Real-world comparative effectiveness of palbociclib plus aromatase inhibitor in HR+/HER2- metastatic breast cancer.

Aim: Provide real-world data on palbociclib as evidence of effectiveness in patient populations from routine clinical practice. Methods: This was a retrospective, observational cohort study of patients with HR+/HER2- metastatic breast cancer treated with palbociclib plus aromatase inhibitor (AI) or AI alone as first-line therapy within the US Oncology Network. Results: Patients treated with palbociclib plus AI (n = 838) versus AI alone (n = 450) had a numerically longer median overall survival (42.1 vs 35.7 months; hazard ratio [HR] = 0.90 [95% CI: 0.75-1.07]; p = 0.117) and a significantly extended real-world progression-free survival (21.0 vs 15.7 months; HR = 0.75 [95% CI: 0.64-0.88]; p = 0.0002) after normalized inverse probability treatment weighting. Conclusion: These real-world results support the use of palbociclib plus AI as first-line treatment in routine clinical practice for patients with HR+/HER2- metastatic breast cancer.

What is this summary about? This summary describes how well palbociclib works when used with an aromatase inhibitor in the real-world setting for people with a certain type of breast cancer that has spread to other areas of the body. Palbociclib stops cancer cells from growing and dividing. An aromatase inhibitor prevents the body from making the hormone estrogen, which is needed for certain types of breast cancer cells to grow. Palbociclib with an aromatase inhibitor is a standard first treatment used for people with this type of breast cancer that needs estrogen to grow and has spread to other areas of the body. In clinics, doctors may not always prescribe the two treatments together. The study wanted to find out if using the two treatments together worked better than using an aromatase inhibitor alone in the real-world setting. What were the results? The results suggest that in this population of patients treated in a real-world setting, people with breast cancer that needs estrogen to grow and has spread to other areas of the body who were treated with palbociclib plus an aromatase inhibitor lived longer without their cancer getting worse than those treated with an aromatase inhibitor alone. What do the results of the study mean? The results support the use of palbociclib with an aromatase inhibitor as a first treatment for breast cancer that has spread to other areas of the body, rather than an aromatase inhibitor only.

Strengthening the interpretability of clinical trial results by assessing the effect of informative censoring on the primary estimand in PRECISION.

BACKGROUND: The ICH E9(R1) addendum states that the strategy to account for intercurrent events should be included when defining an estimand, the treatment effect to be estimated based on the study objective. The estimator used to assess the treatment effect needs to be aligned with the estimand that accounted for intercurrent events. Regardless of the strategy, missing data resulting from patient premature withdrawal could undermine the robustness of the study results. Informative censoring due to dropouts in an events-based study is one such example. Sensitivity analyses using imputation methods are useful to examine the uncertainty due to informative censoring and address the robustness and strength of the study results. METHODS: We assessed the effect of premature patient withdrawal in the PRECISION study, a randomized non-inferiority clinical trial of patients with chronic arthritic pain that compared the cardiovascular safety of three nonsteroidal anti-inflammatory drugs-based treatment policies or paradigms. The protocol-defined use of concomitant or rescue medications was permitted since changes in pain medications due to insufficient analgesia were expected in patients in this long-term study. Anticipating that premature study discontinuations could potentially lead to informative censoring, a supplementary analysis was pre-specified in which censored outcomes due to the premature study discontinuation were imputed based on adverse events that were clinically associated with the primary endpoint (cardiovascular outcome based on the Antiplatelet Trialists Collaboration composite endpoint). Furthermore, tipping point analyses were conducted to test the robustness of the primary analysis results by assuming data censored not at random. The level of increase at which the primary study conclusion would change was estimated. RESULTS: For the analysis of time to first primary endpoint event through 30 months, 4065 out of the 24,081 enrolled patients were lost to follow-up, withdrew consent, or were no longer willing to participate in the study. These withdrawals occurred gradually and resulted in a cumulative total of 5893 censored patient-years of observation (10.2%). The rate of discontinuation and the baseline characteristics of the discontinued patients were similar across the three treatment groups. The non-inferiority conclusion from the primary analysis was confirmed in the supplementary analysis incorporating relevant adverse events. Furthermore, tipping point analyses demonstrated that in order to lose non-inferiority in the primary analysis, the risk of primary endpoint events during the censored observation time would have to increase by more than 2.7-fold in the celecoxib group while remaining constant in the other nonsteroidal anti-inflammatory drugs groups, demonstrating that the scenarios where the study results are invalid appear not plausible. CONCLUSIONS: Supplementary and sensitivity analyses presented to address informative censoring in PRECISION helped to further interpret and strengthen the study results.

