Policy Feedback and the Politics of Childhood Vaccine Mandates: Conflict and Change in California, 2012-2019.

CONTEXT: In 2012, California instituted a new requirement for parents to consult with a clinician before receiving a personal belief exemption to its school entry vaccine mandate. In 2015, the state removed this exemption altogether. In 2019, legislators cracked down on medical exemptions to address their misuse by vaccine refusers and supportive clinicians. This paper explores these political conflicts using 'policy feedback theory,' arguing that personal belief exemptions informed the emergence and approaches of two coalitions whose conflict reshaped California's vaccination policies. METHODS: We analysed legal, policy, academic and media documents; interviewed ten key informants; and deductively analysed transcripts using NVivo 20 transcription software. FINDINGS: California's long-standing vaccination policy inadvertently disseminated two fundamentally incompatible social norms: vaccination is a choice; vaccination is not a choice. Over time, the culture and number of vaccine refusers grew, at least in part because the policy state-sanctioned the norm of vaccine refusal. CONCLUSIONS: The long-term consequences of California's 'mandate + PBE' policy - visible, public, and socially sanctioned vaccine refusal - undermined support for it over time, generating well-defined losses for a large group of people (the vaccinating public) and specifically for the parent activists whose experiences of personal grievance drove their mobilisation for change.

From speculative to real: community attitudes towards government COVID-19 vaccine mandates in Western Australia from May 2021 to April 2022.

Many governments employed mandates for COVID-19 vaccines, imposing consequences upon unvaccinated people. Attitudes towards these policies have generally been positive, but little is known about how discourses around them changed as the characteristics of the disease and the vaccinations evolved. Western Australia (WA) employed sweeping COVID-19 vaccine mandates for employment and public spaces whilst the state was closed off from the rest of the country and world, and mostly with no COVID-19 in the community. This article analyses WA public attitudes during the mandate policy lifecycle from speculative to real. Qualitative interview data from 151 adults were analysed in NVivo 20 via a novel chronological analysis anchored in key policy phases: no vaccine mandates, key worker vaccine mandates, vaccine mandates covering 75% of the workforce and public space mandates. Participants justified mandates as essential for border reopening and, less frequently, for goals such as protecting the health system. However, public discourse focusing on 'getting coverage rates up' may prove counter-productive for building support for vaccination; governments should reinforce end goals in public messaging (reducing suffering and saving lives) because such messaging is likely to be more meaningful to vaccination behaviour in the longer term.

COVID-19 vaccination of at-risk and marginalised groups: recentering the state in vaccine uptake.

Recent studies have used the World Health Organization's new Behavioural and Social Drivers (BeSD) framework to analyse vaccine uptake. However, this study of COVID-19 vaccination among marginalised population groups highlights the framework's limitations regarding the centrality of the state in shaping people's vaccination intentions in high income countries. We conducted interviews and focus groups with service providers and community members to explore COVID-19 vaccination amongst Western Australians experiencing homelessness and/or from other marginalised populations (such as people with substance use dependence). Analysing this data iteratively to emphasise the state's role and functions, we elaborate how trauma and mistrust of government drive thoughts, feelings, and social interactions regarding vaccination programs, which are mutually reinforcing and which inhibit individuals' willingness to engage. Government systems that leave some populations behind increase those populations' susceptibility to misinformation. Policies may generate new unintended problems: social service providers worried about vaccine advocacy damaging clients' trust, especially in the context of vaccine mandates. Reframing the state's responsibility for designing culturally and socially appropriate services, we outline how end-users and trusted providers can lead this process. We share a new framework, "Recentering the State in Vaccine Uptake," arising from our analyses.

BET inhibitors as a therapeutic intervention in gastrointestinal gene signature-positive castration-resistant prostate cancer.

