Search results for: ecologicat status

Authors: Kuladip Jana

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Benzo(a)pyrene [B(a)P] is an environmental toxicant present mostly in cigarette smoke and car exhaust, is an aryl hydrocarbon receptor (AhR) ligand that exerts its toxic effects on both male and female reproductive systems. In this study, the effect of B(a)P at different doses (0.1, 0.25, 0.5, 1 and 5 mg /kg body weight) was studied on male reproductive system of rat. A significant decrease in cauda epididymal sperm count and motility along with the presence of sperm head abnormalities and altered epididymal and testicular histology were documented following B(a)P treatment. B(a)P treatment resulted apoptotic sperm cells as observed by TUNEL and Annexin V-PI assay with increased ROS, altered sperm mitochondrial membrane potential (ΔΨm) with a simultaneous decrease in the activity of antioxidant enzymes and GSH status. TUNEL positive apoptotic cells also observed in testis as well as isolated germ and Leydig cells following B(a)P exposure. Western Blot analysis revealed the activation of p38MAPK, cytosolic translocation of cytochrome-c, up-regulation of Bax and inducible nitric oxide synthase (iNOS) with cleavage of PARP and down-regulation of BCl2 in testis upon B(a)P treatment. The protein and mRNA levels of testicular key steroidogenesis regulatory proteins like StAR, cytochrome P450 IIA1 (CYPIIA1), 3β HSD, 17β HSD showed a significant decrease in a dose dependent manner while an increase in the expression of cytochrome P450 1A1 (CYP1A1), Aryl hydrocarbon Receptor (AhR), active caspase- 9 and caspase- 3 following B(a)P exposure. We conclude that exposure of benzo(a)pyrene caused testicular gamatogenic and steroidogenic disorders by induction of oxidative stress, inhibition of StAR and other steroidogenic enzymes along with activation of p38MAPK and initiated caspase-3 mediated germ and Leydig cell apoptosis.The possible protective role of naturally occurring phytochemicals against B(a)P induced testicular toxicity needs immediate consideration. Curcumin and resveratrol separately were found to protect against B(a)P induced germ cell apoptosis, and their combinatorial effect was more significant. Our present study in isolated testicular germ cell population from adult male Wistar rats, highlighted their synergistic protective effect against B(a)P induced germ cell apoptosis. Curcumin-resveratrol co-treatment decreased the expression of pro-apoptotic proteins like cleaved caspase 3,8,9, cleaved PARP, Apaf1, FasL, tBid. Curcumin-resveratrol co-treatment decreased Bax/Bcl2 ratio, mitochondria to cytosolic translocation of cytochrome c and activated the survival protein Akt. Curcumin-resveratrol decreased the expression of p53 dependent apoptotic genes like Fas, FasL, Bax, Bcl2, Apaf1.Curcumin-resveratrol co-treatment thus prevented B(a)P induced germ cell apoptosis. B(a)P induced testicular ROS generation and oxidative stress were significantly ameliorated with curcumin and resveratrol. Curcumin-resveratrol co-treatment prevented B(a)P induced nuclear translocation of AhR and CYP1A1 production. The combinatorial treatment significantly inhibited B(a)P induced ERK 1/2, p38 MAPK and JNK 1/2 activation. B(a)P treatment increased the expression of p53 and its phosphorylation (p53 ser 15). Curcumin-resveratrol co-treatment significantly decreased p53 level and its phosphorylation (p53 ser 15). The study concludes that curcumin-resveratrol synergistically modulated MAPKs and p53, prevented oxidative stress, regulated the expression of pro and anti-apoptotic proteins as well as the proteins involved in B(a)P metabolism thus protected germ cells from B(a)P induced apoptosis.

Keywords: benzo(a)pyrene, germ cell, apoptosis, oxidative stress, resveratrol, curcumin

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Authors: Jia H. Wong, Jingli Zhang, Habsah Mohamad, Iswatun H. Abdullah Ripain, Muhammad Bilal, Amelia J. Lloyd, Abdul A. Mohamed Yusoff, Jafri M. Abdullah

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Epilepsy is one of the most common neurological diseases affecting more than 50 million of people worldwide. Epilepsy is a state of recurrent, spontaneous seizures with multiple syndromes and symptoms of different causes of brain dysfunction, prognosis, and treatments; characterized by transient, occasional and stereotyped interruptions of behavior whereby the excitatory-inhibitory activities within the central nervous system (CNS) are thrown out of balance due to various kinds of interferences. The goal of antiepileptic treatment is to enable patients to be free from seizures or to achieve control of seizures through surgical treatment and/or pharmacotherapy. Pharmacotherapy through AED plays an important role especially in countries with epilepsy treatment gap due to costs and availability of health facilities, skills and resources, yet there are about one-third of the people with epilepsy have drug-resistant seizures. Hence, this poses considerable challenges to the healthcare system and the effort in providing cost-effective treatment as well as the search for alternatives to treatment and management of epilepsy. Enhancement of γ-aminobutyric acid (GABA)-mediated inhibitory neurotransmission is one of the key mechanisms of actions of antiepileptic drugs. GABA type > a receptors (GABAAR) are ligand-gated ion channels that mediate rapid inhibitory neurotransmission upon the binding of GABA with a heteropentameric structure forming a central pore that is permeable to the influx of chloride ions in its activated state. The major isoform of GABAA receptors consists of two α1, two β2, and one γ2 subunit. It is the most abundantly expressed combinations in the brain and the most commonly researched through Xenopus laevis oocytes. With the advancing studies on ethnomedicine and traditional treatments using medicinal plants, increasing evidence reveal that spice and herb plants with medicinal properties play an important role in the treatment of ailments within communities across different cultures. Capsaicin is the primary natural capsaicinoid in hot peppers of plant genus Capsicum, consist of an aromatic ring, an amide linkage and a hydrophobic side chain. The study showed that capsaicins conferred neuroprotection in status epilepticus mouse models through anti-ictogenic, hypothermic, antioxidative, anti-inflammatory, and anti-apoptotic actions in a dose-dependent manner. In this study, five capsaicin derivatives were tested for their ability to increase the GABA-induced chloride current on α1β2γ2S of GABAAR expressed on Xenopus laevis oocytes using the method of two-microelectrode voltage clamp. Two of the capsaicin derivatives, IS5 (N-(4-hydroxy-3-methoxybenzyl)-3-methylbutyramide) and IS10 (N-(4-hydroxy-3-methoxybenzyl)-decanamide) at a concentration of 30µM were able to significantly increase the GABA-induced chloride current with p=0.002 and p=0.026 respectively. This study were able to show the enhancement effect of two capsaicin derivatives with moderate length of hydrocarbon chain on this receptor subtype, revealing the promising inhibitory activity of capsaicin derivatives through enhancement of GABA-induced chloride current and further investigations should be carried out to verify its antiepileptic effects in animal models.