Cardiovascular Safety of Celecoxib, Naproxen, or Ibuprofen for Arthritis.

BACKGROUND: The cardiovascular safety of celecoxib, as compared with nonselective nonsteroidal antiinflammatory drugs (NSAIDs), remains uncertain. METHODS: Patients who required NSAIDs for osteoarthritis or rheumatoid arthritis and were at increased cardiovascular risk were randomly assigned to receive celecoxib, ibuprofen, or naproxen. The goal of the trial was to assess the noninferiority of celecoxib with regard to the primary composite outcome of cardiovascular death (including hemorrhagic death), nonfatal myocardial infarction, or nonfatal stroke. Noninferiority required a hazard ratio of 1.12 or lower, as well as an upper 97.5% confidence limit of 1.33 or lower in the intention-to-treat population and of 1.40 or lower in the on-treatment population. Gastrointestinal and renal outcomes were also adjudicated. RESULTS: A total of 24,081 patients were randomly assigned to the celecoxib group (mean [±SD] daily dose, 209±37 mg), the naproxen group (852±103 mg), or the ibuprofen group (2045±246 mg) for a mean treatment duration of 20.3±16.0 months and a mean follow-up period of 34.1±13.4 months. During the trial, 68.8% of the patients stopped taking the study drug, and 27.4% of the patients discontinued follow-up. In the intention-to-treat analyses, a primary outcome event occurred in 188 patients in the celecoxib group (2.3%), 201 patients in the naproxen group (2.5%), and 218 patients in the ibuprofen group (2.7%) (hazard ratio for celecoxib vs. naproxen, 0.93; 95% confidence interval [CI], 0.76 to 1.13; hazard ratio for celecoxib vs. ibuprofen, 0.85; 95% CI, 0.70 to 1.04; P<0.001 for noninferiority in both comparisons). In the on-treatment analysis, a primary outcome event occurred in 134 patients in the celecoxib group (1.7%), 144 patients in the naproxen group (1.8%), and 155 patients in the ibuprofen group (1.9%) (hazard ratio for celecoxib vs. naproxen, 0.90; 95% CI, 0.71 to 1.15; hazard ratio for celecoxib vs. ibuprofen, 0.81; 95% CI, 0.65 to 1.02; P<0.001 for noninferiority in both comparisons). The risk of gastrointestinal events was significantly lower with celecoxib than with naproxen (P=0.01) or ibuprofen (P=0.002); the risk of renal events was significantly lower with celecoxib than with ibuprofen (P=0.004) but was not significantly lower with celecoxib than with naproxen (P=0.19). CONCLUSIONS: At moderate doses, celecoxib was found to be noninferior to ibuprofen or naproxen with regard to cardiovascular safety. (Funded by Pfizer; ClinicalTrials.gov number, NCT00346216 .).

Predictors of Neuropsychiatric Adverse Events with Smoking Cessation Medications in the Randomized Controlled EAGLES Trial.