A subgroup of castration-resistant prostate cancer (CRPC) aberrantly expresses a gastrointestinal (GI) transcriptome governed by two GI-lineage-restricted transcription factors, HNF1A and HNF4G. In this study, we found that expression of GI transcriptome in CRPC correlates with adverse clinical outcomes to androgen receptor signaling inhibitor treatment and shorter overall survival. Bromo- and extra-terminal domain inhibitors (BETi) downregulated HNF1A, HNF4G, and the GI transcriptome in multiple CRPC models, including cell lines, patient-derived organoids, and patient-derived xenografts, while AR and the androgen-dependent transcriptome were largely spared. Accordingly, BETi selectively inhibited growth of GI transcriptome-positive preclinical models of prostate cancer. Mechanistically, BETi inhibited BRD4 binding at enhancers globally, including both AR and HNF4G bound enhancers while gene expression was selectively perturbed. Restoration of HNF4G expression in the presence of BETi rescued target gene expression without rescuing BRD4 binding. This suggests that inhibition of master transcription factors expression underlies the selective transcriptional effects of BETi. SIGNIFICANCE: GI transcriptome expression in CRPC is regulated by the HNF1A-HNF4G-BRD4 axis and correlates with worse clinical outcomes. Accordingly, BET inhibitors significantly reduce tumor cell growth in multiple GI-transcriptome-positive preclinical models of CRPC. Our studies point that expression of GI transcriptome could serve as a predictive biomarker to BETi therapy response.

Medical exemptions to mandatory vaccinations: The state of play in Australia and a pressure point to watch.

Australia's mandatory vaccination policies have historically allowed for non-medical exemptions (NMEs), but this changed in 2016 when the Federal Government discontinued NMEs for childhood vaccination requirements. Australian states introduced further mandatory vaccination policies during the COVID-19 pandemic for a range of occupations including healthcare workers (HCWs). There is global evidence to suggest that medical exemptions (MEs) increase following the discontinuation of NMEs; the new swathe of COVID-19 mandatory vaccination policies likely also placed further pressure on ME systems in many jurisdictions. This paper examines the state of play of mandatory vaccination and ME policies in Australia by outlining the structure and operation of these policies for childhood vaccines, then for COVID-19, with a case study of HCW mandates. Next, the paper explores HCWs' experiences in providing vaccine exemptions to patients (and MEs in particular). Finally, the paper synthesizes existing literature and reflects on the challenges of MEs as a pressure point for people who do not want to vaccinate and for the clinicians who care for them, proposing areas for future research and action.

Amyloid plaques and normal ageing have differential effects on microglial Ca2+ activity in the mouse brain.

In microglia, changes in intracellular calcium concentration ([Ca2+]i) may regulate process motility, inflammasome activation, and phagocytosis. However, while neurons and astrocytes exhibit frequent spontaneous Ca2+ activity, microglial Ca2+ signals are much rarer and poorly understood. Here, we studied [Ca2+]i changes of microglia in acute brain slices using Fluo-4-loaded cells and mice expressing GCaMP5g in microglia. Spontaneous Ca2+ transients occurred ~ 5 times more frequently in individual microglial processes than in their somata. We assessed whether microglial Ca2+ responses change in Alzheimer's disease (AD) using AppNL-G-F knock-in mice. Proximity to Aß plaques strongly affected microglial Ca2+ activity. Although spontaneous Ca2+ transients were unaffected in microglial processes, they were fivefold more frequent in microglial somata near Aß plaques than in wild-type microglia. Microglia away from Aß plaques in AD mice showed intermediate properties for morphology and Ca2+ responses, partly resembling those of wild-type microglia. By contrast, somatic Ca2+ responses evoked by tissue damage were less intense in microglia near Aß plaques than in wild-type microglia, suggesting different mechanisms underlying spontaneous vs. damage-evoked Ca2+ signals. Finally, as similar processes occur in neurodegeneration and old age, we studied whether ageing affected microglial [Ca2+]i. Somatic damage-evoked Ca2+ responses were greatly reduced in microglia from old mice, as in the AD mice. In contrast to AD, however, old age did not alter the occurrence of spontaneous Ca2+ signals in microglial somata but reduced the rate of events in processes. Thus, we demonstrate distinct compartmentalised Ca2+ activity in microglia from healthy, aged and AD-like brains.

