Extreme Outcome Research Articles

Acquired long QT interval syndrome as a predictor of sudden cardiac death: Causes, diagnostic criteria, and management strategy

Despite medical advances in diagnosis and treatment, cardiovascular disease remains the leading cause of death worldwide. Sudden cardiac death, an extreme and irreversible outcome of cardiac arrest, is observed in 50% of cases and is often the first suddenly detected pathology. Long QT syndrome is a variant of electrical heart disease resulting from both congenital and acquired dysfunction and/or regulation of cardiomyocyte ion channels, accompanied by impaired depolarization and repolarization of the ventricular myocardium and characterized by QT prolongation and T abnormalities on the electrocardiogram, clinically accompanied by syncope, bidirectional spindle ventricular tachycardia of the “pirouette” type (torsade de pointes), associated with a high risk of sudden cardiac death or sudden arrhythmic death syndrome. Effective management of these patients requires an individualized approach: careful examination, calculation of corrected QT, determination of typology (hereditary or acquired syndrome), risk assessment using the Tisdale scale, and selection of optimal therapy. Treatment should be comprehensive and include pharmacological (beta-adrenergic blockers, correction of electrolyte balance) and surgical (implantable cardioverter-defibrillator and left-sided thoracic sympathetic denervation of the heart), lifestyle (avoidance of drugs that contribute to prolongation of the QT interval, avoidance of specific arrhythmia triggers (active swimming, exposure to loud noises)) and regular consultation with a cardiologist. Early diagnosis and a comprehensive approach are key to successful prevention of sudden cardiac death in patients with Long QT syndrome.

Hotbeds of climate vulnerability: marginalization, informality, and invisibilization of Roma slums in Romania

ABSTRACT The term hotbed of vulnerability (or HoV) has recently been used to describe growing inequalities and the increased exposure of marginalized spaces to climate change impacts. What has been less addressed so far is how HoVs are the result of intersecting social processes (marginalization, informality and invisibilization) that expel racialized populations from the space of safe habitation and subject them, via territorial stigmatization and relegation, to the foreseeable impacts of climate change. HoVs emerge as the extreme outcome of the processes mentioned above, through which the concentration of multiple sources of vulnerability coalesces in one location and shapes the exposure, sensitivity and adaptive capacity of marginalized families. This paper uses quantitative and qualitative data to flesh out the characteristics of HoVs, first by means of a survey in 96 segregated Roma communities in Romania and, second, using an extended case study of Dăroaia, a Roma community in the Apuseni Mountains affected by floods in July 2021. Our results indicate that there are indeed synergistic effects that occur in HoVs and that these cannot be addressed only by technical means but require instead a comprehensive consideration of their social roots. Continued marginalization, informality, and invisibilization all interact to reproduce HoVs, thereby deepening their vulnerability.

Social Inequities in Access to Dental Care in Australian Adults over Time.

Social inequities in dental caries are reflected by both inequities in the social structures that contribute to disease severity and inequities in the provision of dental care. This study aimed to describe social differentials in the dental caries experience among Australian adults across a 13-y period and to examine if the highest magnitude of oral health inequities persisted across dental caries prevalence (decayed teeth [DT]) or its management (missing teeth [MT], filled teeth [FT]). Data were from 2 population-based cross-sectional surveys of Australian adult oral health conducted in 2004-2006 (National Survey of Adult Oral Health-1 [NSAOH-1], n = 5,505) and 2017-2018 (NSAOH-2, n = 5,022). In each survey, representative samples of adults were obtained through a 3-stage, stratified sample design within metropolitan and regional areas in each state/territory. Clinical outcomes included the prevalence and mean of DT, MT, FT, and DMFT. Equivalized household income was grouped into approximately quartiles from low to high. Across all income quartiles, the mean DT and % DT >0 was higher in NSAOH-2 than in NSAOH-1. The increase in prevalence was highest in the third highest income group (prevalence difference [PD] = 8.4, from 24.1 to 32.5). Similarly, % MT >0 was lower in NSAOH-2 than in NSAOH-1 across all income groups, with the decrease most marked for the lowest income group (PD = -6.5, from 74.1 to 67.8). Across all income quartiles, % FT >0 was lower in NSAOH-2 than in NSAOH-1. The decrease was the most marked for the lowest income group (PD = -8.9, from 81.1 to 72.2). The findings confirm that although oral health inequities decreased for the most extreme management outcome of dental caries (MT), inequities increased for experience of that disease (DT) and the more conservative management of dental caries (FT). For all D, M, and F components (DMFT), inequities between the lowest and highest household income groups increased from 2004-2006 to 2017-2018. This study found that social inequities in oral health (experience of untreated dental caries and missing teeth) increased between the most socially advantaged and disadvantaged groups between 2004-2006 and 2017-2018. This suggests that models of dental service provision in Australia are increasingly benefitting those who can afford and access the care and who arguably need the services less than their less socially advantaged counterparts do.