BACKGROUND: Pre-treatment factors that increase smokers' risk of experiencing neuropsychiatric adverse events (NPSAEs) when quitting smoking are unknown. OBJECTIVE: To identify baseline smoker characteristics beyond the history of mental illness that predict which participants were more likely to experience moderate to severe NPSAEs in EAGLES. DESIGN: A prospective correlational cohort study in the context of a multinational, multicenter, double-blind, randomized trial. PARTICIPANTS: Smokers without (N = 3984; NPC)/with (N = 4050; PC) histories of, or current clinically stable, psychiatric disorders including mood (N = 2882; 71%), anxiety (N = 782; 19%), and psychotic (N = 386; 10%) disorders. INTERVENTIONS: Bupropion, 150 mg twice daily, or varenicline, 1 mg twice daily, versus active control (nicotine patch, 21 mg/day with taper) and placebo for 12 weeks with 12-week non-treatment follow-up. MAIN MEASURES: Primary safety outcome was the incidence of a composite measure of moderate/severe NPSAEs. Associations among baseline demographic/clinical characteristics and the primary safety endpoint were analyzed post hoc via generalized linear regression. KEY RESULTS: The incidence of moderate to severe NPSAEs was higher among smokers in the PC (238/4050; 5.9%) than in the NPC (84/3984; 2.1%). Three baseline characteristics predicted increased risk for experiencing clinically significant NPSAEs when quitting regardless of carrying a psychiatric diagnosis: current symptoms of anxiety (for every ~ 4-unit increase in HADS anxiety score, the absolute risk of occurrence of the NPSAE endpoint increased by 1% in both PC and NPC); prior history of suicidal ideation and/or behavior (PC, 4.4% increase; P = 0.001; NPC, 4.1% increase; P = 0.02), and being of White race (versus Black: PC, 2.9% ± 0.9 [SE] increase; P = 0.002; and NPC, 3.4% ± 0.8 [SE] increase; P = 0.001). Among smokers with psychiatric disorders, younger age, female sex, history of substance use disorders, and proxy measures of nicotine dependence or psychiatric illness severity also predicted greater risk. There were no significant interactions between these characteristics and treatment. Smokers with unstable psychiatric disorders or with current, active substance abuse were excluded from the study. CONCLUSIONS: Irrespective of cessation pharmacotherapy use, smokers attempting to quit were more likely to experience moderate to severe NPSAEs if they reported current anxiety or prior suicidal ideation at baseline and were White. In smokers with a psychiatric history, female sex, younger age, and greater severity of nicotine dependence were also predictive. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01456936.

Enhancement of phytochemical content and drying efficiency of onions (Allium cepa L.) through blanching.

BACKGROUND: This study investigated the effect of blanching (60, 70 and 80 °C for 1, 3, 5 and 10 min) combined with oven drying at 60 °C on the phenolic compounds, antioxidant activity, colour and drying characteristics (drying time, drying rate constant, effective moisture diffusivity and activation energy) of onion slices. RESULTS: Blanching of onion slices at 60 °C for 3 min and at 70 °C for 1 min prior to drying increased their bioactive compounds and antioxidant activity compared to the control samples and other treatments. Eighteen drying models were evaluated. The Modified Page and two-term exponential models best represented the drying data. The effective diffusivity ranged from 3.32 × 10-11 m2 s-1 (control) to 5.27 × 10-11 m2 s-1 , 5.01 × 10-11 m2 s-1 , and 4.74 × 10-11 m2 s-1 for onions blanched at 60 °C, 70 °C and 80 °C, respectively. The higher activation energy was observed for the control (unblanched) sample and slightly lower values were found for 1 min- and 3 min-blanched samples, confirming the higher drying efficiency as a result of the blanching pre-treatment. CONCLUSION: The use of blanching as a pre-treatment before drying of onions resulted in enhanced phytochemical content and drying efficiency. © 2017 Society of Chemical Industry.

An evaluation of increasing sample size based on conditional power.

We evaluate properties of sample size re-estimation (SSR) designs similar to the promising zone design considered by Mehta and Pocock (2011). We evaluate these designs under the assumption of a true effect size of 1.1 down to 0.4 of the protocol-specified effect size by six measures: 1. The probability of a sample size increase, 2. The mean proportional increase in sample size given an increase; 3 and 4. The mean true conditional power with and without a sample size increase; 5 and 6. The expected increase in sample size and power due to the SSR procedure. These measures show the probability of a sample size increase and the cost/benefit for given true effect sizes, particularly when the SSR may either be pursuing a small effect size of little clinical importance or be unnecessary when the true effect size is close to the protocol-specified effect size. The results show the clear superiority of conducting the SSR late in the study and the inefficiency of a mid-study SSR. The results indicate that waiting until late in the study for the SSR yields a smaller, better targeted set of studies with a greater increase in overall power than a mid-study SSR.

Evaluation of polyphenolic content and antioxidant activity in two onion varieties grown under organic and conventional production systems.