The timing of recurrence after endoscopic papillectomy.

BACKGROUND: Endoscopic papillectomy (EP) offers a safe and effective method for resection of ampullary adenomas. Data regarding the long-term resolution of adenoma following EP are limited. The aim of this study therefore was to examine the timing of recurrence after EP of ampullary adenomas. METHODS: This was a single-center retrospective study including patients who received EP for ampullary adenomas from 8/2000 to 1/2018. Patients with confirmed complete eradication of adenoma were included in the recurrence analysis with recurrence defined as finding adenomatous histology after 1 negative surveillance endoscopy. Kaplan-Meier estimates were calculated to determine recurrence rates. RESULTS: Of the 165 patients who underwent EP, 136 patients (mean age 61.9, 51.5% female) had adenomatous histology with a mean lesion size of 21.2 mm. A total of 124 (91.2%) achieved complete eradication with a follow-up of 345.8 person-years. Recurrence occurred in 20 (16.1%) patients at a mean of 3.2 (± 3) years (range 0.5-9.75 years) for a recurrence rate of 5.8 (95% CI 3.6-8.8) per 100 person-years. Nine (45%) recurrences occurred after the 1st 2 years of surveillance. Recurrence rate did not differ by baseline pathology [low-grade dysplasia: 5.2 (95% CI 3.0-9.0), high-grade dysplasia: 6.9 (95% CI 2.3-15.5), adenocarcinoma: 7.7 (95% CI 0.9-25.1)]. CONCLUSION: Recurrence remains a significant concern after EP. Given the timing of recurrence, long surveillance periods may be necessary. Larger multicenter studies are needed, however, to determine appropriate surveillance intervals.

Attitudes, perceptions, and experiences of Western Australians towards vaccine safety surveillance systems following COVID-19 vaccines: A qualitative descriptive study.

OBJECTIVE: Concerns regarding adverse events following immunisation are a barrier to vaccine uptake. Health professionals use vaccine safety surveillance systems (VSSSs) to monitor vaccines and inform the public of safety data. With little known about public attitudes, perceptions, and experiences with VSSS, we examined them in the context of COVID-19 vaccinations in Western Australia. METHODS: Researchers conducted 158 qualitative interviews between March 2021 and May 2022 within the broader [name redacted] project. Data regarding VSSS were coded in NVivo using the deductive and inductive methods. RESULTS: Despite some not knowing about VSSS, participants expected follow-up post COVID-19 vaccination. Vaccine hesitant or refusing participants knew about VSSS and regarded these systems positively. Additional considerations concerned the reliability of data collected by VSSS. CONCLUSION: Perceptions of VSSS signal a lack of understanding about how these systems work. Future studies should further explore the public's understanding of VSSS, whether VSSS improves vaccine confidence, and how governments can better communicate to the public about VSSS. IMPLICATIONS FOR PUBLIC HEALTH: Lack of understanding of how VSSS operate may be stymying attempts to build public vaccine confidence. Healthcare providers and governments could build public knowledge and understanding of VSSS to mitigate concerns of adverse events following immunisation.

Childhood vaccine refusal and what to do about it: a systematic review of the ethical literature.

