Clinical Trial Quality Assessment in Adult Spinal Surgery: What Do Publication Status, Funding Source, and Result Reporting Tell Us?

Study Design Narrative Review Objectives The objective of this study was to compare publication status of clinical trials in adult spine surgery registered on ClinicalTrials.gov by funding source as well as to identify other trends in clinical trials in adult spine surgery. Methods All prospective, comparative, therapeutic (intervention-based) trials of adult spinal disease that were registered on ClinicalTrials.gov with a start date of January 1, 2000 and completion date before December 17, 2018 were included. Primary outcome was publication status of published or unpublished. A bivariate analysis was used to compare publication status to funding source of industry vs non-industry. Results Our search identified 107 clinical trials. The most common source of funding was industry (62 trials, 57.9% of total), followed by University funding (26 trials, 24.3%). The results of 76 trials (71.0%) were published, with industry-funded trials less likely to be published compared to non–industry-funded trials (62.9% compared to 82.2%, P = .03). Of the 31 unpublished studies, 13 did not report any results on ClinicalTrials.gov , and of those with reported results, none was a positive trial. Conclusions Clinician researchers in adult spine surgery should be aware that industry-funded trials are less likely to go on to publication compared to non–industry-funded trials, and that negative trials are frequently not published. Future opportunities include improvement in result reporting and in publishing negative studies.

Impact of the COVID-19 Pandemic on Non-COVID-19 Clinical Trials

Randomized controlled trials (RCT) were impacted by the COVID-19 pandemic, but no systematic analysis has evaluated the overall impact of COVID-19 on non-COVID-19-related RCTs. The ClinicalTrials.gov database was queried in February 2020. Eligible studies included all randomized trials with a start date after 1 January 2010 and were active during the period from 1 January 2015 to 31 December 2020. The effect of the pandemic period on non-COVID-19 trials was determined by piece-wise regression models using 11 March 2020 as the start of the pandemic and by time series analysis (models fitted using 2015–2018 data and forecasted for 2019–2020). The study endpoints were early trial stoppage, normal trial completion, and trial activation. There were 161,377 non-COVID-19 trials analyzed. The number of active trials increased annually through 2019 but decreased in 2020. According to the piece-wise regression models, trial completion was not affected by the pandemic (p = 0.56) whereas trial stoppage increased (p = 0.001). There was a pronounced decrease in trial activation early during the pandemic (p < 0.001) which then recovered. The findings from the time series models were consistent comparing forecasted and observed results (trial completion p = 0.22; trial stoppage p < 0.01; trial activation, p = 0.01). During the pandemic, there was an increase in non-COVID-19 RCTs stoppage without changes in RCT completion. There was a sharp decline in new RCTs at the beginning of the pandemic, which later recovered.

CLIMATIC CHARACTERISTICS OF THE COLD PERIOD IN UFA

The article presents the results of a study of the climatic characteristics of the cold period in the city of Ufa of the Republic of Bashkortostan in the modern period. For the analysis, the authors used traditional processing methods. To identify climate changes, different base periods were considered (1961-1990, 1981-2010, 1991-2020). In some cases, time series of long-term observations were available only since 1973, so in these cases two base periods were distinguished. The statistical characteristics and changes in air temperature and its amplitude, the dates of the beginning/end and duration of the cold period, the amount of precipitation, relative humidity, the height of the snow cover and its moisture reserves, the dates of establishment/destruction and the duration of the snow cover are analyzed. Correlations between climatic indicators are shown. The study revealed that in all months of the cold period there is a tendency to increase air temperature, while the greatest contribution is made by an increase in minimum temperatures. A steady reduction in the duration of the cold period was found due to the shift of the start date to a later date, and the end date to an earlier one. The amount of precipitation tends to increase. Due to the reduction of the cold period, the duration of the snow cover in the city of Ufa decreases.

Optimal Planning of Hotel Renovation Projects

This paper presents the development of a novel model for optimizing the planning of hotel renovation projects to maximize hotel revenues during renovation work while minimizing project cost. The model is developed in three main modules: optimization, scheduling, and hotel profit modules. The model integrates an innovative methodology that enables renovation planners to select which hotels to renovate during any fiscal year based on an allocated renovation budget and identify an optimal floor renovation start date, optimal overtime hours usage and number of assigned crews for each renovation activity, and an optimal floor renovation order in each hotel. An application example of three hotels is analyzed to illustrate the use of the model and demonstrate its capabilities. The results of this analysis illustrate the novel contributions of the model and its original capability in generating optimal plans for hotel renovation projects that enable hotel owners to maximize revenues of their hotels during renovation work while minimizing hotel renovation costs.

