An examination of the relationship between risk perceptions, cultural-religious beliefs and coping during COVID-19 pandemic control in South Asian countries: a systematic review.

BACKGROUND: Covid 19 was declared as a public health emergency by the World Health Organisation (WHO) due to its rapid spread and catastrophic effects on health. It affected around 119 M people with mortality rate of 0.27% worldwide, including South-Asians. This review aims to understand the risk perceptions, cultural religious beliefs and the coping mechanisms of South Asians during the Covid 19 pandemic. METHODS: We conducted a systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The following search engines were used: Medline, Cochrane Library, PsycINFO, CINAHL, and Web of Science. Included studies investigated perceptions and opinions of individuals on knowledge, risk and protective factors, native faith based practices, and attitudes towards the COVID-19 pandemic. RESULTS: The database search produced 282 articles to screen. The final narrative synthesis included five studies comprising of 13,476 participants from Pakistan, India, Nepal, and Bangladesh. Ten studies, comprising 7,893 participants, were eligible and included for meta-analysis. The overall pooled prevalence with maximum heterogeneity for correct knowledge of symptoms, hand washing or use of sanitizers, face masking use of herbal or traditional remedies and physical distancing or avoidance of contact was reported through meta-analysis. CONCLUSION: The review brings forth a useful comparison of individual and cultural differences in KAP, risk perceptions and coping strategies. This review highlights the need for and importance of tailored information dissemination, culturally sensitive risk communication, targeted educational interventions, community engagement and empowerment, policy, and infrastructure improvements, as well as continued research and data collection. By addressing these implications, efforts to mitigate the impact of COVID-19 can be more effective and equitable across diverse populations. PROSPERO REGISTRATION: CRD42021246475.

Is equipoise a useful concept to justify randomised controlled trials in the cultural context of Pakistan? A survey of clinicians in relation to a trial of talking therapy for young people who self-harm.

BACKGROUND: Clinical equipoise, also defined as the uncertainty principle, is considered essential when recruiting subjects to a clinical trial. However, equipoise is threatened when clinicians are influenced by their own preferences. Little research has investigated equipoise in the context of trial recruitment. METHODS: This cross-sectional survey sought clinicians' views (operationalised as 11 statements relating to treatments offered in a trial of a psychological intervention for young people) about equipoise and individual treatment preferences in the context of moral justification for recruiting young people at risk of self-harm or suicide to a randomised controlled trial (RCT) to evaluate the Youth Culturally Adapted Manual Assisted Psychological Intervention (Y-CMAP) in Pakistan. We compared the views of clinicians involved in Y-CMAP RCT recruitment to those of a sample of clinicians not involved in trial recruitment but treating similar patients, comparing their sociodemographic characteristics and the proportions of those in each group agreeing with each statement. RESULTS: There was a response rate of 96% (75/78). Findings showed that, during trial recruitment and before the RCT results were known, the majority of all responding clinicians (73.3%) considered Y-CMAP to be an effective treatment for young people at risk of self-harm or suicide. Although there was an acknowledgement of individual preferences for the intervention, there was near consensus (90%) on the need to conduct an RCT for reaching an evidence-based decision. However, there were no significant differences in the proportion of recruiting clinicians reporting a treatment preference for Y-CMAP than non-recruiting clinicians (31 (88.6%) versus 36 (90%), p = 0.566). A significantly higher proportion of non-recruiting clinicians (87.5%) as compared to (48.5%) in the trial (p = 0.000) stated that there may be other treatments that may be equally good for the patients, seemingly undermining a preference for the intervention. Those reporting a treatment preference also acknowledged that there was nothing on which this preference was based, however confident they felt about them, thus accepting clinical equipoise as ethical justification for conducting the RCT. There was a significant group difference in views that treatment overall is better as a result of young patients' participation in the Y-CMAP trial (p = 0.015) (i.e. more clinicians not involved in the trial agreed with this statement). Similarly, more clinicians not involved in the trial agreed on the perceived availability of other treatment options that were good for young people at risk of self-harm (p < 0.05). CONCLUSIONS: The paper highlights that clinicians in Pakistan accept the notion of clinical equipoise as an ethical justification for patient participation in RCTs. The need for conducting RCTs to generate evidence base and to reduce bias was considered important by the clinical community.