BACKGROUND: Parental refusal of routine childhood vaccination remains an ethically contested area. This systematic review sought to explore and characterise the normative arguments made about parental refusal of routine vaccination, with the aim of providing researchers, practitioners, and policymakers with a synthesis of current normative literature. METHODS: Nine databases covering health and ethics research were searched, and 121 publications identified for the period Jan 1998 to Mar 2022. For articles, source journals were categorised according to Australian Standard Field of Research codes, and normative content was analysed using a framework analytical approach. RESULTS: Most of the articles were published in biomedical journals (34%), bioethics journals (21%), and journals that carry both classifications (20%). Two central questions dominated the literature: (1) Whether vaccine refusal is justifiable (which we labelled 'refusal arguments'); and (2) Whether strategies for dealing with those who reject vaccines are justifiable ('response arguments'). Refusal arguments relied on principlism, religious frameworks, the rights and obligations of parents, the rights of children, the medico-legal best interests of the child standard, and the potential to cause harm to others. Response arguments were broadly divided into arguments about policy, arguments about how individual physicians should practice regarding vaccine rejectors, and both legal precedents and ethical arguments for vaccinating children against a parent's will. Policy arguments considered the normative significance of coercion, non-medical or conscientious objections, and possible reciprocal social efforts to offset vaccine refusal. Individual physician practice arguments covered nudging and coercive practices, patient dismissal, and the ethical and professional obligations of physicians. Most of the legal precedents discussed were from the American setting, with some from the United Kingdom. CONCLUSIONS: This review provides a comprehensive picture of the scope and substance of normative arguments about vaccine refusal and responses to vaccine refusal. It can serve as a platform for future research to extend the current normative literature, better understand the role of cultural context in normative judgements about vaccination, and more comprehensively translate the nuance of ethical arguments into practice and policy.

Endoscopic iatrogenic esophageal perforation and management: a retrospective outcome analysis in the modern era.

INTRODUCTION: Iatrogenic esophageal perforation (IEP) is a severe adverse event (AE) of upper endoscopy procedures (UEPs) associated with morbidity. Management has shifted from surgery to endotherapy with clip closure (CC), self-expanding metal stent (SEMS), and vacuum therapy (VT). Limited analyses measure outcomes during contemporary interventional endoscopy periods. METHODS: IEPs associated with EGD, upper EUS, small bowel enteroscopy (SBE), and ERCP at a 3-hospital academic center from January 2011 to December 2023 were identified retrospectively from a centralized AE database. Additional information was obtained from medical records. Statistical analysis was performed using Microsoft Excel and STATA. RESULTS: Thirty-two IEPs from 26 EGDs, 4 EUS, 1 SBE, and 1 ERCP were identified. IEPs occurred mostly after dilation (bougie N = 7; balloon, N = 5) or foreign body removal (N = 6). Most IEPs occurred in the lower esophagus (N = 10) or gastroesophageal junction (N = 8). Diagnosis was made at a median 2 h after the injury by endoscopy (N = 14), CT scan (N = 12), esophagram (N = 5), or x-ray (N = 1). Initial treatment included conservative therapy alone (N = 7), CC (N = 3), SEMS (N = 14), SEMS plus CC (N = 3), or surgery (N = 3). Eleven patients required additional treatment including repeat SEMS or adjustment (N = 4) or VT (N = 1). No surgical interventions were required after 2013. The median hospital stay was 3 days. Disposition included discharge to home (N = 25), long-term care facility (N = 2), 4 deaths (12.5% of IEPs), and 1 unknown. CONCLUSIONS: IEPs are rare and occur throughout the esophagus after any UEP. The majority are recognized immediately and managed with endotherapy, or rarely, surgery today. These characteristics likely explain the low mortality in this study.

Making salient ethics arguments about vaccine mandates: A California case study.

Vaccine mandates can take many forms, and different kinds of mandates can implicate an array of values in diverse ways. It follows that good ethics arguments about particular vaccine mandates will attend to the details of individual policies. Furthermore, attention to particular mandate policies-and to attributes of the communities they aim to govern-can also illuminate which ethics arguments may be more salient in particular contexts. If ethicists want their arguments to make a difference in policy, they should attend to these kinds of empirical considerations. This paper focuses on the most common and contentious vaccine mandate reform in the contemporary United States: the elimination of nonmedical exemptions (NMEs) to school and daycare vaccine mandates. It highlights, in particular, debates about California's Senate Bill 277 (SB277), which was the first successful recent effort to eliminate NMEs in that country. We use media, secondary sources, and original interviews with policymakers and activists to identify and evaluate three ethics arguments offered by critics of SB277: parental freedom, informed consent, and children's rights to care and education. We then turn to one ethics argument often offered by advocates of SB277: harm prevention. We note, however, that three arguments for mandates that are common in the immunization ethics literature-fairness/free-riding, children's rights to vaccination, and utilitarianism-did not play a role in debates about SB277.

