Liver Injury Caused by Green Tea Extract in PD-1-/- Mice: An Impaired Immune Tolerance Model for Idiosyncratic Drug-Induced Liver Injury.

Idiosyncratic drug-induced liver injury (IDILI) is an idiosyncratic drug reaction that is specific to an individual and can lead to liver failure and even death. The mechanism of IDILI remains poorly understood, but most IDILI appears to be immune-mediated. We have developed the first validated animal model by using a PD-1-/- mouse model in combination with anti-CTLA-4 to block immune checkpoints and impair immune tolerance. Treatment of these mice with drugs that cause IDILI in humans led to delayed-onset liver injury with characteristics similar to IDILI in humans. The current study investigates the effects of green tea extract, a weight-loss dietary supplement that has been reported to cause IDILI in humans. Green tea extracts contain a highly variable content of catechins including (-)-epigallocatechin gallate, the major catechin in green tea formulations. If the liver injury caused by green tea extract in humans is immune-mediated, it may occur in our impaired immune tolerance model. Female PD-1-/- mice treated with anti-CTLA-4 antibody and green tea extract (500 mg/kg), a dose that is considered a no-observed-adverse-effect level for liver in rodents, produced a delayed onset increase in serum alanine transaminase levels and an increase in hepatic CD8+ T cells. In contrast, the response in male PD-1-/- mice was less pronounced, and there was no evidence of liver injury in wild-type mice. These findings are consistent with the hypothesis that the IDILI caused by green tea extract is immune-mediated and is similar to IDILI caused by medications that are associated with IDILI.

Randomized Controlled Trial for Paclitaxel-coated Balloon versus Plain Balloon Angioplasty in Dysfunctional Hemodialysis Vascular Access: 12-month Outcome from a Nonsponsored Trial.

BACKGROUND: Plain balloon angioplasty is regarded as the mainstay of treatment for failing vascular access with high success rate, but the poor treatment durability creates significant workload and increases patient morbidity. The study aims to compare target lesion primary patency rate at 12 months between paclitaxel-coated balloon (DCB) versus plain old balloon angioplasty (POBA) for treatment of dysfunctional vascular access. METHODS: This nonsponsored-randomized trial enrolled 40 patients with dysfunctional dialysis access at a single center. Patients were randomized into In.Pact Admiral Paclitaxel DCB or POBA after lesion crossing regardless of lesion type. Patients are followed up under surveillance protocol. Patients, hemodialysis staff, and sonographer are blinded to the treatment arms. Twelve-month primary patency rate in both arms are evaluated. RESULTS: 40 patients were recruited since June 2016 and were allocated to the DCB or POBA group. The mean age is 58 and 57 years with comparable demographic parameters. The locations of target lesion were comparable in both groups (juxta and arteriovenous anastomosis, cannulation site, and fistula/graft), with similar mean target lesion stenosis 69.8 +/- 15.8% for DCB and 69.5 +/- 13.6% for POBA (P = 0.95), and the lesion length for DCB is 45.8 +/- 38.4 mm and 50.2 +/- 33.5 mm for POBA (P = 0.70). Patients in DCB performed significantly better in terms of primary patency at 6 months 85% versus 55% (P = 0.007). The superiority in primary patency in DCB group exists at 12 months 65% versus 30% (P = 0.007). CONCLUSIONS: Paclitaxel balloon angioplasty approach provides significant better primary patency in dysfunctional arteriovenous access at 12 months in our nonsponsored-randomized trial.

The Health Care Sector's Experience of Blockchain: A Cross-disciplinary Investigation of Its Real Transformative Potential.

