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Chapter 3 focuses on Jenner and the discovery of vaccination, specifically his translation of the vague notion that cowpox prevented smallpox into a more precise body of knowledge which could distinguish between varieties of cowpox and be the basis for the development of protocols for its effective use. Given the rarity of cowpox, his use of humanised cowpox (vaccine), propagated on children, was to prove critical to the success and viability of the practice. Publishing his findings in 1798, Jenner had to wait a year for his new mode of prophylaxis to gain acceptance. Initially, London-based physicians – Woodville conducting clinical trials and Pearson distributing vaccine – made much of the running. Jenner, however, reasserted his leadership in the field and made championship of vaccination his principal occupation. After considering reports on Jenner’s discovering of cowpox inoculation and making it available to the world, the British parliament granted him a premium in 1802. The Royal Jennerian Society was established in 1803 to promote and support the practice.
Journalists routinely live-tweet high-profile criminal trials, a practice that raises questions about access to justice and the principle of open court. Does social media open up the justice system? There is a normative debate in the literature about the use of Twitter and social media in the courtroom. This paper takes on this debate by exploring the relationship between digital technologies and criminal justice. Through a systematic examination of journalists’ tweets during two key trials (Ghomeshi and Saretzky), we ask to what extent can the live-tweeting of court proceedings achieve greater access to justice in Canada? We argue that while the live-tweeting does provide more access to court, potentially furthering the principle of open court, the nature of this access provides little in the way of increased engagement with the public and its understanding of the legal system. This paper makes contributions to both the legal studies and digital politics literatures.
This introductory chapter highlights the significance and timeliness of this book in the context of ongoing alleged international crimes in Southeast Asia, alongside the legacy of colonialism, historic international crimes trials (particularly after World War II), and past atrocities. It then draws upon international criminal law and international relations, especially constructivist, literature to define the ‘norm’ of international criminal justice. It explains why this book draws upon constructivist localisation theories with reference to the concepts of time, space, and direction. This approach provides an explanation for the book’s method and structure.
This rejoinder notes that several key points were discussed in response to the authors' review of brief psychosocial interventions for personality disorders. In particular, the commentary suggested that understanding key mechanisms of change and moderators of treatment outcome were especially important to make forward progress in streamlining treatments for personality disorders. Here the authors highlight several shared candidate mechanisms of change across brief treatments for personality disorders, including a focus on education regarding emotion regulation, interpersonal processes, and instilling hope and expectancies for change. They also discuss the possibility that moderators of treatment outcome should be examined across types of outcomes. Moreover, some outcomes may be more amenable to brief treatments than others. Recommendations for future research in this area are discussed.
The last several decades have witnessed the emergence of several efficacious treatments for personality disorders, yet many of these treatments are lengthy and resource-intensive. There is a pressing public health need to identify briefer treatment options for the treatment of personality disorders. The present contribution is a comprehensive review of brief (i.e., less than one-year) psychosocial interventions for personality disorders. The authors' search criteria yielded 66 articles, which they summarize in this chapter. Of note, only a minority of these studies were randomized controlled trials, and nearly half focused on borderline personality disorders. A few brief treatments appear to be efficacious for personality disorders, namely short-term dynamic psychotherapy for Cluster C personality disorders, as well as manual-assisted cognitive therapy, six-month dialectical behavior therapy, and emotion regulation group therapy for borderline personality disorder and/or self-injury. Recommendations for future research in this area are discussed.
Despite the advancements in the development of pharmacological interventions for personality disorders (PDs), clinicians should be relatively cautious about the potential benefits of using pharmacological agents for the treatment of PDs when facing therapeutic decisions for individual patients. The pharmacological management of PDs is considerably complex; frequent treatment drop-out, non-compliance, and adverse effects illustrate why having a good therapeutic relationship with patients is a particularly important factor for the success of pharmacological treatment of PDs. Results from clinical trials for PDs may not be generalizable for individual patients in the community. PDs are heterogeneous conditions associated with many psychiatric disorders. Yet, clinical trials frequently include highly selected populations that do not necessarily correspond to typical patients with PDs found in community settings. Considering that PDs frequently co-occur with other psychiatric diagnoses, a promising approach to future research in PDs should consider the development of treatment algorithms based on co-occurring disorders. This approach is likely to resonate with prescribing physicians trained to evaluate patients systematically for the presence or absence of specific disorders. For instance, this approach has been increasingly studied in gambling disorder, with promising findings reported thus far.