Keywords: α1β2γ2 GABAA receptors, α1β2γ2S, antiepileptic, capsaicin derivatives, two-microelectrode voltage clamp, Xenopus laevis oocytes

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Authors: Yiqi Zhu, Jean Francois Trani, Rameez Ulhassan

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Extreme weather phenomena increased by 46% between 2007 and 2017 and have become more intense with the rise in global average temperatures. This increased intensity of climate variations often induces humanitarian crises and particularly affects vulnerable populations in low- and middle-income countries (LMICs). Expectant and lactating mothers are among the most vulnerable groups. Pakistan ranks 10th among the most affected countries by climate disasters. In 2022, monsoon floods submerged a third of the country, causing the loss of 1,500 lives. Approximately 650,000 expectant and lactating mothers faced systematic stress from climatic disasters. Our study used participatory methods to investigate the systematic impact of climatic disasters on maternal health. In March 2023, we conducted six Group Model Building (GMB) workshops with healthcare workers, fathers, and mothers separately in two of the most affected areas in Pakistan. This study was approved by the Islamic Relief Research Review Board. GMB workshops consist of three sessions. In the first session, participants discussed the factors that impact maternal health. After identifying the factors, they discussed the connections among them and explored the system structures that collectively impact maternal health. Based on the discussion, a causal loop diagram (CLD) was created. Finally, participants discussed action ideas that could improve the system to enhance maternal health. Based on our discussions and the causal loop diagram, we identified interconnected factors at the family, community, and policy levels. Mothers and children are directly impacted by three interrelated factors: food insecurity, unstable housing, and lack of income. These factors create a reinforcing cycle that negatively affects both mothers and newborns. After the flood, many mothers were unable to produce sufficient breastmilk due to their health status. Without breastmilk and sufficient food for complementary feeding, babies tend to get sick in damp and unhygienic environments resulting from temporary or unstable housing. When parents take care of sick children, they miss out on income-generating opportunities. At the community level, the lack of access to clean water and sanitation (WASH) and maternal healthcare further worsens the situation. Structural failures such as a lack of safety nets and programs associated with flood preparedness make families increasingly vulnerable with each disaster. Several families reported that they had not fully recovered from a flood that occurred ten years ago, and this latest disaster destroyed their lives again. Although over twenty non-profit organizations are working in these villages, few of them provide sustainable support. Therefore, participants called for systemic changes in response to the increasing frequency of climate disasters. The study reveals the systematic vulnerabilities of mothers and children after climatic disasters. The most vulnerable populations are often affected the most by climate change. Collaborative efforts are required to improve water and forest management, strengthen public infrastructure, increase access to WASH, and gradually build climate-resilient communities. Governments, non-governmental organizations, and the community should work together to develop and implement effective strategies to prevent, mitigate, and adapt to climate change and its impacts.

Keywords: climatic disasters, maternal health, Pakistan, systematic impact, flood, disaster relief.

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Authors: E Tambo, O. O. Olalubi, E. C. Ugwu, J. Y. Ngogang

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Despite the World Health Organization (WHO) declaration of international health emergency concern, the status quo of responses and efforts to stem the worst-recorded Ebola epidemic Ebola outbreak is still precariously inadequate in most of the affected in West. Mining natural resources have been shown to play a key role in both motivating and fuelling ethnic, civil and armed conflicts that have plagued a number of African countries over the last decade. Revenues from the exploitation of natural resources are not only used in sustaining the national economy but also armies, personal enrichment and building political support. Little is documented on the mining and ecological impact on the emergence and geographical distribution of Ebola in Africa over time and space. We aimed to provide a better understanding of the interconnectedness among issues of mining natural, resource management, mining conflict and post-conflict on Ebola outbreak and how wealth generated from abundant natural resources could be better managed in promoting research and development towards strengthening environmental, socioeconomic and health systems sustainability on Ebola outbreak and other emerging diseases surveillance and responses systems prevention and control, early warning alert, durable peace and sustainable development rather than to fuel conflicts, resurgence and emerging diseases epidemics in the perspective of community and national/regional approach. Our results showed the first assessment of systematic impact of all major minerals conflict events diffusion over space and time and mining activities on nine Ebola genesis and geo-distribution in affected countries across Africa. We demonstrate how, where and when mining activities in Africa increase ecological degradation, conflicts at the local level and then spreads violence across territory and time by enhancing the financial capacities of fighting groups/ethnics and diseases onset. In addition, led process of developing minimum standards for natural resource governance; improving governmental and civil society capacity for natural resource management, including the strengthening of monitoring and enforcement mechanisms; understanding the post-mining and conflicts community or national reconstruction and rehabilitation programmes in strengthening or developing community health systems and regulatory mechanisms. In addition the quest for the control over these resources and illegal mining across the landscape forest incursion provided increase environmental and ecological instability and displacement and disequilibrium, therefore affecting the intensity and duration of mining and conflict/wars and episode of Ebola outbreaks over time and space. We highlight the key findings and lessons learnt in promoting country or community-led process in transforming natural resource wealth from a peace liability to a peace asset. The imperative necessity for advocacy and through facilitating intergovernmental deliberations on critical issues and challenges affecting Africa community transforming exploitation of natural resources from a peace liability to outbreak prevention and control. The vital role of mining in increasing government revenues and expenditures, equitable distribution of wealth and health to all stakeholders, in particular local communities requires coordination, cooperative leadership and partnership in fostering sustainable developmental initiatives from mining context to outbreak and other infectious diseases surveillance responses systems in prevention and control, and judicious resource management.