BACKGROUND: Academic literature highlights blockchain's potential to transform health care, particularly by seamlessly and securely integrating existing data silos while enabling patients to exercise automated, fine-grained control over access to their electronic health records. However, no serious scholarly attempt has been made to assess how these technologies have in fact been applied to real-world health care contexts. OBJECTIVE: The primary aim of this paper is to assess whether blockchain's theoretical potential to deliver transformative benefits to health care is likely to become a reality by undertaking a critical investigation of the health care sector's actual experience of blockchain technologies to date. METHODS: This mixed methods study entailed a series of iterative, in-depth, theoretically oriented, desk-based investigations and 2 focus group investigations. It builds on the findings of a companion research study documenting real-world engagement with blockchain technologies in health care. Data were sourced from academic and gray literature from multiple disciplinary perspectives concerned with the configuration, design, and functionality of blockchain technologies. The analysis proceeded in 3 stages. First, it undertook a qualitative investigation of observed patterns of blockchain for health care engagement to identify the application domains, data-sharing problems, and the challenges encountered to date. Second, it critically compared these experiences with claims about blockchain's potential benefits in health care. Third, it developed a theoretical account of challenges that arise in implementing blockchain in health care contexts, thus providing a firmer foundation for appraising its future prospects in health care. RESULTS: Health care organizations have actively experimented with blockchain technologies since 2016 and have demonstrated proof of concept for several applications (use cases) primarily concerned with administrative data and to facilitate medical research by enabling algorithmic models to be trained on multiple disparately located sets of patient data in a secure, privacy-preserving manner. However, blockchain technology is yet to be implemented at scale in health care, remaining largely in its infancy. These early experiences have demonstrated blockchain's potential to generate meaningful value to health care by facilitating data sharing between organizations in circumstances where computational trust can overcome a lack of social trust that might otherwise prevent valuable cooperation. Although there are genuine prospects of using blockchain to bring about positive transformations in health care, the successful development of blockchain for health care applications faces a number of very significant, multidimensional, and highly complex challenges. Early experience suggests that blockchain is unlikely to rapidly and radically revolutionize health care. CONCLUSIONS: The successful development of blockchain for health care applications faces numerous significant, multidimensional, and complex challenges that will not be easily overcome, suggesting that blockchain technologies are unlikely to revolutionize health care in the near future.

Critical Contact Lens Oxygen Transmissibility and Tear Lens Oxygen Tension to Preclude Corneal Neovascularization.

OBJECTIVE: The purpose of this study is to determine the peripheral oxygen transmissibility (pDk/t) and respective central oxygen transmissibility (cDk/t) in soft contact lenses (SCLs) which might preclude SCL-driven corneal neovascularization (NV) in healthy myopic SCL users. METHODS: Twenty subjectively successful SCL-wearing patients who presented with asymptomatic but active peripheral corneal NV (not ghost vessels) were recruited as study patients. Twenty-one patients who did not have NV were similarly recruited as controls. Demographic data were collected. Corneal NV was documented and photographed. Current habitual SCLs were collected and thicknesses measured to allow for the calculation of both pDk/t and cDk/t and estimation of local tear oxygen tensions. RESULTS: No statistical differences between study and control groups in patient age, refraction, or the numbers of years, days per week, or hours per day patients reported SCL wear were identified. Statistically significant differences were found between the two groups for both pDk/t (P=0.006) and cDk/t (P=0.004): mean (±SD) pDk/t was 38.0±23.5 and 19.2±17.7 Fatt units for control and study corneas, respectively. Mean cDk/t were 80.0±54.4 and 36.8±33.1 Fatt units for control and study corneas, respectively. Peripheral tear oxygen tension that "protected" corneas from vascular filling was over 84 mm Hg. CONCLUSION: Maintaining a pDk/t above 30 to 40 Fatt units with daily wear SCLs should protect most normal corneas from NV as a complication of SCL wear.

The discrete scar in prominent ear correction: a digital 3-dimensional analysis to determine the ideal incision for otoplasty.

INTRODUCTION: Various postauricular incision sites can be used for prominent ear correction depending on technique and surgeon preference. No study has previously looked at the most aesthetic (least visible) location for the postauricular scar. We investigated the visibility of various scar locations on the posterior ear from a third person perspective through a "Visibility Arc"-a formal assessment of the range of degrees where a particular scar is visible. The objective was to determine the least visible incision-that is, the scar with the shortest visibility arc. METHODS: Normal ears were marked with 3 different color markers to simulate postoperative scar position, namely, (1) black in auriculocephalic sulcus, (2) blue in the sulcus of the antihelical fold/groove, and (3) green between black and blue. Starting laterally from the right ear toward the left ear, each head was photographed across 180 degrees posteriorly, at 10-degree intervals to determine which colored line (corresponding to a particular scar location) was visible over what "visibility arc." RESULTS: Forty individual ears were analyzed. Scars located in the sulcus of the antihelical fold had the shortest average visible arc, which was a 70-degree arc. The auriculocephalic sulcus had the largest visibility arc, and was most obvious of all of the scar locations-a 100-degree arc. The scar location in between these 2 locations had an 80-degree arc. CONCLUSIONS: The least visible scar for pinnaplasty rests in the groove of the antihelix posteriorly, with scars slightly medial to this almost as discrete. The most visible scars when viewed from behind will be those in the "traditional" location of the auriculocephalic sulcus.