A Review of Prognosis Model Associated With Cardiogenic Shock After Acute Myocardial Infarction

Objective: Cardiogenic shock seriously affects the survival rate of patients. However, few prognostic models are concerned with the score of cardiogenic shock, and few clinical studies have validated it. In order to optimize the diagnosis and treatment of myocardial infarction complicated with cardiogenic shock and facilitate the classification of clinical trials, the prognosis score model is urgently needed.Methods: Cardiogenic shock, severe case, prognosis score, myocardial infarction and external verification were used as the search terms to search PubMed, Embase, Web of Science, Cochrane, EBSCO (Medline), Scopus, BMC, NCBI, Oxford Academy, Science Direct, and other databases for pertinent studies published up until 1 August 2021. There are no restrictions on publication status and start date. Filter headlines and abstracts to find articles that may be relevant. The list of references for major studies was reviewed to obtain more references.Results and Conclusions: The existing related models are in urgent need of more external clinical verifications. In the meanwhile, with the development of molecular omics and the clinical need for optimal treatment of CS, it is urgent to establish a prognosis model with higher differentiation and coincidence rates.

Herbivore-Mediated Selection on Floral Display Covaries Nonlinearly With Plant-Antagonistic Interaction Intensity Among Primrose Populations

Quantifying the relations between plant-antagonistic interactions and natural selection among populations is important for predicting how spatial variation in ecological interactions drive adaptive differentiation. Here, we investigate the relations between the opportunity for selection, herbivore-mediated selection, and the intensity of plant-herbivore interaction among 11 populations of the insect-pollinated plant Primula florindae over 2 years. We experimentally quantified herbivore-mediated directional selection on three floral traits (two display and one phenological) within populations and found evidence for herbivore-mediated selection for a later flowering start date and a greater number of flowers per plant. The opportunity for selection and strength of herbivore-mediated selection on number of flowers varied nonlinearly with the intensity of herbivory among populations. These parameters increased and then decreased with increasing intensity of plant-herbivore interactions, defined as an increase in the ratio of herbivore-damaged flowers per individual. Our results provide novel insights into how plant-antagonistic interactions can shape spatial variation in selection on floral traits and contribute toward understanding the mechanistic basis of geographic variation in angiosperm flowers.

PENGARUH OBESITAS TERHADAP SIKLUS MENSTRUASI PADA REMAJA DI DESA RAMBAH TENGAH HILIR KECAMATAN RAMBAH KABUPATEN ROKAN HULU

The menstrual cycle is the distance between the start date of the last menstrual period and the start of the next menstruation which occurs repeatedly every month. Regular cycles every month with a span of 21 to 35 days each menstrual period and the length of menstruation lasts 3-7 days. Menstrual cycle abnormalities are a sign of some abnormalities in the cervix, uterine cancer, breast cancer, and infertility. There are several factors that affect the menstrual cycle such as physical activity, stress, diet, hormonal factors, food consumed, enzymes in the body and BMI. Menstrual cycle can be influenced by body weight, physical activity, stress level, and ovarian disorders. This research uses a descriptive method, which is a research method that describes certain variables in research with a cross-sectional design. The population is 287 people. Samples obtained by accidental technique obtained 32 teenagers. The results of this study showed that the average data for adolescents with BMI 29.29 ± 3.3 had abnormal menstrual cycles. The statistical test results obtained a p value of 0.025, which means that there is an influence between obesity on the menstrual cycle in adolescents

Treatment Patterns and Outcomes in Lenalidomide-Exposed Multiple Myeloma Patients in Real-World Settings: A Multi-Center Retrospective Study