Keywords: mining, mining conflicts, mines, ecological, Ebola, outbreak, mining companies, miners, impact

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Authors: Ananya Barui, Provas Banerjee, Jyotirmoy Chatterjee

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Application of optical technology in medicine and biology has a long track-record. In this endeavor, OCT is able to attract both engineers and biologists to work together in the field of photonics for establishing a striking non-invasive imaging technology. In contrast to other in vivo imaging modalities like Raman imaging, confocal imaging, two-photon microscopy etc. which can perform in vivo imaging upto 100-200 micron depth due to limitation in numerical aperture or scattering, however, OCT can achieve high-resolution imaging upto few millimeters of tissue structures depending on their refractive index in different anatomical location. This tomographic system depends on interference of two light waves in an interferometer to produce a depth profile of specimen. In wound healing, frequent collection of biopsies for follow-up of repair process could be avoided by such imaging technique. Real time skin OCT (the optical biopsy) has efficacy in deeper and faster illumination of cutaneou tissue to acquire high resolution cross sectional images of their internal micro-structure. Swept Source-OCT (SS-OCT), a novel imaging technique, can generate high-speed depth profile (~ 2 mm) of wound at a sweeping rate of laser with micron level resolution and optimum coherent length of 5-6 mm. Normally multi-layered skin tissue depicts different optical properties along with variation in thickness, refractive index and composition (i.e. keratine layer, water, fat etc.) according to their anatomical location. For instance, stratum corneum, the upper-most and relatively dehydrated layer of epidermis reflects more light and produces more lucid and a sharp demarcation line with rest of the hydrated epidermal region. During wound healing or regeneration, optical properties of cutaneous tissue continuously altered with maturation of wound bed. More mature and less hydrated tissue component reflects more light and becomes visible as a brighter area in comparison to immature region which content higher amount water or fat that depicts as a darker area in OCT image. Non-healing wound possess prolonged inflammation and inhibits nascent proliferative stage. Accumulation of necrotic tissues also prevents the repair of non-healing wounds. Due to high resolution and potentiality to reflect the compositional aspects of tissues in terms of their optical properties, this tomographic method may facilitate in differentiating non-healing and acute wounds in addition to clinical observations. Non-invasive OCT offers better insight regarding specific biological status of tissue in health and pathological conditions, OCT images could be associated with histo-pathological ‘gold standard’. This correlated SS-OCT and microscopic evaluation of the wound edges can provide information regarding progressive healing and maturation of the epithelial components. In the context of searching analogy between two different imaging modalities, their relative performances in imaging of healing bed were estimated for probing an alternative approach. Present study validated utility of SS-OCT in revealing micro-anatomic structure in the healing bed with newer information. Exploring precise correspondence of OCT images features with histo-chemical findings related to epithelial integrity of the regenerated tissue could have great implication. It could establish the ‘optical biopsy’ as a potent non-invasive diagnostic tool for cutaneous pathology.

Keywords: histo-pathology, non invasive imaging, OCT, wound healing

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Authors: Michelle C. S. Azevedo, Priscila M. Colavite, Carolina F. Francisconi, Ana P. Trombone, Gustavo P. Garlet

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VIP (vasoactive intestinal peptide) know as a potential protective factor in the view of its marked immunosuppressive properties. In this work, we investigated a possible association of VIP with the clinical status of experimental periapical granulomas and the association with expression markers in the lesions potentially associated with periapical lesions pathogenesis. C57BL/6WT mice were treated or not with recombinant VIP. Animals with active/progressive (N=40), inactive/stable (N=70) periapical granulomas and controls (N=50) were anesthetized and the right mandibular first molar was surgically opened, allowing exposure of dental pulp. Endodontic pathogenic bacterial strains were inoculated: Porphyromonas gingivalis, Prevotella nigrescens, Actinomyces viscosus, and Fusobacterium nucleatum subsp. polymorphum. The cavity was not sealed after bacterial inoculation. During lesion development, animals were treated or not with recombinant VIP 3 days post infection. Animals were killed after 3, 7, 14, and 21 days of infection and the jaws were dissected. The extraction of total RNA from periodontal tissues was performed and the integrity of samples was checked. qPCR reaction using TaqMan chemistry with inventoried primers were performed in ViiA7 equipment. The results, depicted as the relative levels of gene expression, were calculated in reference to GAPDH and β-actin expression. Periodontal tissues from upper molars were vested and incubated supplemented RPMI, followed by processing with 0.05% DNase. Cell viability and couting were determined by Neubauer chamber analysis. For flow cytometry analysis, after cell counting the cells were stained with the optimal dilution of each antibody; (PE)-conjugated and (FITC)-conjugated antibodies against CD4, CD25, FOXP3, IL-4, IL-17 and IFN-γ antibodies, as well their respective isotype controls. Cells were analyzed by FACScan and CellQuest software. Results are presented as the number of cells in the periodontal tissues or the number of positive cells for each marker in the CD4+FOXp3+, CD4+IL-4+, CD4+IFNg+ and CD4+IL-17+ subpopulations. The levels mRNA were measured by qPCR. The VIP expression was predominated in inactive lesions, as well part of the clusters of cytokine/Th markers identified as protective factors and a negative correlation between VIP expression and lesion evolution was observed. A quantitative analysis of IL1β, IL17, TNF, IFN, MMP2, RANKL, OPG, IL10, TGFβ, CTLA4, COL5A1, CTGF, CXCL11, FGF7, ITGA4, ITGA5, SERP1 and VTN expression was measured in experimental periapical lesions treated with VIP 7 and 14 days after lesion induction and healthy animals. After 7 days, all targets presented a significate increase in comparison to untreated animals. About migration kinetics, profile of chemokine receptors expression of TCD4+ subsets and phenotypic analysis of Tregs, Th1, Th2 and Th17 cells during the course of experimental periodontal disease evaluated by flow cytometry and depicted as the number of positive cells for each marker. CD4+IFNg+ and CD4+FOXp3+ cells migration were significate increased 7 days post VIP treatment. CD4+IL17+ cells migration were significate increased 7 and 14 days post VIP treatment, CD4+IL4+ cells migration were significate increased 14 and 21 days post VIP treatment compared to the control group. In conclusion, our experimental data support VIP involvement in determining the inactivity of periapical lesions. Financial support: FAPESP #2015/25618-2.