Tissue-resident memory T cells in protective immunity to influenza virus.

Influenza virus is an important human pathogen with significant pandemic potential. Tissue-resident memory T cells (Trm) in the lung provide critical protection against influenza, but unlike Trm at other mucosal sites, Trm in the respiratory tract (RT) are subject to rapid attrition in mice, mirroring the decline in protective immunity to influenza virus over time. Conversely, dysfunctional Trm can drive fibrosis in aged mice. The requirement for local antigen to induce and maintain RT Trm must be considered in vaccine strategies designed to induce this protective immune subset. Here, we discuss recent studies that inform our understanding of influenza-specific respiratory Trm, and the factors that influence their development and persistence. We also discuss how these biological insights are being used to develop vaccines that induce Trm in the RT, despite the limitations to monitoring Trm in humans.

An intelligent composite model incorporating global / regional X-rays and clinical parameters to predict progressive adolescent idiopathic scoliosis curvatures and facilitate population screening.

BACKGROUND: Adolescent idiopathic scoliosis (AIS) affects up to 5% of the population. The efficacy of school-aged screening remains controversial since it is uncertain which curvatures will progress following diagnosis and require treatment. Patient demographics, vertebral morphology, skeletal maturity, and bone quality represent individual risk factors for progression but have yet to be integrated towards accurate prognostication. The objective of this work was to develop composite machine learning-based prediction model to accurately predict AIS curves at-risk of progression. METHODS: 1870 AIS patients with remaining growth potential were identified. Curve progression was defined by a Cobb angle increase in the major curve of ≥6° between first visit and skeletal maturity in curves that exceeded 25°. Separate prediction modules were developed for i) clinical data, ii) global/regional spine X-rays, and iii) hand X-rays. The hand X-ray module performed automated image classification and segmentation tasks towards estimation of skeletal maturity and bone mineral density. A late fusion strategy integrated these domains towards the prediction of progressive curves at first clinic visit. FINDINGS: Composite model performance was assessed on a validation cohort and achieved an accuracy of 83.2% (79.3-83.6%, 95% confidence interval), sensitivity of 80.9% (78.2-81.9%), specificity of 83.6% (78.8-84.1%) and an AUC of 0.84 (0.81-0.85), outperforming single modality prediction models (AUC 0.65-0.78). INTERPRETATION: The composite prediction model achieved a high degree of accuracy. Upon incorporation into school-aged screening programs, patients at-risk of progression may be prioritized to receive urgent specialist attention, more frequent follow-up, and pre-emptive treatment. FUNDING: Funding from The Society for the Relief of Disabled Children was awarded to GKHS.

Toxic effects of octocrylene on zebrafish larvae and liver cell line (ZFL).

Octocrylene (OC) is a broad-spectrum ultraviolet-absorbing chemical used in sunscreen and other personal care products. Its health effects are a concern because it has been detected in water, fish, humans, and food chains. In vivo and in vitro investigations were performed in zebrafish (Danio rerio) larvae and a zebrafish liver cell line (ZFL), respectively, to understand the potential risks and molecular mechanisms of OC toxicity. The 96-h median lethal concentration (LC50) of OC was determined to be 251.8 µM in larvae and 5.5 µM in ZFL cells. Quantitative real-time PCR (qRT-PCR) showed that OC induced the expression of genes for CYPs (CYP1A, CYP3A65), estrogen receptors (ERα, ERß1, GPER), vitellogenin (VTG1), and sex determination (BRCA2, CYP19A, DMRT1, SOX9A), both in vitro and in vivo. A whole-transcriptome sequencing method was used to evaluate the gene expression profile of larvae exposed to OC. OC was found to mediate the biosynthesis of estrogens (such as estriol) and affect the antioxidant pathway (glutathione transferases and peroxisome). These findings clarify the toxic effects and molecular mechanisms of OC and support banning its use in cosmetics.

Modernising medical regulation: where are we now?