"Fighting the pandemic!" Western Australian pharmacists' perspectives on COVID-19 vaccines: A qualitative study.

BACKGROUND: In Western Australia, community pharmacists are authorized to administer a range of vaccines without a prescription. Since mid-July 2021, pharmacists can also administer Coronavirus Disease 2019 (COVID-19) vaccines. Little is known about how pharmacists think and feel about giving and receiving COVID-19 vaccines and how they discuss it with patients. AIM: This study aimed to explore Western Australian pharmacists' perceptions on being vaccinated with, administering, and communicating about COVID-19 vaccines. METHODS: Semi structured interviews were conducted with 20 pharmacists from metropolitan and regional areas of Western Australia across a two-week period in July and early August 2021. Interview transcripts were coded using NVivo 20 and data was thematically analyzed using the framework method. RESULTS: Most pharmacists (n = 16, 80 %) had received at least one dose of a COVID-19 vaccine. Some expressed difficulty accessing the vaccine while two unvaccinated pharmacists were hesitant to receive it due to concerns about vaccine development. The majority of pharmacists spoke positively about administering the vaccines, discussing perceived facilitators such as designated vaccination days but also perceived barriers such as inadequate financial reimbursement compared to other healthcare providers. Many pharmacists obtained their information from Australian government sources and training modules. Pharmacists were only passively promoting COVID-19 vaccines, with conversations mostly initiated by patients. Most pharmacists specified they would highlight the common side effects when administering the vaccine and would provide patients with written information. CONCLUSION: The majority of pharmacists were willing to administer and be vaccinated with COVID-19 vaccines. Since pharmacists play an important role in increasing vaccine uptake, governments should provide equitable reimbursement to pharmacists in line with other vaccinators such as General Practitioners. We welcome the recent resources produced by governments and pharmacy professional organizations to help pharmacists actively promote the vaccines since this work was undertaken.

Measuring Salivary Cortisol to Assess the Effect of Natural Environments on Stress Level in Acute Patients With Severe Brain Injuries: An Exploratory Study.

BACKGROUND: Salivary cortisol is a safe and non-invasive measure of hypothalamic-pituitary-adrenal axis function and is used as a biomarker of the human stress response. Natural environments are recognized to contribute to help reduce the effect of stress. OBJECTIVE: To determine the feasibility of a salivary cortisol collection protocol for acute severely brain-injured patients, and to explore the influence of exposure to natural settings on salivary cortisol concentration as an index of stress level. METHODS: An exploratory study on 17 acute patients with severe brain injury was performed. We collected salivary samples in a closed hospital ward and a therapeutic garden at the start of the session and after 30 minutes of rest time. Physiological parameters, level of communication, and subjective well-being were also assessed. RESULTS: The primary objectives regarding the feasibility of the protocol were met overall. We found no significant differences in cortisol values when including the whole population. However, cortisol values were significantly higher in the indoor environment in patients with communication attempts. CONCLUSIONS: A salivary collection protocol with brain-injured patients in the acute phase is feasible and safe, and this type of measurement could pave the way for future research supporting the benefits of nature as an additional resource in their neurorehabilitation.

West Australian parents' views on vaccinating their children against COVID-19: a qualitative study.