Keywords: chronic inflammation, cytokines, osteolytic lesions, VIP (Vasoactive Intestinal Peptide)

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Authors: Kuladip Jana, Bhaswati Banerjee, Parimal C. Sen

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Benzo(a)pyrene [B(a)P] is an environmental toxicant present mostly in cigarette smoke and car exhaust, is an aryl hydrocarbon receptor (AhR) ligand that exerts its toxic effects on both male and female reproductive systems along with carcinogenesis in skin, prostate, ovary, lung and mammary glands. Our study was focused on elucidating the molecular mechanism of B(a)P induced male reproductive toxicity and its prevention with phytochemical like resveratrol. In this study, the effect of B(a)P at different doses (0.1, 0.25, 0.5, 1 and 5 mg /kg body weight) was studied on male reproductive system of Wistar rat. A significant decrease in cauda epididymal sperm count and motility along with the presence of sperm head abnormalities and altered epididymal and testicular histology were documented following B(a)P treatment. B(a)P treatment resulted apoptotic sperm cells as observed by TUNEL and Annexin V-PI assay with increased Reactive Oxygen Species (ROS), altered sperm mitochondrial membrane potential (ΔΨm) with a simultaneous decrease in the activity of antioxidant enzymes and GSH status. TUNEL positive apoptotic cells also observed in testis as well as isolated germ and Leydig cells following B(a)P exposure. Western Blot analysis revealed the activation of p38 mitogen activated protein kinase (p38MAPK), cytosolic translocation of cytochrome-c, upregulation of Bax and inducible nitric oxide synthase (iNOS) with cleavage of poly ADP ribose polymerase (PARP) and down regulation of BCl2 in testis upon B(a)P treatment. The protein and mRNA levels of testicular key steroidogenesis regulatory proteins like steroidogenic acute regulatory protein (StAR), cytochrome P450 IIA1 (CYPIIA1), 3β hydroxy steroid dehydrogenase (3β HSD), 17β hydroxy steroid dehydrogenase (17β HSD) showed a significant decrease in a dose dependent manner while an increase in the expression of cytochrome P450 1A1 (CYP1A1), Aryl hydrocarbon Receptor (AhR), active caspase- 9 and caspase- 3 following B(a)P exposure. We conclude that exposure of benzo(a)pyrene caused testicular gamatogenic and steroidogenic disorders by induction of oxidative stress, inhibition of StAR and other steroidogenic enzymes along with activation of p38MAPK and initiated caspase-3 mediated germ and Leydig cell apoptosis. Next we investigated the role of resveratrol on B(a)P induced male reproductive toxicity. Our study highlighted that resveratrol co-treatment with B(a)P maintained testicular redox potential, increased serum testosterone level and prevented steroidogenic dysfunction with enhanced expression of major testicular steroidogenic proteins (CYPIIA1, StAR, 3β HSD,17β HSD) relative to treatment with B(a)P only. Resveratrol suppressed B(a)P-induced testicular activation of p38 MAPK, ATF2, iNOS and ROS production; cytosolic translocation of Cytochome c and Caspase 3 activation thereby prevented oxidative stress of testis and inhibited apoptosis. Resveratrol co-treatment also decreased B(a)P-induced AhR protein level, its nuclear translocation and subsequent CYP1A1 promoter activation, thereby decreased protein and mRNA levels of testicular cytochrome P4501A1 (CYP1A1) and prevented BPDE-DNA adduct formation. Our findings cumulatively suggest that resveratrol prevents activation of B(a)P by modulating the transcriptional regulation of CYP1A1 and acting as an antioxidant thus prevents B(a)P-induced oxidative stress and testicular apoptosis.