PURPOSE: This paper aims to outline and comment on the changes to medical regulation in the UK that provide the background to a special issue of the Journal of Health Organization and Management on regulating doctors. DESIGN/METHODOLOGY/APPROACH: This paper takes the form of a review. FINDINGS: Although the UK medical profession enjoyed a remarkably stable regulatory structure for most of the first 150 years of its existence, it has undergone a striking transformation in the last decade. Its regulatory form has mutated from one of state-sanctioned collegial self-regulation to one of state-directed bureaucratic regulation. The erosion of medical self-regulation can be attributed to: the pressures of market liberalisation and new public management reforms; changing ideologies and public attitudes towards expertise and risk; and high profile public failures involving doctors. The "new" UK medical regulation converts the General Medical Council into a modern regulator charged with implementing policy, and alters the mechanisms for controlling and directing the conduct and performance of doctors. It establishes a new set of relationships between the medical profession and the state (including its agencies), the public, and patients. ORIGINALITY/VALUE: This paper adds to the literature by identifying the main features of the reforms affecting the medical profession and offering an analysis of why they have taken place.

Toxic effects and transcriptome analyses of zebrafish (Danio rerio) larvae exposed to benzophenones.

Sunscreen chemicals, such as benzophenones (BPs), are common environmental contaminants that are posing a growing health concern due to their increasing presence in water, fish, and human systems. Benzoresorcinol (BP1), oxybenzone (BP3), and dioxybenzone (BP8) are the most commonly used BPs for their ability to protect from sunburn by absorbing a broad spectrum of ultraviolet radiation. In this study, zebrafish larvae were used as an in vivo model to investigate the potential risks and molecular mechanisms of the toxic effects of BPs. The effects of these BPs on the gene expression in the aryl hydrocarbon receptor pathway, estrogen receptor pathway, and sex differentiation were detected using quantitative real-time PCR. All BPs were found to function as agonists of the estrogen receptors α and ß1, indicating that these BPs likely undergo similar molecular metabolism in vivo, whereby they can activate cytochrome P450 genes and promote the expression of CYP19A and DMRT1. Furthermore, the gene expression profile of larvae after BP3 exposure was evaluated using a whole transcriptome sequencing approach. BP3 affected estradiol biosynthesis and sex differentiation. It also regulated gonadotropin-releasing hormone, thus interfering with the endocrine system. As a xenobiotic toxicant, BP3 upregulated the expression of cytochrome P450 genes (CYP1A and CYP3A65) and glutathione metabolism-related genes (GSTA, GSTM, and GSTP). It also interfered with the nervous system by regulating the calcium signaling pathway. These findings will be useful for understanding the toxicity mechanisms and metabolism of BPs in aquatic organisms and promote the regulation of these chemicals in the environment.

Loss of elastic fiber integrity and reduction of vascular smooth muscle contraction resulting from the upregulated activities of matrix metalloproteinase-2 and -9 in the thoracic aortic aneurysm in Marfan syndrome.

Thoracic aortic aneurysm (TAA) is the life-threatening complication of Marfan syndrome (MFS), a connective tissue disorder caused by mutations in the fibrillin-1 gene. TAA is characterized by degradation of elastic fiber, suggesting the involvement of matrix metalloproteinase (MMP)-2 and -9, the activation of which is regulated by TIMP (tissue inhibitor of MMP) types 1 and 2. We hypothesized that MMP-2 and -9 were upregulated during TAA formation in Marfan syndrome, causing loss of elastic fibers and structural integrity. We studied mice, from 3 to 12 months, heterozygous for a mutant Fbn1 allele encoding a cysteine substitution in fibrillin-1 (Fbn1(C1039G/+), designated as "Marfan" mice) (n=120), the most common class of mutation in Marfan syndrome. The littermates, Fbn1(+/+) served as controls (n=120). In Marfan aneurysmal thoracic aorta, mRNA and protein expression of MMP-2 and -9 were detected at 3 months and peaked at 6 months of age, accompanied by severe elastic fiber fragmentation and degradation. From 3 to 9 months, the MMP-2/TIMP-2 ratio increased by 43% to 63% compared with the controls. Dilated thoracic aorta demonstrated increased elasticity but distention caused a pronounced loss of contraction, suggesting weakening of the aortic wall. Breaking stress of the aneurysmal aorta was 70% of the controls. Contraction in response to depolarization and receptor stimulation decreased in the aneurysmal thoracic aorta by 50% to 80%, but the expression of alpha-smooth muscle actin between the 2 strains was not significantly different. This report demonstrates the upregulation of MMP-2 and -9 during TAA formation in Marfan syndrome. The resulting elastic fiber degeneration with deterioration of the aortic contraction and mechanical properties may explain the pathogenesis of TAA.