Perceived coercion, perceived pressures and procedural justice arising from global lockdowns during the COVID-19 pandemic: A scoping review.

This aim of this scoping review is to map what is known about perceived coercion, perceived pressures and procedural justice within the context of the general population's experience of 'lockdowns' imposed by governments worldwide in response to the increased transmission of COVID-19. Arksey & O'Malley's (2005) framework for conducting scoping reviews was chosen. A sensitive search strategy was devised and conducted using PubMed, Scopus, and Web of Science using the following search terms: (adherence OR acceptance OR agreement OR trust OR distrust OR compliance OR willing*) OR (perceived coerc* OR percept* coerc* OR pressure OR force OR influence OR control OR threat OR justice) AND (lockdown) AND (COVID OR SARS-CoV-2 OR COVID-19). The database search initially produced 41,628 articles to screen. A total of 40 articles were included in this review and the following five themes were identified from the studies: perceived acceptability and willingness to adhere to lockdown; perceived control during lockdown; perceived pressures arising from lockdown; perceived threat of sanction from others and the procedural (in)justice of lockdown. Our synthesis suggests that i) individuals experienced an initial willingness and tolerance of lockdown that lessened over time as perceptions of personal control decreased; ii) that social influences may pressure individuals to follow or break lockdown rules; and iii) that justifiability and proportionality together with individuals' perceptions of harm from COVID-19 may impact the extent to which individuals adhere to lockdown. Furthermore, the review found an absence of information regarding specific individual characteristics and circumstances that increase the likelihood of experiencing perceived coercion and its related constructs and highlights a need for a better understanding of the cultural and socioeconomic factors affecting perceptions of, and adherence to, lockdown.

An ethics of anthropology-informed community engagement with COVID-19 clinical trials in Africa.

The COVID-19 pandemic has reinforced the critical role of ethics and community engagement in designing and conducting clinical research during infectious disease outbreaks where no vaccine or treatment already exists. In reviewing current practices across Africa, we distinguish between three distinct roles for community engagement in clinical research that are often conflated: 1) the importance of community engagement for identifying and honouring cultural sensitivities; 2) the importance of recognising the socio-political context in which the research is proposed; and 3) the importance of understanding what is in the interest of communities recruited to research according to their own views and values. By making these distinctions, we show that current practice of clinical research could draw on anthropology in ways which are sometimes unnecessary to solicit local cultural values, overlook the importance of socio-political contexts and wider societal structures within which it works, potentially serving to reinforce unjust political or social regimes, and threaten to cast doubt on the trustworthiness of the research. We argue that more discerning anthropological engagement as well as wider collaboration with other social scientists and those working in the humanities is urgently needed to improve the ethics of current biomedical and pharmaceutical research practice in Africa.

Proteome and Network Analysis Provides Novel Insights Into Developing and Established Chemotherapy-Induced Peripheral Neuropathy.

Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating side-effect of cancer therapies. So far, the development of CIPN cannot be prevented, neither can established CIPN be reverted, often leading to the cessation of necessary chemotherapy. Thus, there is an urgent need to explore the mechanistic basis of CIPN to facilitate its treatment. Here we used an integrated approach of quantitative proteome profiling and network analysis in a clinically relevant rat model of paclitaxel-induced peripheral neuropathy. We analysed lumbar rat DRG at two critical time points: (1) day 7, right after cessation of paclitaxel treatment, but prior to neuropathy development (pre-CIPN); (2) 4 weeks after paclitaxel initiation, when neuropathy has developed (peak-CIPN). In this way we identified a differential protein signature, which shows how changes in the proteome correlate with the development and maintenance of CIPN, respectively. Extensive biological pathway and network analysis reveals that, at pre-CIPN, regulated proteins are prominently implicated in mitochondrial (dys)function, immune signalling, neuronal damage/regeneration, and neuronal transcription. Orthogonal validation in an independent rat cohort confirmed the increase of ß-catenin (CTNNB1) at pre-CIPN. More importantly, detailed analysis of protein networks associated with ß-catenin highlights translationally relevant and potentially druggable targets. Overall, this study demonstrates the enormous value of combining animal behaviour with proteome and network analysis to provide unprecedented insights into the molecular basis of CIPN. In line with emerging approaches of network medicine our results highlight new avenues for developing improved therapeutic options aimed at preventing and treating CIPN.

Preclinical evidence for mitochondrial DNA as a potential blood biomarker for chemotherapy-induced peripheral neuropathy.

Chemotherapy-induced peripheral neuropathy (CIPN) is a serious dose-limiting side effect of several first-line chemotherapeutic agents including paclitaxel, oxaliplatin and bortezomib, for which no predictive marker is currently available. We have previously shown that mitochondrial dysfunction is associated with the development and maintenance of CIPN. The aim of this study was to evaluate the potential use of mitochondrial DNA (mtDNA) levels and complex I enzyme activity as blood biomarkers for CIPN. Real-time qPCR was used to measure mtDNA levels in whole blood collected from chemotherapy- and vehicle-treated rats at three key time-points of pain-like behaviour: prior to pain development, at the peak of mechanical hypersensitivity and at resolution of pain-like behaviour. Systemic oxaliplatin significantly increased mtDNA levels in whole blood prior to pain development. Furthermore, paclitaxel- and bortezomib-treated animals displayed significantly higher levels of mtDNA at the peak of mechanical hypersensitivity. Mitochondrial complex I activity in whole blood was assessed with an ELISA-based Complex I Enzyme Activity Dipstick Assay. Complex I activity was not altered by any of the three chemotherapeutic agents, either prior to or during pain-like behaviour. These data demonstrate that blood levels of mtDNA are altered after systemic administration of chemotherapy. Oxaliplatin, in particular, is associated with higher mtDNA levels before animals show any pain-like behaviour, thus suggesting a potential role for circulating mtDNA levels as non-invasive predictive biomarker for CIPN.

Recognising values and engaging communities across cultures: towards developing a cultural protocol for researchers.

Efforts to build research capacity and capability in low and middle income countries (LMIC) has progressed over the last three decades, yet it confronts many challenges including issues with communicating or even negotiating across different cultures. Implementing global research requires a broader understanding of community engagement and participatory research approaches. There is a considerable amount of guidance available on community engagement in clinical trials, especially for studies for HIV/AIDS, even culturally specific codes for recruiting vulnerable populations such as the San or Maori people. However, the same cannot be said for implementing research in global health. In an effort to build on this work, the Pakistan Institute of Living and Learning and University College London in the UK sought to better understand differences in beliefs, values and norms of local communities in Pakistan. In particular, they have sought to help researchers from high income countries (HIC) understand how their values are perceived and understood by the local indigenous researchers in Pakistan. To achieve this end, a group discussion was organised with indigenous researchers at Pakistan Institute of Living and Learning. The discussion will ultimately help inform the development of a cultural protocol for researchers from HIC engaging with communities in LMIC. This discussion revealed five common themes; (1) religious principles and rules, (2) differing concepts of and moral emphasis on autonomy and privacy, (3) importance of respect and trust; (4) cultural differences (etiquette); (5) custom and tradition (gift giving and hospitality). Based on the above themes, we present a preliminary cultural analysis to raise awareness and to prepare researchers from HIC conducting cross cultural research in Pakistan. This is likely to be particularly relevant in collectivistic cultures where social interconnectedness, family and community is valued above individual autonomy and the self is not considered central to moral thinking. In certain cultures, HIC ideas of individual autonomy, the notion of informed consent may be regarded as a collective family decision. In addition, there may still be acceptance of traditional professional roles such as 'doctor knows best', while respect and privacy may have very different meanings.