Keywords: benzo(a)pyrene, resveratrol, testis, apoptosis, cytochrome P450 1A1 (CYP1A1), aryl hydrocarbon receptor (AhR), p38 MAPK/ATF2/iNOS

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Authors: Sopio Totibadze

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Although the legal framework of Georgia reflects the main principles of gender equality and is in line with the international situation (UNDP, 2018), Georgia remains a male-dominated society. This means that men prevail in many areas of social, economic, and political life, which frequently gives women a subordinate status in society and the family (UN women). According to the latest study, “violence against women and girls in Georgia is also recognized as a public problem, and it is necessary to focus on it” (UN women). Moreover, the Public Defender's report on the protection of human rights in Georgia (2019) reveals that “in the last five years, 151 women were killed in Georgia due to gender and family violence”. Sadly, these statistics have increased significantly since that time. The issue was acutely reflected in the document published by the Organization for Security and Cooperation in Europe, “Gender Hate Crime” (March 10, 2021). “Unfortunately, the rates of femicide ..... are still high in the country, and distrust of law enforcement agencies often makes such cases invisible, which requires special attention from the state.” More precisely, the cited document considers that there are frequent cases of crimes based on gender-based oppression in Georgia, which pose a threat not only to women but also to people of any gender whose desires and aspirations do not correspond to the gender norms and roles prevailing in society. According to the study, this type of crime has a “significant and lasting impact on the victim(s) and also undermines the safety and cohesion of society and gender equality”. It is well-known that language is often used as a tool for gender oppression (Rusieshvili-Cartledge and Dolidze, 2021; Totibadze, 2021). Therefore, feminist and gender studies in linguistics ultimately serve to represent the problem, reflect on it, and propose ways to solve it. Together with technical advancement in communication, a new form of discrimination has arisen- hate language against women in electronic media discourse. Due to the nature of social media and the internet, messages containing hate language can spread in seconds and reach millions of people. However, only a few know about the detrimental effects they may have on the addressee and society. This paper aims to analyse the hateful comments directed at women on various media platforms to determine (1) the linguistic strategies used while attacking women and (2) the reasons why women may fall victim to this type of hate language. The data have been collected over six months, and overall, 500 comments will be examined for the paper. Qualitative and quantitative analysis was chosen for the methodology of the study. The comments posted on various media platforms, including social media posts, articles, or pictures, have been selected manually due to several reasons, the most important being the problem of identifying hate speech as it can disguise itself in different ways- humour, memes, etc. The comments on the articles, posts, pictures, and videos selected for sociolinguistic analysis depict a woman, a taboo topic, or a scandalous event centred on a woman that triggered a lot of hatred and hate language towards the person to whom the post/article was dedicated. The study has revealed that a woman can become a victim of hatred directed at them if they do something considered to be a deviation from a societal norm, namely, get a divorce, be sexually active, be vocal about feministic values, and talk about taboos. Interestingly, people who utilize hate language are not only men trying to “normalize” the prejudiced patriarchal values but also women who are equally active in bringing down a "strong" woman. The paper also aims to raise awareness about the hate language directed at women, as being knowledgeable about the issue at hand is the first step to tackling it.

Keywords: femicide, hate language, media discourse, sociolinguistics

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Authors: Xue Bai, Ranran He, Chang Liu

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Care planning before the onset of intensive care needs can benefit older adults’ psychological well-being and increases families’ ability to manage caregiving crises and cope with care transitions. Effective care planning requires collaborative ‘team-work’ in families. However, future care planning has not been substantially examined in intergenerational or family contexts, let alone among immigrant families who have to face particular challenges in parental caregiving. From a family systems perspective, this study intends to explore the extent, processes, and contents of intergenerational care planning of Mainland immigrant ageing families in Hong Kong and to examine the intergenerational congruence and discrepancies in the care planning process. Adopting a qualitative research design, semi-structured in-depth interviews were conducted with 17 adult child-older parent pairs and another 33 adult children. In total, 50 adult children who migrated to Hong Kong after the age of 18 with more than three years’ work experience in Hong Kong had at least one parent aged over 55 years old who was not a Hong Kong resident and considered his/herself as the primary caregiver of the parent were recruited. Seventeen ageing parents of the recruited adult children were invited for dyadic interviews. Scarcity of caregiving resources in the context of cross-border migration, intergenerational discrepancies in care planning stages, both generations’ struggle and ambivalence toward filial care, intergenerational transmission of care values, and facilitating role of accumulated family capital in care preparation were primary themes concluded from participants’ narratives. Compared with ageing parents, immigrant adult children generally displayed lower levels of care planning. Although with a strong awareness of parents’ future care needs, few adult children were found engaged in concrete planning activities. This is largely due to their uncertainties toward future life and career, huge work and living pressure, the relatively good health status of their parents, and restrictions of public welfare policies in the receiving society. By contrast, children’s cross-border migration encouraged ageing parents to have early and clear preparation for future care. Ageing parents mostly expressed low filial care expectations when realizing the scarcity of family caregiving resources in the cross-border context. Even though they prefer in-person support from children, most of them prepare themselves for independent ageing to prioritize the next generation’s needs or choose to utilize paid services, welfare systems, friend networks, or extended family networks in their sending society. Adult children were frequently found caught in the dilemma of desiring to provide high quality and in-person support for their parents but lacking sufficient resources. Notably, a salient pattern of intergenerational transmission in terms of family and care values and ideal care arrangement emerged from intergenerational care preparation. Moreover, the positive role of accumulated family capital generated by a reunion in care preparation and joint decision-making were also identified. The findings of the current study will enhance professionals’ and service providers’ awareness of intergenerational care planning in cross-border migration contexts, inform services to alleviate unpreparedness for elderly care and intergenerational discrepancies concerning care arrangements and broaden family services to encompass intergenerational care planning interventions. Acknowledgment: This study is supported by a General Research Grant from the Research Grants Council of the HKSAR, China (Project Number: 15603818).