Prevalence of contact lens-related complications: UCLA contact lens study.

PURPOSE: This study is a cross-sectional analysis of the types and prevalence of contact lens (CL)-related complications among CL wearing patients seen in a university clinic setting. METHODS: Data on CL material and design, care system, and ocular complications were recorded and statistically analyzed for CL wearers. RESULTS: Of the 572 patients (846 eyes) recruited during the study, approximately 50% of the eyes had at least one CL-related complication. Rigid gas permeable (GP) CLs had a statistically lower (P<0.01) average number of complications (0.54 +/- 0.68) than soft contact lenses (SCLs) (0.85 +/- 0.82). Papillae and giant papillary conjunctivitis were the most prevalent complications in both GP and SCL wearers. Silicone SCLs (0.79 +/- 0.76) had a slightly lower, although not statistically different (P=0.23), rate of complication than nonsilicone SCLs (0.90 +/- 0.87). Although not statistically significant (P=0.29), extended wear CL use had a higher complication rate (0.93 +/- 0.84) compared with daily wear (0.73 +/- 0.79). Use of "other" solution, including generic and private label solutions, had the highest rate of complications for both SCLs (1.11 +/- 1.27) and GPs (0.96 +/- 0.93) compared with name brand solutions. CONCLUSIONS: The prevalence of CL-related complications, regardless of lens design, material, and wear modality, highlights the importance of early detection with appropriate professional management and treatment.

Are We There Yet? How and When Specific Biotechnologies Will Improve Human Health.

Patient X: A 67-year-old Caucasian man slips on a patch of ice. He has abrasions to his hands and has sustained significant damage to his hip. At the emergency room, he informs clinicians he takes atorvastatin, metformin, and glimepiride to treat hypertension and Type 2 Diabetes Mellitus (T2DM). X-rays reveal a fractured hip, which will require total hip replacement surgery.

Mechanical and pharmacological approaches to investigate the pathogenesis of Marfan syndrome in the abdominal aorta.

BACKGROUND: Occurrence of disease complications in the abdominal aorta in Marfan syndrome, a connective tissue disorder caused by mutations in the gene encoding fibrillin-1, is relatively rare. We hypothesized that Marfan syndrome could affect the structure, vasomotor function and mechanical property of the abdominal aorta. METHODS AND RESULTS: Abdominal aorta from mice at 3, 6, 9 and 12 months of age, heterozygous for the Fbn1 allele encoding a cysteine substitution (Fbn1(C1039G/+), Marfan mice, n = 50), were compared with those from age-matched control littermates (n = 50). Marfan abdominal aorta demonstrated pronounced elastic fiber degradation and disorganization, concomitant with an increased aortic stiffness during aging. In the isometric force measurement, vasoconstriction in response to membrane depolarization or phenylephrine stimulation was similar in both Marfan and control abdominal aorta. However, Marfan abdominal aorta was less sensitive to the inhibition of the phenylephrine-induced contraction by indomethacin and SQ-29548, during which the release of thromboxane A(2) was one half of that of the controls. Nevertheless, the protein expression of cyclooxygenase-1 and cyclooxygenase-2 detected by Western immunoblotting was not different between the 2 strains. CONCLUSIONS: We demonstrated that Marfan syndrome affected abdominal aorta with respect to matrix elastic fiber organization, aortic stiffness and release of thromboxane A(2).

Public Health Interventions as Regulatory Governance: The Place of Political Theory.

This is a reply to Steve Latham's Article for the Republicanism special issue.

Complexity of contact lens fitting after refractive surgery.