BACKGROUND: Onions contain a number of bioactive compounds, in particular polyphenols. They are rich sources of such compounds in the human diet and offer significant health benefits to the consumer. Demand for organic crops is steadily increasing partly based on the expected health benefits of organic food consumption. The current study examines the influence of organic and conventional crop management practices on bioactive polyphenolic content of onion. RESULTS: We examined the effect of conventional, organic, and mixed cultivation practices on the content of total phenolics, total flavonoids and antioxidant activity in two varieties of onion grown over 4 years in a split-plot factorial systems comparison trial. Levels of total phenolics and total flavonoids showed a significant year-on-year variation and were significantly different between organic and conventional production systems. The levels of total phenolics, total flavonoids and antioxidant activity in general were significantly higher (P < 0.05) under fully organic compared to fully conventional management. CONCLUSION: Organic cultivation practices resulted in significantly higher levels of potential bioactive compounds in onion. © 2016 Society of Chemical Industry.

"Forgotten" Chapters in the History of Transcervical Sterilization: Carl Clauberg and Hans-Joachim Lindemann.

Transcervical sterilization is a non-surgical method of permanent female sterilization that is widely used and critically discussed. A review of the historiography of the method reveals that instances of its coercive use are not included in the historical account. This study offers a reexamination of the work of Carl Clauberg and Hans-Joachim Lindemann, to more deeply contextualize within the framework of current usage the coercive use of transcervical sterilization during the Third Reich and in postwar Germany. This inquiry is based on postwar criminal trial records on Clauberg, and on archival documents detailing Lindemann's activities in 1979. A comparative analysis examines arguments by medical historian Karl-Heinz Roth, and identifies shared characteristics and differences between Clauberg and Lindemann, their methods and scientific connections. The results demonstrate that the technique of transcervical sterilization has an abusive potential that may be explained as a function of the person of the physician, of the scientific method itself, and of societal and political influences. The analysis supports the argument that insights from the cases of Clauberg and Lindemann are transferrable geographically and over time, and have the potential to inform current medical practice, such as transcervical sterilization with the Essure device, whose historiographic exploration remains a desideratum.

Statistical issues in the design, conduct and analysis of two large safety studies.

BACKGROUND/AIMS: The emergence, post approval, of serious medical events, which may be associated with the use of a particular drug or class of drugs, is an important public health and regulatory issue. The best method to address this issue is through a large, rigorously designed safety study. Therefore, it is important to elucidate the statistical issues involved in these large safety studies. METHODS: Two such studies are PRECISION and EAGLES. PRECISION is the primary focus of this article. PRECISION is a non-inferiority design with a clinically relevant non-inferiority margin. Statistical issues in the design, conduct and analysis of PRECISION are discussed. RESULTS: Quantitative and clinical aspects of the selection of the composite primary endpoint, the determination and role of the non-inferiority margin in a large safety study and the intent-to-treat and modified intent-to-treat analyses in a non-inferiority safety study are shown. Protocol changes that were necessary during the conduct of PRECISION are discussed from a statistical perspective. Issues regarding the complex analysis and interpretation of the results of PRECISION are outlined. EAGLES is presented as a large, rigorously designed safety study when a non-inferiority margin was not able to be determined by a strong clinical/scientific method. In general, when a non-inferiority margin is not able to be determined, the width of the 95% confidence interval is a way to size the study and to assess the cost-benefit of relative trial size. CONCLUSION: A non-inferiority margin, when able to be determined by a strong scientific method, should be included in a large safety study. Although these studies could not be called "pragmatic," they are examples of best real-world designs to address safety and regulatory concerns.

Potential for transfer of Escherichia coli O157:H7, Listeria monocytogenes and Salmonella Senftenberg from contaminated food waste derived compost and anaerobic digestate liquid to lettuce plants.