Keywords: intergenerational care planning, mainland immigrants in Hong Kong, migrant family, older adults

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Authors: Cory B. Portner, Julie A. Grauert, Lisa M. Stromme, Shelby D. Anderson, Franji H. Mayes

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Introduction: WASHINGTON state in the Pacific Northwest of the United States is internationally known for its technology industry, fisheries, agriculture, and vistas. On January 21, 2020, Washington state also became known as the first state with a confirmed COVID-19 case in the United States, thrusting the state into the international spotlight as the world came to grips with the global threat of this disease presented. Tourism is Washington state’s fourth-largest industry. Tourism to the state generates over 1.8 billion dollars (USD) in local and state tax revenue and employs over 180,000 people. Communicating with residents, stakeholders, and visitors on the status of disease activity, prevention measures, and response updates was vital to stopping the pandemic and increasing compliance and awareness. Significance: In order to communicate vital public health updates, guidance implementation, and safety measures to the public, the Washington State Department of Health established routine live virtual media briefings to reach audiences via social media, internet television, and broadcast television. Through close partnership with regional broadcast news stations and the state public affairs news network, the Washington State Department of Health hosted 95 media briefings from January 2020 through September 2022 and continues to regularly host live virtual media briefings to accommodate the needs of the public and media. Methods: Our methods quickly evolved from hosting briefings in the cement closet of a military base to being able to produce and stream the briefings live from any home-office location. The content was tailored to the hot topic of the day and to the reporter's questions and needs. Virtual media briefings hosted through inexpensive or free platforms online are extremely cost-effective: the only mandatory components are WiFi, a laptop, and a monitor. There is no longer a need for a fancy studio or expensive production software to achieve the goal of communicating credible, reliable information promptly. With minimal investment and a small learning curve, facilitators and panelists are able to host highly produced and engaging media availabilities from their living rooms. Results: The briefings quickly developed a reputation as the best source for local and national journalists to get the latest and most factually accurate information about the pandemic. In the height of the COVID-19 response, 135 unique media outlets logged on to participate in the briefing. The briefings typically featured 4-5 panelists, with as many as 9 experts in attendance to provide information and respond to media questions. Preparation was always a priority: Public Affairs staff for the Washington State Department of Health produced over 170 presenter remarks, including guidance on talking points for 63 expert guest panelists. Implication For Practice: Information is today’s most valuable currency. The ability to disseminate correct information urgently and on a wide scale is the most effective tool in crisis communication. Due to our role as the first state with a confirmed COVID-19 case, we were forced to develop the most accurate and effective way to get life-saving information to the public. The cost-effective, web-based methods we developed can be applied in any crisis to educate and protect communities under threat, ultimately saving lives from a laptop.

Keywords: crisis communications, public relations, media management, news media

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Authors: Isabelle Barrett

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Natural watercourses provide a range of vital ecosystem services, notably freshwater provision. They also offer highly heterogeneous habitat which supports an extreme diversity of aquatic life. Exploitation of rivers, changing land use and flood prevention measures have led to habitat degradation and subsequent biodiversity loss; indeed, freshwater species currently face a disproportionate rate of extinction compared to their terrestrial and marine counterparts. Large woody debris (LWD) encompasses the trees, large branches and logs which fall into watercourses, and is responsible for important habitat characteristics. Historically, natural LWD has been removed from streams under the assumption that it is not aesthetically pleasing and is thus ecologically unfavourable, despite extensive evidence contradicting this. Restoration efforts aim to replace lost LWD in order to reinstate habitat heterogeneity. This paper aims to assess the current state of such restoration schemes for improving fluvial ecological health in the UK. A detailed review of the scientific literature was conducted alongside a meta-analysis of 25 UK-based projects involving LWD restoration. Projects were chosen for which sufficient information was attainable for analysis, covering a broad range of budgets and scales. The most effective strategies for river restoration encompass ecological success, stakeholder engagement and scientific advancement, however few projects surveyed showed sensitivity to all three; for example, only 32% of projects stated biological aims. Focus tended to be on stakeholder engagement and public approval, since this is often a key funding driver. Consequently, there is a tendency to focus on the aesthetic outcomes of a project, however physical habitat restoration does not necessarily lead to direct biodiversity increases. This highlights the significance of rivers as highly heterogeneous environments with multiple interlinked processes, and emphasises a need for a stronger scientific presence in project planning. Poor scientific rigour means monitoring is often lacking, with varying, if any, definitions of success which are rarely pre-determined. A tendency to overlook negative or neutral results was apparent, with unjustified focus often put on qualitative results. The temporal scale of monitoring is typically inadequate to facilitate scientific conclusions, with only 20% of projects surveyed reporting any pre-restoration monitoring. Furthermore, monitoring is often limited to a few variables, with biotic monitoring often fish-focussed. Due to their longer life cycles and dispersal capability, fish are usually poor indicators of environmental change, making it difficult to attribute any changes in ecological health to restoration efforts. Although the potential impact of LWD restoration may be positive, this method of restoration could simply be making short-term, small-scale improvements; without addressing the underlying symptoms of degradation, for example water quality, the issue cannot be fully resolved. Promotion of standardised monitoring for LWD projects could help establish a deeper understanding of the ecology surrounding the practice, supporting movement towards adaptive management in which scientific evidence feeds back to practitioners, enabling the design of more efficient projects with greater ecological success. By highlighting LWD, this study hopes to address the difficulties faced within river management, and emphasise the need for a more holistic international and inter-institutional approach to tackling problems associated with degradation.

