;95%CI -1.90% to -0.38%), which further decreased after 02/2015 (-1.78%/month;95%CI -2.70% to -0.38%). Decreases in respiratory-related mortality (-2.45%/month;95%CI -4.38% to -0.47%) and severe exacerbation (-1,90%/month;95%CI -3.04% to -0.75%) rates were only observed after 02/2015. These observations tended to be more pronounced in women than in men and in higher socioeconomic status groups (less deprived) than in lower socioeconomic status groups (more deprived).ConclusionsThe arrival of newer bronchodilators was chronologically associated with reduced trends in severe exacerbation, all-cause and respiratory-related mortality rates among people with COPD > 65 years. Our findings document population benefits on key patient-relevant outcomes in the years following the introduction of newer once-daily long-acting bronchodilators and their combinations, which were likely multifactorial. Public health efforts should focus on closing the gap between lower and higher socioeconomic status groups.

Trends in extreme rainfall and their relationship to flooding episodes in Vhembe district, South Africa

Extreme weather events, such as heavy rainfall, are being increased by climate change in various regions, and such events often cause floods. This study examined the trends and variability of extreme rainfall indices using daily rainfall data (1981–2023) from three study sites at different socio-economic development spectra in Vhembe District, Limpopo Province, South Africa. The analyses focus on indices such as the annual total rainfall from wet days (PRCPTOT), the maximum number of consecutive dry days (CDD) and wet days (CWD), annual maximum 1-day and 5-day rainfall (RX1 day and RX5 day), the Simple Daily Intensity Index (SDII), the number of days exceeding varying amounts of precipitation (R10, R20, R40) and the annual number of wet days with rainfall greater than the 95th and 99th percentile (R95p and R99p) of the 1981–2023 daily rainfall. We discuss the observed trends in extreme rainfall indices in light of the actual flood occurrences to establish linkages. Several statistically significant and marginal changes in extreme rainfall trends were identified and provided key insights into reported flooding events in the district—flooding episodes were mainly attributed to the significant increases in total precipitation (PRCPTOT) and rainfall exceeding the 99th percentile of daily rainfall (R99p). Other significant contributors were declining CDD and increasing RX1day at Duthuni, increasing R40 at Musina as well as increasing R1 and declining CDD at Sane. However, the low altitude, urbanization, poor waste management and inadequate drainage systems were among the key non-climatic drivers of flood risk across the study sites, but these warrant further investigation. The complex interplay between climatic and non-climatic drivers of flood risk underscores the importance of localized climate studies and the need for adaptive strategies to minimize loss and damage. Overall, this research provides valuable insights into localized extreme rainfall trends, which are essential for developing site-specific flood mitigation and adaptation strategies. However, such initiatives require placing vulnerable communities at the centre in order to develop solutions that are locally led and relevant.

SUICIDE MORTALITY IN THE ELDERLY IN THE MACROREGIONS OF SANTA CATARINA: Temporal trend 2011 to 2020

To analyze the variation in suicide mortality rate among elderly individuals in the macroregions of Santa Catarina (SC), from 2011 to 2020. Ecological study, using data from the Mortality Information System and the Brazilian Institute of Geography and Statistics. Deaths of elderly individuals (60 years or older) with suicide as the underlying cause, according to ICD-10 codes X60-X84, Y10-Y19, and Y87, were included. Segmented linear regression analysis was adopted to calculate the annual percentage variation and significant changes in trend. From 2011 to 2020, there were 1,721 suicide deaths in SC. There was a significant increase in suicide mortality rates among elderly individuals in the state of SC (2016 to 2020) and in the macroregions of Meio Oeste and Serra (2011 to 2020), Grande Oeste (2018 to 2020), and Grande Florianópolis (2016 to 2020). Mortality rates decreased in SC (2011 to 2016) and in the macroregions of Grande Oeste (2011 to 2018), Grande Florianópolis (2011 to 2016), and Foz do Rio Itajaí (2011 to 2020). Suicide mortality rates differ among the macroregions of the state and SC.

Prescribing Trends for Oral Vancomycin and Fidaxomicin after Guideline and Formulary Changes in Ontario, Canada: An Interrupted Time-Series Analysis.

Clostridioides difficile is a pathogen causing diarrheal illness, which can be treated with vancomycin or fidaxomicin. To evaluate changes in monthly prescription volumes for oral vancomycin and fidaxomicin in Ontario community pharmacies following implementation of the 2017 and 2021 updates to guidelines from the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA) and after a 2019 provincial formulary change for vancomycin. An interrupted time-series analysis was conducted from November 2015 to October 2021 using monthly projected prescription volumes obtained from IQVIA's Compuscript database. Level and slope (trend) changes in prescribing were assessed using segmented linear regression. The volume of vancomycin prescriptions increased by 74 prescriptions per month (95% confidence interval [CI] 16 to 132) following implementation of the 2017 guideline update and by 73 prescriptions per month (95% CI 13 to 133) after the 2019 formulary change; however, no statistically significant changes were observed after implementation of the 2021 guideline update. No significant trend changes were observed for fidaxomicin. Guidelines and formulary changes were correlated with increased volume of vancomycin prescriptions.