Enhancing public sector enterprise risk management through interactive information processing.

Federal agencies are increasingly expected to adopt enterprise risk management (ERM). However, public sector adoption of ERM has typically focused on the economic efficiency of tax-financed activities based on control-based practices. This reflects an emphasis on quantifiable concerns that invariably directs attention to risk, that (by definition) relates to identifiable and measurable events, thereby downplaying uncertain and unknown aspects of public exposures. This is a potentially serious shortcoming as government entities often act as society's risk managers of last resort. When extreme events happen what were previously considered private matters can quickly turn into public obligations. Hence, there is a need for proactive assessments of the evolving public risk landscape to discern unpredictable-even unknowable-developments. The article reviews recent empirical studies on public risk management practices, effects of digitalization in public sector institutions, current strategic management research, and insights uncovered from a recent study of risk management practices in federal agencies. On this basis, the article explains how the ability to generate value from ERM can be enhanced when it intertwines with local responsive initiatives and central strategic risk analyses. It can form a dynamic adaptive risk management process where insights from dispersed actors inform updated risk analyses based on local autonomy and open exchange of information. This approach builds on specific structural features embedded in culture-driven aspirations to generate collaborative solutions. Its functional mode is an interactive control system with open discussions across levels and functions in contrast to conventional diagnostic controls that monitor predetermined key performance indicators (KPIs) and key risk indicators (KRIs). Backed by theoretical rationales and empirical research evidence, it is found that applications of ERM frameworks can produce positive results but is unable to deal with a public risk landscape characterized by uncertain unpredictable conditions with potentially extreme outcome effects. It is shown how interactive exchange of fast local insights and slow integrated strategic risk analyses supported by digitized data processing can form a dynamic adaptive system that enable public sector institutions to deal with emergent high-scale exposures. It is explained how the requirement for conducive organizational structures and supportive values require a new strategic risk leadership approach, which is contrasted to observed practices in federal agencies that are constrained by prevailing public governance requirements. The need to deal with uncertainty and unknown conditions demands a cognitive shift in current thinking from a primary focus on risk to also appraise complexity and prepare for the unexpected where data-driven methods can uncover emergent exposures through dynamic information processing. This requires strategic risk leaders that recognize the significance of complex public exposures with many unknowns and a willingness to facilitate digitalized information processing rooted in a collaborative organizational climate. If handled properly, adoption of ERM in public risk management can consider emergent dimensions in complex public exposures applying interactive information processing as a dynamic adaptive risk management approach incorporating digitized methods to solicit collective intelligence for strategic risk updating.

Real-World Treatment Patterns, Discontinuation and Clinical Outcomes in Patients with B-Cell Lymphoproliferative Diseases Treated with BTK Inhibitors in China

Bruton tyrosine kinase inhibitor (BTKi) has demonstrated substantial efficacy in treating B-cell lymphoproliferative diseases (BLPD). Nonetheless, the significant discontinuation rates due to toxicity or financial reasons cannot be overlooked. In China, empirical evidence on the usage of BTKi remains scarce. To address this, a retrospective cohort study was conducted focused on 673 Chinese patients with BLPD who underwent at least one month of BTKi therapy. Median age at BTKi initiation was 60 years. The median duration on BTKi treatment of the whole cohort was 36.4 months. The median post-BTK survival was not reach. BTKi-based treatment was permanently discontinued in 288 (43.8%) patients during follow-up, mostly attributed to progressive disease. Within the first 6 months of BTKi treatment, 76 patients (26.3%) had early treatment discontinuation. Patients with early discontinuation had extreme worse outcome with a median post-discontinuation survival of only 6.9 months. On multivariate analysis, withdrawal BTKi by toxicity and withdrawal BTKi within 6 months retained to be independent predictors of post-BTK survival, after taking account of the response depth, lines of therapy and baseline cytogenetics including 17p deletion. The decision between BTKi monotherapy and combination therapy, along with the preference for first or second-generation BTKi, exerted no significant impact on survival. These observations contribute valuable real-world insights into the utilization of BTKi in China. We concluded that BTKi is an effective and well-tolerated treatment for long-term use in Chinese patient population. However, it is imperative to stress that a proportion of patients discontinue BTKi early, leading to suboptimal outcomes. This study underscores the importance of adherence to BTKi therapy for improved clinical outcomes in real-world patients.