The commentaries (this volume) stressed the need for quality research that can close the gaps between evidence and practice. The recently completed trial by Crawford and colleagues (2018) stands out as a reference point for trial methodology that will advance our understanding of the role of pharmacological management of patients with PDs. Future research trials must expand the outcomes of interest including measures that capture “clinical well-being and quality of life” and more attention to recording adverse effects. Changing functional outcomes remains one of the most challenging issues related to our current evidence-based treatment approaches for patients with PDs. The need to harmonize our approach to measuring functional improvement remains a priority for future intervention research. Pharmacological research will advance by developing a consensus on the best measures to employ, incorporating dimensional models of personality pathology and creating partnerships between patients, clinicians and care providers in order to develop a meaningful research agenda going forward.
We analyze the economic costs and benefits of “community-led total sanitation” (CLTS), a sanitation intervention that relies on community-level behavioral change, in a hypothetical rural region in sub-Saharan Africa with 200 villages and 100,000 people. The analysis incorporates data on the effectiveness of CLTS from recent randomized controlled trials and other evaluations. The net benefits of this intervention are estimated both with and without the inclusion of a positive health externality, that is, the additional reduction in diarrhea for an individual when a sufficient proportion of other individuals in the community construct and use latrines and thereby decrease the overall load of waterborne pathogens and fecal bacteria in the environment. We find that CLTS interventions would pass a benefit–cost test in many situations, but that outcomes are not as favorable as some previous studies suggest. The model results are sensitive to baseline conditions, including the value of time, income level used to calculate the value of a statistical life, discount rate, case fatality rate, diarrhea incidence, and time spent traveling to defecation sites. We conclude that many communities likely have economic investment opportunities that are more attractive than CLTS, and recommend careful economic analysis of CLTS in specific locations.
While the transitional justice model, and “bottom-up” business and human rights strategies place emphasis on the role international actors and powerful foreign courts in the Global North play in advancing victims’ demands for justice, victims of corporate complicity in past human rights violations have rarely received justice using that strategy. This chapter examines the role of national courts in responding to victims’ demands for corporate accountability. It also examines how the Archimedes’ Lever analogy produces “justice from below.”
The first part of the chapter examines “justice form below” through a cross-national comparative analysis. It identifies where, when, and what type of corporate accountability has been achieved. It also considers where progress toward corporate accountability from below through domestic courts has not been achieved. The next section attempts to explain those outcomes, drawing on a continuum of accountability outcomes and case studies to illustrate our argument. The conclusion explores the transformative potential of domestic judicial action in shaping international human rights. It also sets forth a set of guidelines for implementing “justice from below.”
We conducted a meta-analysis of randomised controlled trials (RCT) to examine the effects of strawberry interventions on cardiovascular risk factors. We searched multiple databases including PubMed, Web of Science and Scopus to identify eligible studies published before 19 May 2019. The endpoints were blood pressure, total cholesterol (TC), HDL-cholesterol, LDL-cholesterol, TAG, fasting blood glucose, endothelial function and inflammatory factors. Pooled analyses were performed using random- or fixed-effects models according to a heterogeneity test. We also conducted sub-group analyses by baseline endpoint levels. We included eleven RCT in this meta-analysis (six for blood pressure, seven for lipid profile, seven for fasting blood glucose and six for C-reactive protein (CRP)). Overall, the strawberry interventions significantly reduced CRP levels by 0·63 (95 % CI −1·04, −0·22) mg/l but did not affect blood pressure, lipid profile or fasting blood glucose in the main analyses. Our analysis stratified by baseline endpoint levels showed the strawberry interventions significantly reduced TC among people with baseline levels >5 mmol/l (−0·52 (95 % CI −0·88, −0·15) mmol/l) and reduced LDL-cholesterol among people with baseline levels >3 mmol/l (−0·31 (95 % CI −0·60, −0·02) mmol/l). There was little evidence of heterogeneity in the analysis and no evidence of publication bias. In summary, strawberry interventions significantly reduced CRP levels and may improve TC and LDL-cholesterol in individuals with high baseline levels.