Large-ensemble Monte Carlo: a researcher’s guide to better climate trend uncertainties

Abstract Internal climate variability (ICV) often violates the assumptions of statistical methods, and the climate research community does not have an established approach for addressing resulting biases. Here we argue for a technique we call climate model Large-Ensemble Monte-Carlo (LENS-MC) to inform the selection of statistical methods for real-world application. Until now, scientists have often made best efforts to select methods based on assumptions about the mathematical properties of ICV. LENS-MC relaxes these assumptions and justifies method selection, potentially for a wide range of statistical analyses. We demonstrate LENS-MC using a case study of statistical errors in 20 year trends in global temperature and top-of-atmosphere flux series, comparing results with standard ordinary least squares (OLS). OLS commonly underestimates trend uncertainties, resulting in a higher likelihood of falsely reporting statistically significant trends or changes in trends, for example reporting p &lt; 0.05 in 20 year temperature trends when the statistics are actually equivalent to p &lt; 0.56. LENS-MC tests result in the selection of methods that almost eliminate the low bias in OLS trend standard errors. Using the suggested methods, researchers are less likely to mistakenly report significant trends, and LENS-MC could be widely applied to statistical climate analysis for which model output is available, provided that model ICV displays similar statistical structure, such as in autocorrelation, to observed ICV.

A phase Ib/II study of pacritinib, an interleukin 1 receptor associated kinase 1 (IRAK1) inhibitor, in patients (pts) with solid tumors harboring the 1q21.3 copy number amplification (CNA).

43 Background: The role of IRAK1 pathway in inflammatory and immune response is established in autoimmune diseases but less well-understood in cancer. Chromosome 1q21.3 CNA detected in plasma cell-free DNA was observed in pts with advanced solid tumors, and associated with IRAK1 upregulation. In preclinical animal models, IRAK1 upregulation promoted tumorigenesis, while its inhibition led to decreased tumor growth. Pacritinib is a JAK2/FLT3 inhibitor that is FDA approved for treatment in myelofibrosis, but also have known activity against IRAK1. We hypothesize that pacritinib may be effective in disease control of pts with plasma 1q21.3 CNA. Methods: A phase Ib/II clinical trial was designed to investigate the efficacy of pacritinib in pts with treatment (rx) refractory solid tumors harboring 1q21.3 CNA. Serial pt tumor and blood samples were collected and analyzed to elucidate the effect of IRAK1 inhibition on tumor microenvironment and systemic immune modulation. Results: 330 patients were screened, 1q21.3 CNA was detected in 30.1% of pts. Highest incidence of 1q21.3 CNA positivity was detected in breast cancer (39.8%), colorectal cancer (39.7%) and lung cancer (36.1%). 12 pts were commenced on rx over 3 dose levels (DL) (DL1: n=6, DL2: n=3, DL3: n=3). At DL1 (200mg BID), no DLTs were observed, but 2 pts had G3 transaminitis attributed to drug/disease, and 1 pt had intolerable G2 rash; decision was made for dose reduction. At DL2 (200mg OM, 100mg ON), no DLTs were observed. Reescalation to 200mg BID (DL3) was carried out with no DLT observed. Pacritinib at 200mg BD was declared the recommended phase II dose in pts with solid tumors. In the dose expansion cohort, 8 pts (4 colorectal cancer, 3 hepatobiliary [HPB] cancer, 1 lung cancer) have been enrolled thus far. No objective responses were observed. Within pts with HPB tumors, 1 pt with pancreatic cancer had a progression-free survival (PFS) of 25.0 weeks, and 1 pt with cholangiocarcinoma had a PFS of 15.9 weeks. Preliminary analysis of serial tumor biopsy samples suggest an expansion of CD8+ T cell population with pacritinib rx. Serial peripheral blood mononuclear cells analysis showed no significant trend in change in CD8+ T cell population, but a predominance of PD-1+ T cells with rx, and also an increase in CD4+ T cell population. In the myeloid cell population, there appears to be decrease in dendritic cell population, but no significant change in trend of macrophage was observed. Conclusions: Pacritinib at 200mg BID is safe and tolerable in pts with solid tumors. IRAK1 inhibition appears to modulate immune cell populations both in the tumor microenvironment and systemic circulation. Dose expansion is underway, with potential signal of disease control in HPB tumors. Clinical trial information: NCT04520269 .