Non-inferiority versus superiority trial design for new antibiotics in an era of high antimicrobial resistance: the case for post-marketing, adaptive randomised controlled trials.

Antimicrobial resistance is one of the most important threats to global health security. A range of Gram-negative bacteria associated with high morbidity and mortality are now resistant to almost all available antibiotics. In this context of urgency to develop novel drugs, new antibiotics for multidrug-resistant Gram-negative bacteria (namely, ceftazidime-avibactam, plazomicin, and meropenem-vaborbactam) have been approved by regulatory authorities based on non-inferiority trials that provided no direct evidence of their efficacy against multidrug-resistant bacteria such as Enterobacteriaceae spp, Pseudomonas aeruginosa, Stenotrophomonas maltophilia, Burkholderia cepacia, and Acinetobacter baumannii. The use of non-inferiority and superiority trials, and selection of appropriate and optimal study designs, remains a major challenge in the development, registration, and post-marketing implementation of new antibiotics. Using an example of the development process of ceftazidime-avibactam, we propose a strategy for a new research framework based on adaptive randomised clinical trials. The operational research strategy has the aim of assessing the efficacy of new antibiotics in special groups of patients, such as those infected with multidrug-resistant bacteria, who were not included in earlier phase studies, and for whom it is important to establish an appropriate standard of care.

Mitochondrial dysfunction in the pathogenesis of chemotherapy-induced peripheral neuropathy.

Several first-line chemotherapeutic agents, including taxanes, platinum agents and proteasome inhibitors, are associated with the dose-limiting side effect of chemotherapy-induced peripheral neuropathy (CIPN). CIPN predominantly manifests as sensory symptoms, which are likely due to drug accumulation within peripheral nervous tissues rather than the central nervous system. No treatment is currently available to prevent or reverse CIPN. The causal mechanisms underlying CIPN are not yet fully understood. Mitochondrial dysfunction has emerged as a major factor contributing to the development and maintenance of CIPN. This chapter will provide an overview of both clinical and preclinical data supporting this hypothesis. We will review the studies reporting the nature of mitochondrial dysfunction evoked by chemotherapy in terms of changes in mitochondrial morphology, bioenergetics and reactive oxygen species (ROS) generation. Furthermore, we will discuss the in vivo effects of pharmacological interventions that counteract chemotherapy-evoked mitochondrial dysfunction and ameliorate pain-like behavior.

A Radical Approach to Ebola: Saving Humans and Other Animals.

As the usual regulatory framework did not fit well during the last Ebola outbreak, innovative thinking still needed. In the absence of an outbreak, randomised controlled trials of clinical efficacy in humans cannot be done, while during an outbreak such trials will continue to face significant practical, philosophical, and ethical challenges. This article argues that researchers should also test the safety and effectiveness of novel vaccines in wild apes by employing a pluralistic approach to evidence. There are three reasons to test vaccines in wild populations of apes: i) protect apes; ii) reduce Ebola transmission from wild animals to humans; and iii) accelerate vaccine development and licensing for humans. Data obtained from studies of vaccines among wild apes and chimpanzees may even be considered sufficient for licensing new vaccines for humans. This strategy will serve to benefit both wild apes and humans.

Evoked and Ongoing Pain-Like Behaviours in a Rat Model of Paclitaxel-Induced Peripheral Neuropathy.