Strategy and structure in the current biopharmaceutical industry are a legacy of business conditions that no longer exist. As conditions change, strategy and structure must adapt. The typical large biopharmaceutical company accounts for a tiny (about 1 percent, and shrinking) share of total global biomedical innovation, yet fills its development portfolio with its own internal discoveries. Companies are spending heavily on their own leads, rather than on the best leads, with resulting high failure rates in late stage development. Companies often insist on manufacturing their products in-house, leading to low asset utilization rates, under-investment in new manufacturing technologies, and volatile gross margins. Pressure on gross margins is amplified by the recent and relatively sudden loss of real US pricing power. Communicating product attributes to patients, physicians, and payors has shifted from traditional one-way (e.g., print, TV, radio) media in which companies could control messaging to two-way (e.g., Internet, social media) channels in which companies’ voices must share bandwidth with other points of view. These and other profound changes in biopharmaceutical companies’ operating environment call for similarly profound changes in strategy and structure. The challenges are significant, but entirely addressable, and in several cases, successful transitions in other industries (e.g., integrated circuits, film) may be instructive.
A previous analysis of the Alpha-Tocopherol Beta-Carotene (ATBC) Study on male smokers found that β-carotene supplementation increased the risk of pneumonia 4-fold in those who started smoking at the age of ≥21 years and smoked ≥21 cigarettes/d (a subgroup of 7 % of the study population). The present study hypothesised that β-carotene increases mortality in the same subgroup. The ATBC Study (1985–1993) recruited 29 133 Finnish male smokers (≥5 cigarettes/d) aged 50–69 years. Cox regression models were constructed to estimate the effect of β-carotene supplementation in subgroups. β-Carotene increased mortality (risk ratio 1·56; 95 % CI 1·06, 2·3) in those who started to smoke at ≥21 years and smoked ≥21 cigarettes/d. Within this subgroup, there was strong evidence of further heterogeneity. The effect of β-carotene supplementation was further modified by dietary vitamin C intake, fruit and vegetable intake (P = 0·0004), and by vitamin E supplementation (P = 0·011). Thus, harm from β-carotene was not uniform within the study population. Interactions between β-carotene and vitamins C and E were seen only within a subgroup of 7 % of the ATBC participants, and therefore should not be extrapolated to the general population. Heterogeneity of the β-carotene effect on mortality challenges the validity of previous meta-analyses that have pooled many diverse antioxidants for one single estimate of effect using the assumption that a single estimate equally applies to all antioxidants and all people. Trial registration: ClinicalTrials.gov NCT00342992.
Data on the effect of grape seed extract (GSE) on lipid profiles are inconclusive. We undertook a systematic review and meta-analysis of randomised controlled clinical trials on the effect of GSE on serum lipid profiles. The online databases of PubMed, ISI Web of Science, Scopus, ProQuest, Science Direct and Embase were searched for relevant publications until March 2019, using MeSH and non-MeSH keywords. Study selection, data extraction and quality assessment were completed independently by two investigators. Meta-regression and subgroup analyses were performed to identify the source of heterogeneity. Assessment of study quality was conducted using the Jadad scale. Eleven randomised clinical trials involving 536 participants were included in the present meta-analysis. Combining effect sizes from earlier studies, we found that GSE supplementation significantly decreased serum levels of LDL-cholesterol (−0·17 mmol/l; 95 % CI −0·34, −0·01) and TAG (−0·11 mmol/l; 95 % CI −0·18, −0·05). Although no overall significant effect of GSE supplementation on circulating total- and HDL-cholesterol levels was observed, there were significant reductions in these lipids in studies with <10 weeks of intervention and those that had administered the dosages of <300 mg/d of GSE. In conclusion, GSE supplementation seems to favourably affect serum levels of LDL and TAG concentrations, but it did not affect total- and HDL-cholesterol concentrations.