Rare and extreme outcomes in risky choice

Many real-world decisions involving rare events also involve extreme outcomes. Despite this confluence, decisions-from-experience research has only examined the impact of rarity and extremity in isolation. With rare events, people typically choose as if they underestimate the probability of a rare outcome happening. Separately, people typically overestimate the probability of an extreme outcome happening. Here, for the first time, we examine the confluence of these two biases in decisions-from-experience. In a between-groups behavioural experiment, we examine people’s risk preferences for rare extreme outcomes and for rare non-extreme outcomes. When outcomes are both rare and extreme, people’s risk preferences shift away from traditional risk patterns for rare events: they show reduced underweighting for events that are both rare and extreme. We simulate these results using a small-sample model of decision-making that accounts for both the underweighting of rare events and the overweighting of extreme events. These separable influences on risk preferences suggest that to understand real-world risk for rare events we must also consider the extremity of the outcomes.

Real-world treatment patterns, discontinuation and clinical outcomes in patients with B-cell lymphoproliferative diseases treated with BTK inhibitors in China.

Bruton tyrosine kinase inhibitor (BTKi) has demonstrated substantial efficacy in treating B-cell lymphoproliferative diseases (BLPD). Nonetheless, the significant discontinuation rates due to toxicity or financial reasons cannot be overlooked. In China, empirical evidence on the usage of BTKi remains scarce. To address this, a retrospective cohort study was conducted focused on 673 Chinese patients with BLPD who underwent at least one month of BTKi therapy. Median age at BTKi initiation was 60 years. The median duration on BTKi treatment of the whole cohort was 36.4 months. The median post-BTK survival was not reach. BTKi-based treatment was permanently discontinued in 288 (43.8%) patients during follow-up, mostly attributed to progressive disease. Within the first 6 months of BTKi treatment, 76 patients (26.3%) had early treatment discontinuation. Patients with early discontinuation had extreme worse outcome with a median post-discontinuation survival of only 6.9 months. On multivariate analysis, withdrawal BTKi by toxicity and withdrawal BTKi within 6 months retained to be independent predictors of post-BTK survival, after taking account of the response depth, lines of therapy and baseline cytogenetics including 17p deletion. The decision between BTKi monotherapy and combination therapy, along with the preference for first or second-generation BTKi, exerted no significant impact on survival. These observations contribute valuable real-world insights into the utilization of BTKi in China. We concluded that BTKi is an effective and well-tolerated treatment for long-term use in Chinese patient population. However, it is imperative to stress that a proportion of patients discontinue BTKi early, leading to suboptimal outcomes. This study underscores the importance of adherence to BTKi therapy for improved clinical outcomes in real-world patients.

Panning for gold, but finding helium: Discovery of the ultra-stripped supernova SN 2019wxt from gravitational-wave follow-up observations