PURPOSE: To quantify and describe the complexity of contact lens correction on corneas altered by refractive surgery. DESIGN: A case-control study involving postrefractive surgery patients and controls from one multidisciplinary contact lens practice. METHODS: The contact lens care of one randomly selected eye of 30 postrefractive surgery patients (15 postincisional and 15 postlamellar refractive surgery cases) was retrospectively analyzed and compared with that of 30 age-and-gender matched nonrefractive surgery controls. We quantified the complexity by the number of diagnostic lenses used to establish the initial lens order, the number of ordered lenses required to complete the fit, and the number of office visits during the first 4 months of lens care. Final contact lens optical powers, corrected visual acuities, complications, and lens success/failure were also studied. The nonparametric Mann-Whitney U test was used for statistical analysis. RESULTS: Postrefractive surgery eyes utilized statistically more diagnostic lenses (P =.048), ordered lenses (P =.008), and office visits (P <.0001). There were no statistical differences in the number of office visits, number of diagnostic contact lenses used, and number of ordered contact lenses between the postincisional and postlamellar refractive surgery patients. Although final contact lens optical powers were not significantly different (P =.06) between the two groups, contact lens corrected LogMAR acuities were statistically worse (P =.013) in the postrefractive surgery eyes than in the control group. Contact lens failures occurred in four postrefractive surgery eyes, while no eyes in the control group failed to tolerate contact lenses. CONCLUSIONS: Corneas altered by either incisional or lamellar refractive surgery techniques are more challenging to fit with contact lenses than nonsurgically altered eyes, requiring more lenses and chair time, while resulting in slightly poorer contact lens corrected visions and more failures.

Phenotype of Pseudomonas aeruginosa isolates causing corneal infection between 1997 and 2000.

PURPOSE: To investigate the relationship between functional phenotype of and the associated human corneal infection. METHODS: This was an experimental pilot study of patients presenting with corneal infections at the Jules Stein Eye Institute with presumed infection during the period from 12/30/97 to 9/1/00. Thirteen patients were admitted to the study based on positive identification of the causative pathogen as and patient consent. Data were collected (including bacterial cultures, lens wear schedule and care, gender and age, completed history questionnaire, clinical photographs). Statistical analysis of possible correlations was performed. Phenotypes of were determined, and clinical factors associated with infection were explored. RESULTS: Both invasive and cytotoxic phenotypes of were isolated in equal proportion. Cytotoxic strains and invasive strains were found to be associated with patients younger than 50 years of age and older than 50 years of age, respectively. CONCLUSIONS: remains a significant pathogen in corneal infection, especially during contact lens wear. The age of the patient may influence the phenotype of causing infection. Since invasive and cytotoxic strains have different effects on corneal cells, treatment of the infection might require different approaches depending on this phenotype of the causative bacteria.

How can the criminal law support the provision of quality in healthcare?

BACKGROUND: The egregious failings in patient safety at Mid Staffordshire NHS Foundation Trust between 2005 and 2009 identified by Sir Robert Francis QC in his public inquiry prompted him to recommend the introduction of a new criminal offence into English law in circumstances where a patient dies or is seriously harmed by a breach of fundamental standards. The authors evaluate whether, from the perspective of fairness and justice, a new criminal offence in this context is necessary and desirable. METHODS: The authors considered the basic principles and functions of the criminal law and compared them with the principles and functions of the civil law. They then identify two primary tasks for the criminal law to perform in healthcare settings: (a) to establish primary duties to patients consisting of appropriately graded offences targeted at conduct that harms patients or unjustifiably poses risks to patients, and (b) to establish secondary duties to patients, consisting of offences aimed at punishing and deterring instances in which healthcare management and workers undermine the goals of regulation by lying or giving misleading information to regulatory officials or by obstructing their work. The authors focus on the first of these functions, identifying the scope of existing regulatory schemes that may give rise to criminal liability in English law when applied to healthcare contexts to identify whether a new criminal offence is needed. RESULTS: A gap in the existing regime of criminal liability is identified, and it is this gap which a new criminal offence seeks to fill. The authors suggest how such an offence should be structured, drawing primarily upon foundational principles of criminal liability. It is suggested that a new general offence of wilfully neglecting or ill-treating a patient that can be committed by any healthcare organisation or worker (appropriately defined) is warranted. CONCLUSIONS: The criminal law has an important role to play in the healthcare context. Its central function is not primarily to deter and coerce people into complying with standards of behaviour deemed desirable. Rather, its central function lies in its symbolic and expressive significance, publicly proclaiming that the highly culpable mistreatment of others is wrongful and worthy of public censure and sanction.