The diversion of food wastes from landfill to sustainable disposal methods, such as composting and anaerobic digestion, has led to an increase in the soil amendment products that are now commercially available and which are derived from both of these processes. The use of such products as soil amendments during the production of ready-to-eat (RTE) crops is increasing worldwide. The aim of this study was to investigate the potential of three well-recognised bacterial pathogens of importance to public health, namely Escherichia coli O157:H7, Salmonella Senftenberg and Listeria monocytogenes, to become internalised in lettuce plants from peat growing media amended with contaminated food waste derived compost and anaerobic digestion liquid. The results demonstrated both S. Senftenberg and E. coli O157:H7 are capable of internalisation at lower inoculation levels, compared to previous studies. The internalisation was visualised through confocal microscopy. Internalisation of L. monocytogenes did not occur, however significant levels of L. monocytogenes contamination occurred on the non-sterilised plant surface. Assessing the internalisation potential for each of these pathogens, through the compost and anaerobic digestate matrices, allows for better risk assessment of the use of these products in a horticultural setting.

Levels of potential bioactive compounds including carotenoids, vitamin C and phenolic compounds, and expression of their cognate biosynthetic genes vary significantly in different varieties of potato (Solanum tuberosum L.) grown under uniform cultural conditions.

BACKGROUND: In addition to their high carbohydrate content, potatoes are also an important dietary source of vitamin C and bioactive secondary metabolites, including phenolic compounds and carotenoids, which have been suggested to play a role in human health. The expression of genes encoding key enzymes involved in the synthesis of these compounds was assessed by reverse transcription-quantitative polymerase chain reaction and compared to the accumulation of the corresponding product in seven potato varieties showing contrasting levels of metabolite accumulation. RESULTS: Strong positive correlations were found between phenolic content in the flesh of tubers and transcript levels of phenylalanine ammonia lyase (PAL) and chalcone synthase (CHS) genes. The expression of PAL and CHS was also related to that of AN1, a transcription factor involved in the synthesis of anthocyanins, suggesting that these genes are regulated in a coordinated manner. No clear relationship was found between transcript levels of phytoene synthase (PSY) or L-galactono-1,4-lactone dehydrogenase (GLDH) genes and total carotenoid or vitamin C accumulation, respectively. CONCLUSION: Data indicate that levels of total phenolic and flavonoid compounds in potato are controlled primarily by PAL and CHS gene expression. Transcript levels of PSY and GLDH did not control accumulation of carotenoids or vitamin C.

Acute nonarteritic anterior ischemic optic neuropathy and exposure to phosphodiesterase type 5 inhibitors.

INTRODUCTION: Nonarteritic anterior ischemic optic neuropathy (NAION), a rare visual disorder, has been reported in men using phosphodiesterase type 5 inhibitors (PDE5i) for erectile dysfunction. AIM: We examined whether intermittent use of PDE5i is associated with acute NAION onset within approximately five half-lives following drug ingestion. METHODS: One hundred two ophthalmology centers in the United States and Europe identified potential cases of NAION. An expert adjudication committee conducted a blind review of the records of those with recent PDE5i use to classify cases as Definite, Possible, or not NAION. Subjects provided information on PDEi use via telephone interview. Each NAION case's PDE5i exposure immediately prior to onset was compared against his recent patterns of use in an observational case-crossover design. A sample size of 40 cases with intermittent PDE5i exposure in the 30 days prior to NAION onset was needed to detect an odds ratio (OR) of 3.0 with 80% power. MAIN OUTCOME MEASURES: The daily relative risk for acute NAION on days within five half-lives of PDE5i use vs. other days was estimated via an OR obtained from conditional logistic regression. RESULTS: Among 43 Definite NAION cases with PDE5i exposure in the prior 30 days, the OR was 2.15 (95% confidence interval [CI]: 1.06, 4.34). When 21 Possible NAION cases were included (n = 64), the OR was 2.36 (95% CI: 1.33, 4.19). CONCLUSIONS: We found an approximately twofold increased risk of acute NAION within five half-lives of PDE5i use compared with use in a more prior time period. Bias from inaccurate recall of exposure was unlikely to have substantially affected the results. Based on our results, we estimate that weekly use of PDE5i adds three NAION cases per 100,000 men 50 years and older annually.

Variation in bioactive content in broccoli (Brassica oleracea var. italica) grown under conventional and organic production systems.