We present the results from multi-wavelength observations of a transient discovered during an intensive follow-up campaign of S191213g, a gravitational wave (GW) event reported by the LIGO-Virgo Collaboration as a possible binary neutron star merger in a low latency search. This search yielded SN 2019wxt, a young transient in a galaxy whose sky position (in the 80% GW contour) and distance (∼150 Mpc) were plausibly compatible with the localisation uncertainty of the GW event. Initially, the transient’s tightly constrained age, its relatively faint peak magnitude (Mi ∼ −16.7 mag), and the r-band decline rate of ∼1 mag per 5 days appeared suggestive of a compact binary merger. However, SN 2019wxt spectroscopically resembled a type Ib supernova, and analysis of the optical-near-infrared evolution rapidly led to the conclusion that while it could not be associated with S191213g, it nevertheless represented an extreme outcome of stellar evolution. By modelling the light curve, we estimated an ejecta mass of only ∼0.1 M⊙, with 56Ni comprising ∼20% of this. We were broadly able to reproduce its spectral evolution with a composition dominated by helium and oxygen, with trace amounts of calcium. We considered various progenitor channels that could give rise to the observed properties of SN 2019wxt and concluded that an ultra-stripped origin in a binary system is the most likely explanation. Disentangling genuine electromagnetic counterparts to GW events from transients such as SN 2019wxt soon after discovery is challenging: in a bid to characterise this level of contamination, we estimated the rate of events with a volumetric rate density comparable to that of SN 2019wxt and found that around one such event per week can occur within the typical GW localisation area of O4 alerts out to a luminosity distance of 500 Mpc, beyond which it would become fainter than the typical depth of current electromagnetic follow-up campaigns.

Conspiracy Theory as Individual and Group Behavior: Observations from the Flat Earth International Conference.

Conspiratorial thinking has been with humanity for a long time but has recently grown as a source of societal concern and as a subject of research in the cognitive and social sciences. We propose a three-tiered framework for the study of conspiracy theories: (1) cognitive processes, (2) the individual, and (3) social processes and communities of knowledge. At the level of cognitive processes, we identify explanatory coherence and faulty belief updating as critical ideas. At the level of the community of knowledge, we explore how conspiracy communities facilitate false belief by promoting a contagious sense of understanding, and how community norms catalyze the biased assimilation of evidence. We review recent research on conspiracy theories and explain how conspiratorial thinking emerges from the interaction of individual and group processes. As a case study, we describe observations the first author made while attending the Flat Earth International Conference, a meeting of conspiracy theorists who believe the Earth is flat. Rather than treating conspiracy belief as pathological, we take the perspective that is an extreme outcome of common cognitive processes.

Wild-type and mutant p53 in cancer-related ferroptosis. A matter of stress management?

Cancer cells within tumor masses are chronically exposed to stress caused by nutrient deprivation, oxygen limitation, and high metabolic demand. They also accumulate hundreds of mutations, potentially generating aberrant proteins that can induce proteotoxic stress. Finally, cancer cells are exposed to various damages during chemotherapy. In a growing tumor, transformed cells eventually adapt to these conditions, eluding the death-inducing outcomes of signaling cascades triggered by chronic stress. One such extreme outcome is ferroptosis, a form of iron-dependent non-apoptotic cell death mediated by lipid peroxidation. Not surprisingly, the tumor suppressor p53 is involved in this process, with evidence suggesting that it acts as a pro-ferroptotic factor and that its ferroptosis-inducing activity may be relevant for tumor suppression. Missense alterations of the TP53 gene are extremely frequent in human cancers and give rise to mutant p53 proteins (mutp53) that lose tumor suppressive function and can acquire powerful oncogenic activities. This suggests that p53 mutation provides a selective advantage during tumor progression, raising interesting questions on the impact of p53 mutant proteins in modulating the ferroptotic process. Here, we explore the role of p53 and its cancer-related mutants in ferroptosis, using a perspective centered on the resistance/sensitivity of cancer cells to exogenous and endogenous stress conditions that can trigger ferroptotic cell death. We speculate that an accurate molecular understanding of this particular axis may improve cancer treatment options.

People prefer to predict middle, most likely quantitative outcomes (not extreme ones), but they still over-estimate their likelihood.

Past work showed a tendency to associate verbal probabilities (e.g., possible, unlikely) with extreme quantitative outcomes, and to over-estimate the outcomes' probability of occurrence. In the first four experiments (Experiment 1, Experiments 2a-c), we tested whether this "extremity effect" reflects a general preference for extreme (vs central or less extreme) values of a distribution. Participants made predictions based on a frequency distribution in two scenarios. We did not find a preference for extreme outcomes. Instead, most of the participants made a prediction about the middle, most frequent outcome of the distribution (i.e., the modal outcome), but still over-estimated the outcomes' probabilities. In Experiment 3, we tested whether the over-estimation could be better explained by an "at least"/"at most" reading of the predictions. We found that only a minority of participants interpreted predictions as the lower/upper bounds of an open interval and that these interpretations were not associated with heightened probability estimates. In the final three experiments (Experiments 4a-c), we tested whether participants perceived extreme outcome predictions as more correct, useful and interesting than modal outcome predictions. We found that extreme and modal predictions were considered equally correct, but modal predictions were judged most useful, whereas extreme predictions were judged to be more interesting. Overall, our results indicate that the preference for extreme outcomes is limited to specific verbal probability expressions, whereas the over-estimation of the probability of quantitative outcomes may be more general than anticipated and applies to non-extreme values as well.