Paclitaxel-induced neuropathic pain is a major dose-limiting side effect of paclitaxel therapy. This study characterises a variety of rat behavioural responses induced by intermittent administration of clinically formulated paclitaxel. 2 mg/kg paclitaxel or equivalent vehicle was administered intraperitoneally on days 0, 2, 4, and 6 to adult male Sprague-Dawley rats. Evoked pain-like behaviours were assessed with von Frey filaments, acetone, or radiant heat application to plantar hind paws to ascertain mechanical, cold, or heat sensitivity, respectively. Motor coordination was evaluated using an accelerating RotaRod apparatus. Ongoing pain-like behaviour was assessed via spontaneous burrowing and nocturnal wheel running. Mechanical and cold hypersensitivity developed after a delayed onset, peaked approximately on day 28, and persisted for several months. Heat sensitivity and motor coordination were unaltered in paclitaxel-treated rats. Spontaneous burrowing behaviour and nocturnal wheel running were significantly impaired on day 28, but not on day 7, indicating ongoing pain-like behaviour, rather than acute drug toxicity. This study comprehensively characterises a rat model of paclitaxel-induced peripheral neuropathy, providing the first evidence for ongoing pain-like behaviour, which occurs in parallel with maximal mechanical/cold hypersensitivity. We hope that this new data improve the face validity of rat models to better reflect patient-reported pain symptoms, aiding translation of new treatments to the clinic.

Characterization of a New Protein Family Associated With the Silica Deposition Vesicle Membrane Enables Genetic Manipulation of Diatom Silica.

Diatoms are known for their intricate, silicified cell walls (frustules). Silica polymerization occurs in a compartment called the silica deposition vesicle (SDV) and it was proposed that the cytoskeleton influences silica patterning through the SDV membrane (silicalemma) via interactions with transmembrane proteins. In this work we identify a family of proteins associated with the silicalemma, named SAPs for Silicalemma Associated Proteins. The T. pseudonana SAPs (TpSAPs) are characterized by their motif organization; each contains a transmembrane domain, serine rich region and a conserved cytoplasmic domain. Fluorescent tagging demonstrated that two of the TpSAPs were localized to the silicalemma and that the intralumenal region of TpSAP3 remained embedded in the silica while the cytoplasmic region was cleaved. Knockdown lines of TpSAP1 and 3 displayed malformed valves; which confirmed their roles in frustule morphogenesis. This study provides the first demonstration of altering silica structure through manipulation of a single gene.

Characterization of a rat model of bortezomib-induced painful neuropathy.

BACKGROUND AND PURPOSE: Bortezomib (Velcade®) is a breakthrough treatment for multiple myeloma, significantly improving patient survival. However, its use is limited by painful neuropathy often resulting in dose reduction/cessation of first-line treatment due to lack of treatment. The aim of this study was to characterize a clinically relevant rat model of bortezomib-induced painful neuropathy, using established evoked measures and novel ethological techniques, to aid drug discovery. EXPERIMENTAL APPROACH: Adult male Sprague-Dawley rats were injected i.p. with 0.1 and 0.2 mg·kg-1 bortezomib, or its vehicle, on days 0, 3, 7 and 10. Multiple behavioural approaches were utilized: mechanical hypersensitivity, cold allodynia, heat hypersensitivity, motor co-ordination, burrowing and voluntary wheel running. At maximal bortezomib-induced mechanical hypersensitivity, 200 mg·kg-1 ethosuximide/vehicle and 100 mg·kg-1 phenyl N-tert-butylnitrone (PBN)/vehicle were administered i.p. in separate experiments, and mechanical hypersensitivity assessed 1, 3 and 24 h later. KEY RESULTS: Bortezomib induced dose-related mechanical hypersensitivity for up to 80 days. Bortezomib induced short-term cold allodynia, but no significant change in heat hypersensitivity, motor co-ordination, voluntary wheel running and burrowing behaviour compared to vehicle-treated controls. Systemic PBN and ethosuximide significantly ameliorated bortezomib-induced mechanical hypersensitivity. CONCLUSIONS AND IMPLICATIONS: These data characterize a reproducible rat model of clinical-grade bortezomib-induced neuropathy demonstrating long-lasting pain behaviours to evoked stimuli. Inhibition by ethosuximide and PBN suggests involvement of calcium and/or ROS in bortezomib-induced painful neuropathy. These drugs could be used as preclinical positive controls to assess novel analgesics. As ethosuximide is widely used clinically, translation to the clinic to treat bortezomib-induced painful neuropathy may be possible.