To examine research participants’ levels of satisfaction and perceptions and aid researchers to better engage research volunteers from all racial and ethnic populations in clinical trials. A participant satisfaction survey was developed that focused on three domains to reflect satisfaction with delivery of care, environment, and center operations. In addition, the survey contained open-ended questions to reflect overall experiences and perceptions. Two hundred and seventy-eight participants (55% African American and 29% non-Hispanic Whites) with an average age of 52 years completed the survey.
The results indicated that the majority of the participants rated their satisfaction very highly across all domains. Ninety percent stated they were very satisfied/satisfied or very strongly agreed/agreed in the three domains. Obtaining high-quality care/access to health care professionals (60%), learning more about their illness/disease (60%), and helping others (57%) were noted as important factors in choosing to participate in a trial. Regarding overall experience, majority of respondents stated that friendliness, expertise of staff, learning more about their disease, and contributing to science were important. Further, financial compensation was not a primary motivation for participation. A majority of participants stated that they would participate in future studies and would recommend a friend or a family member to participate in clinical trials.
The findings indicate that the degree of satisfaction with the research staff and with the specific trial itself are important determinants for enrolling, completing a study, and for participating in future trials.
The National Institutes of Health requires data and safety monitoring boards (DSMBs) for all phase III clinical trials. The National Heart, Lung and Blood Institute requires DSMBs for all clinical trials involving more than one site and those involving cooperative agreements and contracts. These policies have resulted in the establishment of DSMBs for many implementation trials, with little consideration regarding the appropriateness of DSMBs and/or key adaptations needed by DSMBs to monitor data quality and participant safety. In this perspective, we review the unique features of implementation trials and reflect on key questions regarding the justification for DSMBs and their potential role and monitoring targets within implementation trials.
Low-carbohydrate diets (LCD) have been promoted for weight control and type 2 diabetes (T2D) management, based on an emerging body of evidence, including meta-analyses with an indication of publication bias. Proposed definitions vary between 50 and 130 g/d, or <10 and <40 % of energy from carbohydrate, with no consensus on LCD compositional criteria. LCD are usually followed with limited consideration for other macronutrients in the overall diet composition, introducing variance in the constituent foods and in metabolic responses. For weight management, extensive evidence supports LCD as a valid weight loss treatment, up to 1–2 years. Solely lowering carbohydrate intake does not, in the medium/long term, reduce HbA1c for T2D prevention or treatment, as many mechanisms interplay. Under controlled feeding conditions, LCD are not physiologically or clinically superior to diets with higher carbohydrates for weight-loss, fat loss, energy expenditure or glycaemic outcomes; indeed, all metabolic improvements require weight loss. Long-term evidence also links the LCD pattern to increased CVD risks and mortality. LCD can lead to micronutrient deficiencies and increased LDL-cholesterol, depending on food selection to replace carbohydrates. Evidence is limited but promising regarding food choices/sources to replace high-carbohydrate foods that may alleviate the negative effects of LCD, demanding further insight into the dietary practice of medium to long term LCD followers. Long-term, high-quality studies of LCD with different food sources (animal and/or plant origins) are needed, aiming for clinical endpoints (T2D incidence and remission, cardiovascular events, mortality). Ensuring micronutrient adequacy by food selection or supplementation should be considered for people who wish to pursue long-term LCD.
This paper describes the development and validation of a new 32-item test of knowledge of good clinical practice (GCP) administered to 625 clinical research coordinators. GCP training is mandated by study sponsors including the US National Institutes of Health. The effectiveness of training is rarely assessed, and the lack of validated tests is an obstacle to assessment. The GCP knowledge test was developed following evaluation of two existing widely used GCP tests to ensure it accurately reflects the content of current training. The final GCP knowledge test demonstrated good reliability (α = 0.69). It is a valid and reliable instrument for measuring knowledge of GCP. The test will be useful in assessing the effectiveness of GCP training programs as well as individuals’ mastery of GCP content.