BACKGROUND: Broccoli and other cruciferous vegetables contain a number of bioactive compounds, in particular glucosinolates and polyphenols, which are proposed to confer health benefits to the consumer. Demand for organic crops is at least partly based on a perception that organic crops may contain higher levels of bioactive compounds; however, insufficient research has been carried out to either support or refute such claims. RESULTS: In this study we examined the effect of conventional, organic, and mixed cultivation practices on the content of total phenolics, total flavonoids, and total and individual glucosinolates in two varieties of broccoli grown over 2 years in a split-plot factorial systems comparison trial. Levels of total phenolics and total flavonoids showed a significant year-on-year variation but were not significantly different between organic and conventional production systems. In contrast, levels of the indolyl glucosinolates glucobrassicin and neoglucobrassicin were significantly higher (P < 0.05) under fully organic compared to fully conventional management. CONCLUSION: Organic cultivation practices resulted in significantly higher levels of glucobrassicin and neoglucobrassicin in broccoli florets; however, other investigated compounds were unaffected by production practices.

Potential of cultivar and crop management to affect phytochemical content in winter-grown sprouting broccoli (Brassica oleracea L. var. italica).

BACKGROUND: Variety and crop management strategies affect the content of bioactive compounds (phenolics, flavonoids and glucosinolates) in green broccoli (calabrese) types, which are cultivated during summer and autumn in temperate European climates. Sprouting broccoli types are morphologically distinct and are grown over the winter season and harvested until early spring. Thus they show considerable potential for development as an import substitution crop for growers and consumers during the 'hungry gap' of early spring. The present study investigated the effect of variety and management practices on phytochemical content in a range of sprouting broccoli varieties. RESULTS: Yields were significantly higher in white sprouting broccoli varieties. Levels of phenolics and flavonoids were in the range 81.64-297.65 and 16.95-104.80 mg 100 g⁻¹ fresh weight, respectively, depending on year and cultivar, and were highest in variety 'TZ 5052' in both years. In-row spacing did not affect flavonoid content. Phenolic and flavonoid content generally increased with increasing floret maturity and levels were high in edible portions of the crop. Crop wastes (leaf and flower) contained 145.9-239.3 and 21.5-116.6 mg 100 g⁻¹ fresh weight total phenolics and flavonoids, respectively, depending on cultivar, tissue and year. Climatic factors had a significant effect on phenolic and flavonoid content. Levels of total and some individual glucosinolates were higher in sprouting broccoli than in the green broccoli variety 'Ironman'. CONCLUSION: Levels of total phenolics, flavonoids and glucosinolates are higher in sprouting than green broccoli types. Sprouting broccoli represents an excellent source of dietary bioactive compounds.

'The Garlic Gambit': an alternative strategy for controlling vine weevil (Otiorhynchus sulcatus F.; Coleoptera: Curculionidae).

Plant protection products derived from plant material are proposed to be a sustainable alternative to conventional synthetic chemical pesticides. This study determines the efficacy of a commercially available bioinsecticide based on garlic (Allium sativum L.; Asparagales: Amaryllidaceae) extract against vine weevil (Otiorhynchus sulcatus F.; Coleoptera: Curculionidae) eggs and larvae in contact, fumigation and a combination of contact and fumigation bioassays under laboratory conditions. Results showed that garlic significantly reduced egg hatch rate compared to the control group when applied as a fumigant. Similarly, the egg hatch rate was reduced compared to the control group when garlic was applied as combined contact and fumigant applications. No effect was observed when the garlic product was applied as a contact application. The bioinsecticide significantly reduced larval survival when either contact or fumigant applications were used. A combined contact and fumigant effect was shown also when vine weevil eggs were exposed to the bioinsecticide for 30 days in plastic containers containing growing media. The number of larvae recovered after this period was significantly reduced compared to the control group. This study demonstrates the potential of garlic-based bioinsecticides, such as Pitcher GR, for vine weevil control. Further studies are, however, needed to determine the efficacy of such bioinsecticides under field conditions and investigate how these products can be most effectively used as a part of a wider vine weevil integrated pest management program.

Cardiovascular safety of varenicline: patient-level meta-analysis of randomized, blinded, placebo-controlled trials.