Keywords: biological monitoring, ecological health, large woody debris, river management, river restoration

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Authors: Alexandria Carey, Angela Starkweather, Ann Horgas, Hwayoung Cho, Jason Beneciuk

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Background/Significance: Over 3.4 million acute axial low back pain (aLBP) cases are treated annually in the United States (US) emergency departments (ED). ED patients with aLBP receive varying verbal and written discharge routine care (RC), leading to ineffective patient self-management. Ineffective self-management increase chronic low back pain (cLPB) transition risks, a chief cause of worldwide disability, with associated costs >$60 million annually. This research addresses this significant problem by evaluating an ED digital pain self-management intervention (EDPSI) focused on improving self-management through improved knowledge retainment, skills, and self-efficacy (confidence) (KSC) thus reducing aLBP to cLBP transition in ED patients discharged with aLBP. The research has significant potential to increase self-efficacy, one of the most potent mechanisms of behavior change and improve health outcomes. Focusing on accessibility and usability, the intervention may reduce discharge disparities in aLBP self-management, especially with low health literacy. Study Questions: This research will answer the following questions: 1) Will an EDPSI focused on improving KSC progress patient self-management behaviors and health status?; 2) Is the EDPSI sustainable to improve pain severity, interference, and pain recurrence?; 3) Will an EDPSI reduce aLBP to cLBP transition in patients discharged with aLBP? Aims: The pilot randomized-controlled trial (RCT) study’s objectives assess the effects of a 12-week digital self-management discharge tool in patients with aLBP. We aim to 1) Primarily assess the feasibility [recruitment, enrollment, and retention], and [intervention] acceptability, and sustainability of EDPSI on participant’s pain self-management; 2) Determine the effectiveness and sustainability of EDPSI on pain severity/interference among participants. 3) Explore patient preferences, health literacy, and changes among participants experiencing the transition to cLBP. We anticipate that EDPSI intervention will increase likelihood of achieving self-management milestones and significantly improve pain-related symptoms in aLBP. Methods: The study uses a two-group pilot RCT to enroll 30 individuals who have been seen in the ED with aLBP. Participants are randomized into RC (n=15) or RC + EDPSI (n=15) and receive follow-up surveys for 12-weeks post-intervention. EDPSI innovative content focuses on 1) highlighting discharge education; 2) provides self-management treatment options; 3) actor demonstration of ergonomics, range of motion movements, safety, and sleep; 4) complementary alternative medicine (CAM) options including acupuncture, yoga, and Pilates; 5) combination therapies including thermal application, spinal manipulation, and PT treatments. The intervention group receives Booster sessions via Zoom to assess and reinforce their knowledge retention of techniques and provide return demonstration reinforcing ergonomics, in weeks two and eight. Outcome Measures: All participants are followed for 12-weeks, assessing pain severity/ interference using the Brief Pain Inventory short-form (BPI-sf) survey, self-management (measuring KSC) using the short 13-item Patient Activation Measure (PAM), and self-efficacy using the Pain Self-Efficacy Questionnaire (PSEQ) weeks 1, 6, and 12. Feasibility is measured by recruitment, enrollment, and retention percentages. Acceptability and education satisfaction are measured using the Education-Preference and Satisfaction Questionnaire (EPSQ) post-intervention. Self-management sustainment is measured including PSEQ, PAM, and patient satisfaction and healthcare utilization (PSHU) requesting patient overall satisfaction, additional healthcare utilization, and pain management related to continued back pain or complications post-injury.

Keywords: digital, pain self-management, education, tool

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Authors: Aastha Arora, Vikas Bhuria, Saurabh Singh, Uma Pathak, Shweta Mathur, Puja P. Hazari, Rajat Sandhir, Ravi Soni, Anant N. Bhatt, Bilikere S. Dwarakanath

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Radiotherapy is an effective curative and palliative option for patients with thoracic malignancies. However, lung injury, comprising of pneumonitis and fibrosis, remains a significant clin¬ical complication of thoracic radiation, thus making it a dose-limiting factor. Also, injury to the lung is often reported as part of multi-organ failure in victims of accidental radiation exposures. Radiation induced inflammatory response in the lung, characterized by leukocyte infiltration and vascular changes, is an important contributing factor for the injury. Therefore, countermeasure agents to attenuate radiation induced inflammatory response are considered as an important approach to prevent chronic lung damage. Although Amifostine, the widely used, FDA approved radio-protector, has been found to reduce the radiation induced pneumonitis during radiation therapy of non-small cell lung carcinoma, its application during mass and field exposure is limited due to associated toxicity and ineffectiveness with the oral administration. The amifostine analogue (DRDE-30) overcomes this limitation as it is orally effective in reducing the mortality of whole body irradiated mice. The current study was undertaken to investigate the potential of DRDE-30 to ameliorate radiation induced lung damage. DRDE-30 was administered intra-peritoneally, 30 minutes prior to 13.5 Gy thoracic (60Co-gamma) radiation in C57BL/6 mice. Broncheo- alveolar lavage fluid (BALF) and lung tissues were harvested at 12 and 24 weeks post irradiation for studying inflammatory and fibrotic markers. Lactate dehydrogenase (LDH) leakage, leukocyte count and protein content in BALF were used as parameters to evaluate lung vascular permeability. Inflammatory cell signaling (p38 phosphorylation) and anti-oxidant status (MnSOD and Catalase level) was assessed by Western blot, while X-ray CT scan, H & E staining and trichrome staining were done to study the lung architecture and collagen deposition. Irradiation of the lung increased the total protein content, LDH leakage and total leukocyte count in the BALF, reflecting endothelial barrier dysfunction. These disruptive effects were significantly abolished by DRDE-30, which appear to be linked to the DRDE-30 mediated abrogation of activation of the redox-sensitive pro- inflammatory signaling cascade, the MAPK pathway. Concurrent administration of DRDE-30 with radiation inhibited radiation-induced oxidative stress by strengthening the anti-oxidant defense system and abrogated p38 mitogen-activated protein kinase activation, which was associated with reduced vascular leak and macrophage recruitment to the lungs. Histopathological examination (by H & E staining) of the lung showed radiation-induced inflammation of the lungs, characterized by cellular infiltration, interstitial oedema, alveolar wall thickening, perivascular fibrosis and obstruction of alveolar spaces, which were all reduced by pre-administration of DRDE-30. Structural analysis with X-ray CT indicated lung architecture (linked to the degree of opacity) comparable to un-irradiated mice that correlated well with the lung morphology and reduced collagen deposition. Reduction in the radiation-induced inflammation and fibrosis brought about by DRDE-30 resulted in a profound increase in animal survival (72 % in the combination vs 24% with radiation) observed at the end of 24 weeks following irradiation. These findings establish the potential of the Amifostine analogue, DRDE-30, in reducing radiation induced pulmonary injury by attenuating the inflammatory and fibrotic responses.