BACKGROUND: Australian children and adolescents were among the last local cohorts offered COVID-19 vaccines. Despite promising initial uptake, coverage subsequently plateaued, requiring further efforts to improve access and build parents' recognition of the importance of COVID-19 vaccination. We sought to understand West Australian (WA) parents' willingness to vaccinate their children to inform strategies for improving uptake at the time in which they were becoming eligible. METHODS: We undertook in-depth qualitative interviews with 30 parents of children aged 5-17 years from June - December 2021. During this period, children aged 12-15 years became eligible for vaccination; children aged 5-11 years became eligible shortly thereafter. Data were thematically analysed in NVivo. RESULTS: Most parents intended on vaccinating their children once eligible. Parents sought to protect their children, to protect the community, to resume travel, and to get back to "normal". They reflected that vaccination against key infectious threats is a routine activity in childhood. Some were concerned about the vaccine, particularly mRNA vaccines, being new technology or impacting fertility. "Wait-awhiles" wanted to see what other parents would do or were delaying until they felt that there was a higher risk of COVID-19 in WA. Most parents of younger children wanted their child to be vaccinated at the general practice clinic due to familiarity and convenience. Parents were particularly eager for clear and consistent messaging about vaccination of children and adolescents, including safety, importance, scientific evidence, and personal stories. CONCLUSION: For future pandemic vaccinations pertaining to children, governments and health officials need to address parents' concerns and meet their preferences for the delivery of the vaccine program to children and adolescents.

Heart failure causes sleepless nights.

Cardiac dysfunction triggers immune-mediated loss of pineal gland melatonin release.

Eliminating nonmedical exemptions: a radical shift in how childhood vaccine mandates govern.

INTRODUCTION: Every state in the US has had school vaccine mandates for decades, and all except West Virginia and Mississippi offered nonmedical exemptions (NMEs) in addition to medical exemptions. Several states recently eliminated NMEs, and others have attempted to do so. These efforts are transforming America's immunization governance. AREAS COVERED: What we call the 'mandates & exemptions' regime of vaccination policy from the 1960s and 1970s functioned to orient parents toward vaccination, but did not coerce or punish them for not vaccinating. The article identifies how policy tweaks in the 2000s - including education requirements and other bureaucratic burdens - delivered enhancements to the 'mandates & exemptions' regime. Finally, the paper illustrates how the recent elimination of NMEs, first in California and then in other states, represents a radical transformation of America's vaccine mandates. EXPERT OPINION: Today's 'unencumbered vaccine mandates' (mandates without exemptions) directly govern and punish non-vaccination, unlike the 'mandates & exemption' regime that aimed to make it harder for parents to avoid vaccination. This kind of policy change introduces new problems for implementation and enforcement, especially within America's underfunded public health system, and in the context of post-COVID public health political conflicts.

Antibiotics online: digital pharmacy marketplaces and pastiche medicine.

The internet enables access to information and the purchasing of medical products of various quality and legality. Research and regulatory attention have focused on the trafficking of illicit substances, potential physical harms of pharmaceuticals, and possibilities like financial fraud. However, there is far less attention paid to antibiotics and other antimicrobials used to treat infections. With online pharmacies affording greater access, caution around antibiotic use is needed due to the increasing health risks of antimicrobial resistance (AMR). The COVID-19 pandemic has helped to normalise digital healthcare and contactless prescribing, amplifying the need for caution. Little is known of how antibiotics are consumed via digital pharmacy and implications for AMR prevention. To expand insight for AMR prevention policy in Australia and internationally, we use digital ethnographic methods to explore how digital pharmacies function in the context of health advice and policy related to AMR, commonly described as antimicrobial stewardship. We find that digital pharmacy marketplaces constitute 'pastiche medicine'. They curate access to pharmaceutical and information products that emulate biomedical authority combined with emphasis on the 'self-assembly' of healthcare. Pastiche medicine empowers the consumer but borrows biomedical expertise about antibiotics, untethering these goods from critical medicine information, and from AMR prevention strategies. We reflect on the implications of pastiche medicine for AMR policy, what the antibiotics case contributes to wider critical scholarship on digital pharmacy, and how medical humanities research might consider researching online consumption in future.