Background Treatment of multiple myeloma (MM) has changed significantly in recent years with the availability of novel agents including monoclonal antibodies (mAbs), proteasome inhibitors (PIs) and immunomodulatory drugs (IMiDs) such as lenalidomide. Despite lenalidomide becoming a standard of care across all lines of myeloma therapy, the population of MM patients refractory to lenalidomide and their real-world clinical management has been poorly studied so far, especially outside the reality of interventional clinical trials (Moreau et. al. Blood Cancer J. 2019). With these considerations in mind, we have performed a retrospective study using two databases to better understand treatment patterns and outcomes of MM patients who were treated with lenalidomide and subsequently became refractory to it. This builds on work previously conducted at other data sources (Willenbacher et. al. EHA Library 2020). Aims The objective of this study was to describe the treatment patterns and outcomes of MM patients exposed to lenalidomide, with a focus on refractory patients, as defined by IMWG (International Myeloma Working Group) consensus, in a real-world clinical setting. Methods The study utilised databases from two participating members of the IQVIA MM real world evidence network: University Hospital Frankfurt (Frankfurt) (Germany) and Portuguese Oncology Institute of Porto (IPO-Porto) (Portugal). Since the native format of databases from participating sites differs, key concepts were harmonised based on pre-agreed definitions. The study population included patients with an initial diagnosis of MM between 01/01/2012 and 31/12/2018 based on the IMWG criteria, were 18 years old or older at the time of diagnosis and received two or more cycles of lenalidomide treatment, alone or in combination, at any dose, excluding patients who only received lenalidomide as maintenance therapy. Patients were defined as refractory to lenalidomide treatment if they progressed on treatment or within 60 days following the end of lenalidomide treatment (excluding maintenance setting). Kaplan-Meier curves were produced to evaluate the time to next treatment (TTNT) and overall survival (OS) for lenalidomide exposed and lenalidomide refractory patients. TTNT was defined as the time between the start date of the line of lenalidomide therapy and the start date of the next line of therapy (LoT) or death due to any cause. OS was defined as the time between the start date of the line of lenalidomide therapy and death due to any cause. Results The cohort included 55 and 42 MM lenalidomide-exposed patients from Germany and Portugal respectively. In Germany, 80% were initially exposed to the lenalidomide in LoT 1, whilst in Portugal 71% received initial lenalidomide treatment in LoT 3. In Portugal, following lenalidomide refractoriness, the majority (78%) of patients received chemotherapy and steroids only whilst in Germany a range of treatment types was observed (mAb-based 33%; PI-based 11%; PI/IMiD combo 11%; mAb/IMiD combo 11%; chemotherapy and steroids only 11%; other 22%). The median OS in months for lenalidomide-exposed refractory patients was 7 in Portugal and 31 in Germany; the median OS for non-refractory patients was 40 in Portugal and was not reached in Germany. The median TTNT in months for lenalidomide-exposed refractory patients was 4 in Portugal and 15 in Germany; the median TTNT for non-refractory patients was 14 in Portugal and 53 in Germany. Conclusion The analysis of real-world data across two countries, showed heterogeneity in lenalidomide treatment patterns, with first exposure typically occurring in LoT 1 or 3. This has led to differences in the calculated TTNT and OS, and as such the results between the two countries cannot be directly compared. The OS from diagnosis for this cohort is being assessed and will provide an insight on the impact of different treatment pathways. Patients who became refractory to lenalidomide moved on to their next treatment much quicker after exposure vs patients who were not refractory to lenalidomide; similarly, patients who became refractory to lenalidomide had shorter OS than patients who were not refractory. Patients typically became refractory early in their treatment journey, indicating a growing population with unmet medical needs. Figure 1 Figure 1. Disclosures Metzler: GSK: Consultancy; Takeda: Consultancy; Janssen: Consultancy; AstraZeneca: Consultancy; Amgen: Consultancy; BMS: Consultancy; Sanofi: Consultancy; Pfizer: Consultancy.

Real World Validation of VTE Risk Models in Newly Diagnosed Multiple Myeloma in a Community Setting