The aim of this study was to investigate the combined effect of n-3 fatty acids (EPA and DHA, at an EPA:DHA ratio of 150:500) and phytosterol esters (PS) on non-alcoholic fatty liver disease (NAFLD) patients. We conducted a randomised, double-blind, placebo-controlled trial. Ninety-six NAFLD subjects were randomly assigned to the following groups: the PS group (receiving 3·3 g/d PS); the FO group (receiving 450 mg EPA + 1500 mg DHA/d); the PS + FO combination group (receiving 3·3 g/d PS and 450 mg EPA + 1500 mg DHA/d) and the PO group (a placebo group). The baseline clinical characteristics of the four groups were similar. The primary outcome was liver:spleen attenuation ratio (L:S ratio). The percentage increase in liver–spleen attenuation (≤1) in the PS + FO group was 36 % (P = 0·083), higher than those in the other three groups (PS group, 11 %, P = 0·519; FO group, 18 %, P = 0·071; PO group, 15 %, P = 0·436). Compared with baseline, transforming growth factor-β (TGF-β) was significantly decreased in the three study groups at the end of the trial (PS, P = 0·000; FO, P = 0·002; PS + FO, P = 0·001) and TNF-α was significantly decreased in the FO group (P = 0·036), PS + FO group (P = 0·005) and PO group (P = 0·032) at the end of the intervention. Notably, TGF-β was reduced significantly more in the PS + FO group than in the PO group (P = 0·032). The TAG and total cholesterol levels of the PS + FO group were reduced by 11·57 and 9·55 %, respectively. In conclusion, co-supplementation of PS and EPA + DHA could increase the effectiveness of treatment for hepatic steatosis.
We provide a closer look at the result of a randomised, placebo-controlled, active-reference (quetiapine XR), flexible-dose, 6-week study of brexpiprazole in schizophrenia, which did not meet its primary endpoint – change from baseline in Positive and Negative Syndrome Scale (PANSS) total score. We also investigate potential expectancy bias from the well-known side-effect profile of the active reference that could have affected the study outcome.
Pre-specified sensitivity analyses of the primary end point were performed using analysis of covariance (ANCOVA) last observation carried forward (LOCF) and observed cases (OC). Post hoc analyses of change from baseline in PANSS total score were performed using the mixed model for repeated measures approach with treatment groups split by having typical adverse events with potential for functional unblinding, for example, somnolence, increase in weight, dizziness, dry mouth and sedation.
Pre-specified sensitivity analyses showed separation from placebo for brexpiprazole at week 6: LOCF, ANCOVA: −4.3 [95% CI (−8.0, −0.5), p = 0.0254]. OC, ANCOVA: −3.9 [95% CI (−7.3, −0.5), p = 0.0260]. Patients treated with brexpiprazole experiencing typical adverse events with potential for functional unblinding before or at Week 2 had a least square (LS) mean PANSS change of −29.5 (improvement), with a difference in change from baseline to Week 6 in PANSS total score between brexpiprazole and placebo of −13.5 [95% CI (−23.1, −4.0), p = 0.0057], and those who did not had an LS mean change of −18.9 and a difference between brexpiprazole and placebo of −2.9 [95% CI (−7.2, 1.4), p = 0.1809].
Pre-specified sensitivity analyses showed separation from placebo for brexpiprazole at Week 6. A post hoc analysis suggested a potential confounding of efficacy rating towards symptom improvement in patients who experience known side effects of quetiapine XR.
The Chinese Communist Party (CCP) prosecuted Japanese military servicemen for war crimes committed during and after the Sino-Japanese War. This paper examines written confessions left by those Japanese war crimes suspects and considers to what extent they were used by the CCP to prosecute sexual violence during the trials. The historical analysis is contextualized by an examination of the representation of the CCP's legal approach to sexual violence in articles from the People's Daily. This paper finds that although accounts of sexual violence are found in the confessions written by suspected Japanese war criminals, the courts did not make rape a focal point of the prosecutions and did not pursue the so-called “comfort women” issue. Furthermore, no victim of rape was called to testify before the court. The CCP's approach to the issue of sexual violence in the 1956 trials closely corresponded to the discourse and propaganda in the People's Daily.