Smoking is a major modifiable risk factor for cardiovascular (CV) disease. Varenicline is a pharmacological aid for smoking cessation. To explore the CV safety of varenicline, we investigated the incidence of CV events in varenicline-treated subjects across all phase 2-4 randomized placebo-controlled clinical trials of ≥12-week treatment duration conducted in smokers aged ≥18 years and sponsored by the drug manufacturer. This manuscript reports a subject-level meta-analysis of time to major adverse cardiovascular events (MACE; defined as CV-related death, nonfatal myocardial infarction, nonfatal stroke) and time to MACE+ (defined as MACE plus worsening or any procedure for peripheral vascular disease, hospitalization for angina, or performance of coronary revascularization). All events were adjudicated by an independent adjudication committee, blind to treatment assignment. Events were assessed during treatment and up to 30 days after the last treatment dose. The primary analytical method was a stratified logrank time-to-event analysis; secondary analyses were meta-analyses of incidence rate ratios and rate differences. Overall, 7002 subjects were included (varenicline: 4190; placebo: 2812) from 15 studies. MACE were reported by 13 varenicline subjects (0.31%) and 6 placebo subjects (0.21%) [hazard ratio, 1.95; 95% confidence interval (CI): 0.79-4.82; P = 0.15; risk difference, 0.006 events per subject-year; 95% CI: -0.003, 0.015, P = 0.19]. MACE+ were reported by 26 varenicline subjects (0.62%) and 12 placebo subjects (0.43%) (hazard ratio, 1.74; 95% CI: 0.91-3.34, P = 0.10; risk difference, 0.010; 95% CI: -0.002, 0.022, P = 0.11). This subject-level meta-analysis of MACE or MACE+ up to 30 days posttreatment in placebo-controlled clinical trials of varenicline found a trend toward increased incidence of these events in varenicline-treated patients that did not reach statistical significance. The overall number of events was low and the absolute risk of CV events with varenicline was small.

Effect of organic, conventional and mixed cultivation practices on soil microbial community structure and nematode abundance in a cultivated onion crop.

BACKGROUND: Responses of the soil microbial and nematode community to organic and conventional agricultural practices were studied using the Teagasc Kinsealy Systems Comparison trial as the experimental system. The trial is a long-term field experiment which divides conventional and organic agriculture into component pest-control and soil treatment practices. We hypothesised that management practices would affect soil ecology and used community level physiological profiles, microbial and nematode counts, and denaturing gradient gel electrophoresis (DGGE) to characterise soil microbial communities in plots used for onion (Allium cepa L.) cultivation. RESULTS: Microbial activity and culturable bacterial counts were significantly higher under fully organic management. Culturable fungi, actinomycete and nematode counts showed a consistent trend towards higher numbers under fully organic management but these data were not statistically significant. No differences were found in the fungal/bacterial ratio. DGGE banding patterns and sequencing of excised bands showed clear differences between treatments. Putative onion fungal pathogens were predominantly sequenced under conventional soil treatment practices whilst putative soil suppressive bacterial species were predominantly sequenced from the organic pest-control treatment plots. CONCLUSION: Organic management increased microbial activity and diversity. Sequence data was indicative of differences in functional groups and warrants further investigation.

The civil rights of disabled children in physiotherapy practices.

PURPOSE: This study aimed to explore the experiences of civil rights of disabled children receiving physiotherapy in New Zealand. As yet there is limited attention given to this topic in rehabilitation literature. METHODS: We conducted a qualitative study that drew on the fields of childhood studies and disability studies to address the study aim. Seven disabled children who used local physiotherapy services (aged between four and 14 years) were interviewed using child-centered methods. In addition, their parents were interviewed individually, and eight rehabilitation professionals and disability advocates took part in a focus group discussion. Interpretive thematic analysis was used to analyze findings. FINDINGS: The participating disabled children all appreciated being informed about physiotherapy, but had individual preferences regarding involvement in decision making. They described positive and negative influences on their experiences, but indicated they may not have been asked by adults about these. Parents, professionals and advocates described that attempting to promote a positive experience for children is constrained by understandings regarding the purposes and practices of physiotherapy. CONCLUSIONS: Our findings suggest it is important to get an understanding of individual children's views and preferences regarding physiotherapy in order to promote opportunities for choice, control and satisfaction. In this way physiotherapists can ensure disabled children's civil rights are realized in practice.

Decoding attraction: Improving vine weevil monitoring by exploiting key sensory cues.