Paclitaxel-induced painful neuropathy is associated with changes in mitochondrial bioenergetics, glycolysis, and an energy deficit in dorsal root ganglia neurons.

Painful neuropathy is the major dose-limiting side effect of paclitaxel chemotherapy. Mitochondrial dysfunction and adenosine triphosphate (ATP) deficit have previously been shown in peripheral nerves of paclitaxel-treated rats, but the effects of paclitaxel in the dorsal root ganglia (DRGs) have not been explored. The aim of this study was to determine the bioenergetic status of DRG neurons following paclitaxel exposure in vitro and in vivo. Utilising isolated DRG neurons, we measured respiratory function under basal conditions and at maximal capacity, glycolytic function, and Adenosine diphosphate (ADP)/ATP levels at 3 key behavioural timepoints; prior to pain onset (day 7), peak pain severity and pain resolution. At day 7, maximal respiration and spare reserve capacity were significantly decreased in DRG neurons from paclitaxel-treated rats. This was accompanied by decreased basal ATP levels and unaltered ADP levels. At peak pain severity, respiratory function was unaltered, yet glycolytic function was significantly increased. Reduced ATP and unaltered ADP levels were also observed at the peak pain timepoint. All these effects in DRG neurons had dissipated by the pain resolution timepoint. None of these paclitaxel-evoked changes could be replicated from in vitro paclitaxel exposure to naive DRG neurons, demonstrating the impact of in vivo exposure and the importance of in vivo models. These data demonstrate the nature of mitochondrial dysfunction evoked by in vivo paclitaxel in the DRG for the first time. Furthermore, we have identified paclitaxel-evoked changes in the bioenergetics of DRG neurons, which result in a persistent energy deficit that is causal to the development and maintenance of paclitaxel-induced pain.

How informed is declared altruism in clinical trials? A qualitative interview study of patient decision-making about the QUEST trials (Quality of Life after Mastectomy and Breast Reconstruction).

BACKGROUND: Randomised controlled trials (RCTs) often fail to recruit sufficient participants, despite altruism being cited as their motivation. Previous investigations of factors influencing participation decisions have been methodologically limited. This study evaluated how women weigh up different motivations after initially expressing altruism, and explored their understanding of a trial and its alternatives. The trial was the 'Quality of Life after Mastectomy and Breast Reconstruction' (QUEST) trial. METHODS: Thirty-nine women participated in qualitative interviews 1 month post-surgery. Twenty-seven women (10 trial decliners and 17 acceptors) who spontaneously mentioned 'altruism' were selected for thematic analysis. Verbatim transcripts were coded independently by two researchers. Participants' motivations to accept or decline randomisation were cross-referenced with their understanding of the QUEST trials and the process of randomisation. RESULTS: The seven emerging themes were: (1) altruism expressed by acceptors and decliners; (2) overriding personal needs in decliners; (3) pure altruism in acceptors; (4) 'hypothetical altruism' amongst acceptors; (5) weak altruism amongst acceptors; (6) conditional altruism amongst acceptors; and (7) sense of duty to participate. Poor understanding of the trial rationale and its implications was also evident. CONCLUSIONS: Altruism was a motivating factor for participation in the QUEST randomised controlled trials where the main outcomes comprised quality of life and allocated treatments comprised established surgical procedures. Women's decisions were influenced by their understanding of the trial. Both acceptors and decliners of the trial expressed 'altruism', but most acceptors lacked an obvious treatment preference, hoped for personal benefits regarding a treatment allocation, or did not articulate complete understanding of the trial. TRIAL REGISTRATION: QUEST A, ISRCTN38846532 ; Date assigned 6 January 2010. QUEST B, ISRCTN92581226 ; Date assigned 6 January 2010.