Denial of pregnancy and neonaticide: A historical overview and case report

While denial of pregnancy and neonaticide are rare, they are potentially associated and share some risk factors. Neonaticide has been proposed as the extreme outcome of a denial of pregnancy. However, the process leading to such a possible outcome is not yet fully understood. The primary goal of this essay is to examine the various definitions and ambiguities surrounding the denial of pregnancy. The case of a young woman with a history of two denied pregnancies with diverse characteristics and outcomes, the latest of which resulted in neonaticide, is then reported and examined. A forensic psychiatric evaluation was also performed to reconstruct the woman's mental state at the time of the crime. The forensic pathological analysis of the newborn, abandoned near the sea while still alive, is described. The victim's body showed signs of shaken baby syndrome. We contend that differing levels of awareness during a denial of pregnancy might not be predictive of the potential delivery outcome in terms of threat to the newborn's survival, according to the forensic pathological and psychopathological data of the current case. Early identification of women affected by denial of pregnancy who pose a danger of committing infanticide is hampered by both intrinsic traits (dissimulation, unawareness, low propensity to seek assistance) and environmental factors (isolation, low socioeconomic level, poor education.). A previous history of denial of pregnancy should activate health and support services to reduce the potential risks for the mother and the child.

Suicide prevention research: A bibliometric analysis from 1982 to 2021

Background:Suicide is the most extreme outcome of a mental health crisis and should therefore be a key priority in any mental health prevention response. Objetive:the aim of this study was to identify the scientific production and its temporal evolution related to suicide prevention. Method: To do this, a quantitative, descriptive and bibliometric type study was carried out, which allows us to know the current situation regarding this issue. The analysis wasperformed using Scopus’ own metrics and the use of the Bibliometrix software. Results:The results indicate that, through the keywords used, 272 articles were found, with the United Kingdom and United States being the geographical territories with the highest production, the year 2018 as the year with the mostnotable amount of research, together with the area of medicine theyaccount for 60,2% of these, throughout the 40 years of investigation. Conclusions:Overall, our analyses shed light on the strong growth of research in suicidology. We believe that these bibliometric analyses can be useful in guiding researchers, institutions, and countries in the prevention of suicide.

Selection-driven adaptation to the extreme Antarctic environment in the Emperor penguin.

The eco-evolutionary history of penguins is characterised by shifting from temperate to cold environments. Breeding in Antarctica, the Emperor penguin appears as an extreme outcome of this process, with unique features related to insulation, heat production and energy management. However, whether this species actually diverged from a less cold-adapted ancestor, more ecologically similar to its sister species, the King penguin, is still an open question. As the Antarctic colonisation likely resulted in vast changes in selective pressure experienced by the Emperor penguin, the relative quantification of the genomic signatures of selection, unique to each sister species, could answer this question. Applying phylogeny-based selection tests on 7651 orthologous genes, we identified a more pervasive selection shift in the Emperor penguin than in the King penguin, supporting the hypothesis that its extreme cold adaptation is a derived state. Furthermore, among candidate genes under selection, four (TRPM8, LEPR, CRB1, and SFI1) were identified before in other cold-adapted homeotherms, like the woolly Mammoth, while other 161 genes can be assigned to biological functions relevant to cold adaptation identified in previous studies. Location and structural effects of TRPM8 substitutions in Emperor and King penguin lineages support their functional role with putative divergent effects on thermal adaptation. We conclude that extreme cold adaptation in the Emperor penguin largely involved unique genetic options which, however, affect metabolic and physiological traits common to other cold-adapted homeotherms.