BACKGROUND: Monitoring is an integral component of integrated pest management (IPM) programmes used to inform crop management decisions. Vine weevil, Otiorhynchus sulcatus F. (Coleoptera: Curculionidae), continues to cause economically significant losses in horticultural crops due to an inability to reliably detect the presence of this species before crop damage occurs. To improve vine weevil monitoring we investigated the behavioural responses of adult vine weevils to visual (monitoring tool shade/colour, height and diameter as well as the effect of monitoring tool and plant density) and olfactory (host plant and conspecifics) cues under glasshouse conditions. RESULTS: Monitoring tool shade, height and diameter all influenced monitoring tool efficacy, with individuals exhibiting a preference for black, tall and wide monitoring tools. The total number of individuals recorded in monitoring tools increased with monitoring tool density. By contrast, plant density did not influence the number of individuals recorded in monitoring tools. Yew-baited monitoring tools retained a larger number of individuals compared to unbaited ones. Similarly, more vine weevils were recorded in monitoring tools baited with yew and conspecifics than in unbaited monitoring tools or those baited with only yew. Baiting monitoring tools with conspecifics alone did not enhance the number of vine weevils recorded in monitoring tools. CONCLUSIONS: Our study confirms that visual and olfactory cues influence vine weevil behaviour. This provides information on key factors that influence vine weevil monitoring tool efficacy and can be used to inform the development of a new monitoring tool for this pest. © 2023 The Authors. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

Real-World Tumor Response of Palbociclib in Combination With an Aromatase Inhibitor as First-Line Therapy in Pre/Perimenopausal Women With Metastatic Breast Cancer.

BACKGROUND: Limited real-world data exist regarding the efficacy of palbociclib in combination with endocrine therapy in pre/perimenopausal women with metastatic breast cancer. OBJECTIVE: We aimed to compare real-world tumor responses among pre/perimenopausal women who initiated palbociclib plus an aromatase inhibitor (AI) or AI monotherapy as first-line treatment for hormone receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer. METHODS: This retrospective observational cohort study (NCT05012644) used electronic health record data from The US Oncology Network. Tumor responses were determined based on treating clinicians' assessments of radiologic evidence for changes in disease burden. Normalized inverse probability treatment weighting was used to balance baseline characteristics between treatment cohorts. RESULTS: Of 196 pre/perimenopausal women, 116 and 80 were in the palbociclib plus AI cohort and AI cohort, respectively. Real-world response rates (complete or partial response) were 52.1% and 46.2%, respectively (odds ratio, 1.27 [95% confidence interval 0.72‒2.24]). Among patients with one or more tumor assessments on treatment, real-world response rates were 60.0% in the palbociclib plus AI cohort (n = 103) and 49.9% in the AI cohort (n = 71; odds ratio, 1.51 [95% confidence interval 0.82‒2.77]). CONCLUSIONS: This real-world analysis suggests that pre/perimenopausal patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer appear more likely to respond to palbociclib plus AI versus AI alone as first-line therapy, which may support the combination as a standard-of-care treatment for this patient population.

Palbociclib (Ibrance^®) is a medicine for patients with metastatic breast cancer (MBC). Metastatic means that the cancer has spread to other places in the body. Patients take palbociclib with hormone therapy, such as an aromatase inhibitor (AI). Palbociclib plus an AI is a treatment for a type of MBC called HR+/HER2‒ MBC. HR+/HER2‒ stands for hormone receptor positive, human epidermal growth factor receptor 2 negative. Researchers wanted to observe responses to treatment in routine clinical practice among women with HR+/HER2­ MBC who had not reached menopause. A response is if a tumor shrinks or disappears after treatment. This study used healthcare information reported in electronic medical records of patients seen by doctors in The US Oncology Network. This study included 196 women with HR+/HER2­ MBC who had not reached menopause and had not received prior treatment for MBC. A total of 116 women received palbociclib plus an AI, and 80 women received an AI alone. Researchers used standard statistical approaches to balance baseline characteristics between the two treatment groups. These adjustments made the groups more similar so that researchers could compare treatment responses. Sixty percent of patients who took palbociclib plus an AI responded, compared with 50% of patients who took an AI alone. These results suggest that palbociclib plus an AI may benefit women with HR+/HER2‒ MBC who have not reached menopause.