Background: Multiple Myeloma (MM) is associated with increased risk for venous thromboembolism (VTE). Treatment, such as dexamethasone, immunomodulatory drugs (IMID), alkylating agents, and doxorubicin, alter hemostatic pathways and thus promote thrombogenesis 1. MM patients with VTE have a 3-fold increase in mortality compared to those without VTE, so identifying those at risk and aiming to prevent VTE events is important 2. Several clinical VTE risk prediction scores have been developed, including the SAVED score, IMPEDE VTE score, and more recently the PRISM score 2,4,5. The National Comprehensive Cancer Network suggests that patient with MM on IMID therapy should be on aspirin, or therapeutic anticoagulation for those at "high risk"3. However, it remains unclear which risk model, if any, should be used.Our objective was to validate the three published risk assessment tools in a community setting and assess the predictive ability of each. Methods: We conducted a retrospective chart review of all patients with newly diagnosed multiple myeloma who started chemotherapy at Gundersen Health System (La Crosse, WI) between 2010 and 2020 who had at least 6 months of follow up documented. Patients with prior indication for ongoing therapeutic anticoagulation or a diagnosis of VTE within 6 months prior to starting therapy were excluded. Total scores for IMPEDE VTE, SAVED and PRISM scores were calculated from the chemotherapy start date. Statistical analysis included Chi-square, Fisher's exact and Wilcoxon rank sum tests, and Kaplan Meier survival analysis. A p-value ≤ 0.05 was considered significant and all analysis was completed in SAS version 9.4. Results: Our cohort contained 123 patients diagnosed with MM. Average age was 68 years (SD 12.1, range 37-92). Our study included 68 (55%) males and 55 (45%) females with 121 (98%) being White/Caucasian. The mean BMI of patients was 29.4 kg/m2 (SD 7.0, range 18.6-54.4). Kaplan Meier survival analysis showed a 5-year survival rate of 53.1% (95% CI [42.7%, 63.4%]). In the entire cohort, 10 (8.1%) patients were diagnosed with VTE (as compared to 5.8% in IMPEDE study, 8.7% in SAVED study and 8.2% in PRISM study) with 80.0% occurring within 6 months of treatment start date. Aspirin was the most frequently used agent for thromboprophylaxis with 88 (86.3%) patients receiving either 81, 162, or 325 mg of aspirin. IMID therapy was given to 76 (61.8%) patients, 114 (92.7%) received dexamethasone and 114 (92.7%) received proteasome inhibitors. Amongst those on IMIDs, 72 (94.7%) patients received prophylaxis, most commonly aspirin. Abnormal metaphase cytogenetics were noted in 104 (85.4%) patients. Neither the IMPEDE VTE (p=0.6), SAVED (p=0.9) nor PRISM risk scores (p=0.3) were able to statistically predict VTE outcome in our patient population. Using the IMPEDE score, 7 patients in the intermediate risk group and 3 patients in the low-risk group had a VTE. In the SAVED model, 5 patients in the low-risk group and 5 patients in the high-risk group had a VTE. Using the PRISM risk score, all 10 of the patients with VTE were in the intermediate risk group. Most patients who were on IMID therapy fell into the intermediate risk group on the IMPEDE VTE and PRISM scoring systems, and the SAVED score had an approximately equal patient distribution between the high risk and low risk group. Conclusions: Our patients with multiple myeloma had similar rates of VTE as compared to the published models, with the majority occurring in the first 6 months of chemotherapy. In total, our patients on IMID therapy received appropriate prophylaxis with aspirin. Overall, 8.1% of our patients had a VTE event. However, none of the three risk models were able to predict the development of VTE. In fact, many of the VTE events occurred in patients who were felt to be low or intermediate risk. While the sample size is small and from a single health system, we had excellent follow up and ability to closely examine each chart for treatment and outcomes. Further efforts should focus on collaboration across institutions to increase the sample size, to validate and compare existing models. The majority of myeloma treatment occurs in the community; thus, it is important to ensure the findings are reproducible in that patient population. Disclosures No relevant conflicts of interest to declare.

South African Winter Rainfall Zone Shifts: A Comparison of Seasonality Metrics For Cape Town From 1841-1899 and 1933-2020

Mounting evidence across South Africa’s southwestern winter rainfall zone (WRZ) reflects consistent drying since ~1980 and projected trends suggest this will continue. However, limited evidence exists for the region’s rainfall seasonality changes. To improve our understanding of these WRZ drying trends, especially within the context of Cape Town’s 2015-2017 “Day Zero” drought, it is necessary to explore long-term rainfall seasonality trends. Thus, we use the longest WRZ meteorological record from the South African Astronomical Observatory (SAAO) in Cape Town to investigate rainfall seasonality shifts during 1841-2020. Consistent with recorded poleward migrations of the subtropical high-pressure belt and mid-latitude westerlies, known drivers behind the drought and drying trends, calculated trends demonstrate strengthening of WRZ conditions, primarily from a later start-date trend leading to a shorter wet-season. Long-term drying trends are quantified for the wet- and dry-seasons, however, analysis of trend evolution reveals much variability, reflecting that drying has only persisted since ~1892. Comparative analyses of the first and last 59 years of 1841-2020 reveals a rainfall decline of ~10% across both seasons – highlighting that the extreme “Day Zero” drought was not only driven by wet-season rainfall declines. Results demonstrate that these drying trends were consistently driven by a long-term decline in rain day counts and a more recent decline in average rainfall per rain day. Correspondence between our results and projected rainfall seasonality trends suggests the trends we quantified will likely continue, thus improvements and continuation of existing water conservation and management strategies are imperative for Cape Town.