Distance learning technology in training competent master of dentistry under extreme conditions by evaluation of foreign students

The object of research: Masters of Dentistry professional training in Bogomolets National Medical University (Kyiv, Ukraine) with the distance learning technology
 Investigated problem: Educational process in extreme condition as pandemics and wars, possible ways to solve the problem how students and teachers cope with both challenges in Ukraine on the way of preparing competent doctor from the point of view of foreign students.
 The main scientific results: Preliminary data of medical university students from foreign countries - future masters in dentistry of the Bogomolets Medical University (Kyiv, Ukraine) survey, conducted in term April-November 2022 about their perceptions of online learning and teaching in extreme conditions as they experienced during lockdown in terms of COVID -19 outbreak and continuing russian`s aggressive war in Ukraine. Our findings from survey concern questions of student`s general view on online educational technology as well peculiarities of approaches in teaching we can use for acceptable in such extreme conditions educational outcome. We start discussion about some useful methodological approaches for distance education technology in extreme conditions.
 The area of practical use of the research results: Sharing with educational community our experience and features about distant learning in extreme conditions of dental students.

Robust and Efficient Assessment of Potency (REAP) as a quantitative tool for dose-response curve estimation.

The median-effect equation has been widely used to describe the dose-response relationship and identify compounds that activate or inhibit specific disease targets in contemporary drug discovery. However, the experimental data often contain extreme responses, which may significantly impair the estimation accuracy and impede valid quantitative assessment in the standard estimation procedure. To improve the quantitative estimation of the dose-response relationship, we introduce a novel approach based on robust beta regression. Substantive simulation studies under various scenarios demonstrate solid evidence that the proposed approach consistently provides robust estimation for the median-effect equation, particularly when there are extreme outcome observations. Moreover, simulation studies illustrate that the proposed approach also provides a narrower confidence interval, suggesting a higher power in statistical testing. Finally, to efficiently and conveniently perform common lab data analyses, we develop a freely accessible web-based analytic tool to facilitate the quantitative implementation of the proposed approach for the scientific community.

Identifying transient ischemic attack (TIA) patients at high-risk of adverse outcomes: development and validation of an approach using electronic health record data

BackgroundRisk-stratification tools that have been developed to identify transient ischemic attack (TIA) patients at risk of recurrent vascular events typically include factors which are not readily available in electronic health record systems. Our objective was to evaluate two TIA risk stratification approaches using electronic health record data.MethodsPatients with TIA who were cared for in Department of Veterans Affairs hospitals (October 2015—September 2018) were included. The six outcomes were mortality, recurrent ischemic stroke, and the combined endpoint of stroke or death at 90-days and 1-year post-index TIA event. The cohort was split into development and validation samples. We examined the risk stratification of two scores constructed using electronic health record data. The Clinical Assessment Needs (CAN) score is a validated measure of risk of hospitalization or death. The PREVENT score was developed specifically for TIA risk stratification.ResultsA total of N = 5250 TIA patients were included in the derivation sample and N = 4248 in the validation sample. The PREVENT score had higher c-statistics than the CAN score across all outcomes in both samples. Within the validation sample the c-statistics for the PREVENT score were: 0.847 for 90-day mortality, 0.814 for 1-year mortality, 0.665 for 90-day stroke, and 0.653 for 1-year stroke, 0.699 for 90-day stroke or death, and 0.744 for 1-year stroke or death. The PREVENT score classified patients into categories with extreme nadir and zenith outcome rates. The observed 1-year mortality rate among validation patients was 7.1%; the PREVENT score lowest decile of patients had 0% mortality and the highest decile group had 30.4% mortality.ConclusionsThe PREVENT score had strong c-statistics for the mortality outcomes and classified patients into distinct risk categories. Learning healthcare systems could implement TIA risk stratification tools within electronic health records to support ongoing quality improvement.RegistrationClinicalTrials.gov Identifier: NCT02769338.

Destined to Brexit? British Pathways to Membership in the European Communities 1945–73

AbstractThis article explores whether and how the United Kingdom was destined to Brexit before it even joined the European Communities in 1973. Drawing on archival sources, media reports and literature about Britain's arduous relationship with ‘Europe’, it argues that four features made the Brexit outcome more likely. They were the accession to the EC as a measure of last resort which prevented the construction of a new sustainable narrative about a brighter future in ‘Europe’; the political elites’ use of the issue of EC membership or further integration for short term party gains; highly exaggerated hopes that membership in and by itself would cure Britain's economic ills or give it a new global leadership role; and a colonial style diplomacy that severely underestimated Britain's growing dependency on its continental European neighbours. In conclusion, the article argues that it nevertheless required the formation of a parochial political elite of little Englanders to achieve the extreme outcome of Brexit.

Sensitivity to missing not at random dropout in clinical trials: Use and interpretation of the trimmed means estimator.

Outcome values in randomized controlled trials (RCTs) may be missing not at random (MNAR), if patients with extreme outcome values are more likely to drop out (eg, due to perceived ineffectiveness of treatment, or adverse effects). In such scenarios, estimates from complete case analysis (CCA) and multiple imputation (MI) will be biased. We investigate the use of the trimmed means (TM) estimator for the case of univariable missingness in one continuous outcome. The TM estimator operates by setting missing values to the most extreme value, and then “trimming” away equal fractions of both groups, estimating the treatment effect using the remaining data. The TM estimator relies on two assumptions, which we term the “strong MNAR” and “location shift” assumptions. We derive formulae for the TM estimator bias resulting from the violation of these assumptions for normally distributed outcomes. We propose an adjusted TM estimator, which relaxes the location shift assumption and detail how our bias formulae can be used to establish the direction of bias of CCA and TM estimates, to inform sensitivity analyses. The TM approach is illustrated in a sensitivity analysis of the CoBalT RCT of cognitive behavioral therapy (CBT) in 469 individuals with 46 months follow‐up. Results were consistent with a beneficial CBT treatment effect, with MI estimates closer to the null and TM estimates further from the null than the CCA estimate. We propose using the TM estimator as a sensitivity analysis for data where extreme outcome value dropout is plausible.

A Review of Tick and Tick Control Strategies in Pakistan

Background: In Pakistan, ticks are a major problem for livestock and humans. These can spread a wide range of infections including protozoan, viruses, and bacteria such as spirochetes and rickettsiae. Ticks are found in all ecological and geographic zones of Pakistan. Bovine Babesiosis and Theileriosis have been documented in Pakistan. Crimean-Congo hemorrhagic fever (CCHF) is a tick-borne viral disease that affects those who work with cattle, like slaughterhouse workers, vets, and hospitals. There are at least 40 tick species, mostly Haemaphysalis, Hyalomma, and Rhipicephalus. In Pakistan, CCHF is spread by Hyalomma ticks, posing a severe risk to human health. Ticks are most prevalent in the summer (June–September) and goats rather than sheep in Pakistan. Tick-borne infections include Anaplasma, Babesia, and Theileria spp., more common in sheep than goats. In the previous sixteen years, occasional CCHF outbreaks have been documented in Pakistan, with a 24% fatality rate. Mass tick control efforts have been initiated in Punjab and Sind provinces to control tick populations and zoonotic disease spread. These tick control campaigns use a lot of Deltamethrin and Ivermectin. Deltamethrin and Ivermectin can harm the ecosystem and suggested alternate tick control approaches. Deltamethrin can damage the kidneys of insect-eating birds and disrupt the life cycle of aquatic organisms when mixed with stream water. This is because roughly 60%-80% of the whole dose is excreted by the animal and is not metabolized by the animal. Dung deterioration can be hampered by a reduction of dung beetles. Tick control methods have been used for decades worldwide. But only chemical technique is still practised in Pakistan. Each method's efficacy varies with tick number, dispersion, morphology, and host species. Results: The goal of the literature review was to discuss ticks and tick management measures used on domestic animals in Pakistan and offer new and successful techniques. This article reviews the most widely used tick management methods in Pakistan. According to studies, ticks and tick-borne diseases cause significant economic losses to livestock globally. Chemicals (acaricides) are overused to treat ticks on domestic and wild animals. Tickbots, bait boxes, vaccines, natural fauna, and bio-pesticides should be promoted and used to control ticks. Conclusion: The literature concluded that tick and tick-borne diseases are a significant cause of economic losses to the livestock throughout the globe. The chemicals (acaricides) are excessively applied against ticks on domestic and wild animals. Other new techniques like tickbot, bait boxes, the discovery of vaccines, natural fauna and biopesticides should be promoted and applied to control the ticks. These strategies will have an extreme outcome on reducing the tick population. Keywords: Ticks, Ectoparasites, Congo Haemorrhagic Fever, Wild animals, Integrated tick management, Pakistan