Keywords: amifostine, fibrosis, inflammation, lung injury radiation

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Authors: Ghidey Ghebreyohanes, Eltahir Awad Gasim Khalil, Zemenfes Tsighe, Faiza Ali

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Background: reproductive health (RH) is a state of physical, mental and social well-being in all matters relating to the reproductive system at all stages of life. In East Africa including Eritrea, adolescents comprise more than a quarter of the population. The region holds the highest rates of sexually transmitted diseases, HIV, unwanted pregnancy and unsafe abortion with its complications. Young girls carry the highest burden of reproductive health problems due to their risk taking behavior, lack of knowledge, peer pressure, physiologic immaturity and low socioeconomic status. Design: this was a Community-based, randomized, case-controlled and pre-test-post-test intervention study. Setting: Zoba Debub was randomly selected out of the six zobas in Eritrea. The four high schools out of the 26 in Zoba Debub were randomly selected as study target schools. Over three quarter of the people live on farming. The target population was female students attending grade nine with majority of these girls live in the distant villages and walk to school. The study participants were randomly selected (n=165) from each school. Furthermore, the 1 intervention and 3 controls for the study arms were assigned randomly. Objectives: this study aimed to assess the effectiveness of peer reproductive health education in improving knowledge, attitude, and health service use of high school adolescent girls in Eritrea Methods: the protocol was reviewed and approved by the Scientific and Ethics Committees of Faculty of Nursing Sciences, University of Khartoum. Data was collected using pre-designed and pretested questionnaire emphasizing on reproductive health knowledge, attitude and practice. Sample size was calculated using proportion formula (α 0.01; power of 95%). Measures used were scores and proportions. Descriptive and inferential statistics, t-test and chi square at (α .01), 99% confidence interval were used to compare changes of pre and post-intervention scores using SPSS soft ware. Seventeen students were selected for peer educators by the school principals and other teachers based on inclusion criteria that include: good academic performance and acceptable behavior. One peer educator educated one group composed of 8-10 students for two months. One faculty member was selected to supervise peer educators. The principal investigator conducted the training of trainers and provided supervision and discussion to peer educators every two weeks until the end of intervention. Results: following informed consent, 627 students [164 in intervention and 463 in the control group] with a ratio of 1 to 3, were enrolled in the study. The mean age for the total study population was 15.4±1.0 years. The intervention group mean age was 15.3±1.0 year; while the control group had a mean age of 15.4±1.0. The mean ages for the study arms were similar (p= 0.4). The majority (96 %) of the study participants are from Tigrigna ethnic group. Reproductive knowledge scores which was calculated out of a total 61 grade points: intervention group (pretest 6.7 %, post-test 33.6 %; p= 0.0001); control group (pretest 7.3 %, posttest 7.3 %, p= 0.92). Proportion difference in attitude calculated out of 100%: intervention group (pretest 42.3 % post test 54.7% p= 0.001); controls group (pretest 45%, post test 44.8 p= 0.7). Proportion difference in Practice calculated out of 100 %: intervention group (pretest 15.4%, post test 80.4 % p= 0.0001); control group (pretest 16.8%, posttest 16.9 % p= 0.8). Mothers were quoted as major (> 90 %) source of reproductive health information. All focus group discussants and most of survey participants agreed on the urgent need of reproductive health information and services for adolescent girls. Conclusion: reproductive health knowledge and use of facilities is poor among adolescent girls in sub-urban Eretria. School-based peer reproductive health education is effective and is the best strategy to improve reproductive health knowledge and attitudes.

Keywords: reproductive health, adolescent girls, eretria, health education

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Authors: Mohamed Sameer Mughal, Andrew D. Ross, Damian J. Fearon

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Background: The fast-paced changing landscape of UK Higher Education Institution (HEIs) is poised by changes and challenges affecting Middle Managers (MM) in their job roles. MM contribute to the success of HEIs by balancing the equilibrium and pass organization strategies from senior staff towards operationalization directives to junior staff. However, this study showcased from the data analyzed during the semi structured interviews; MM job role is becoming more complex due to changes and challenges creating colossal pressures and workloads in day-to-day working. Current development programmes provisions by Human Resources (HR) departments in such HEIs are not feasible, applicable, and matching the true essence and requirements of MM who suggest that programmes offered by HR are too generic to suit their precise needs and require tailor made espousal to work effectively in their pertinent job roles. Methodologies: This study aims to capture demands of MM Development Needs (DN) by means of a conceptual model as conclusive part of the research that is divided into 2 phases. Phase 1 initiated by carrying out 2 pilot interviews with a retired Emeritus status professor and HR programmes development coordinator. Key themes from the pilot and literature review subsidized into formulation of 22 set of questions (Kvale and Brinkmann) in form of interviewing questionnaire during qualitative data collection. Data strategy and collection consisted of purposeful sampling of 12 semi structured interviews (n=12) lasting approximately an hour for all participants. The MM interviewed were at faculty and departmental levels which included; deans (n=2), head of departments (n=4), subject leaders (n=2), and lastly programme leaders (n=4). Participants recruitment was carried out via emails and snowballing technique. The interviews data was transcribed (verbatim) and managed using Computer Assisted Qualitative Data Analysis using Nvivo ver.11 software. Data was meticulously analyzed using Miles and Huberman inductive approach of positivistic style grounded theory, whereby key themes and categories emerged from the rich data collected. The data was precisely coded and classified into case studies (Robert Yin); with a main case study, sub cases (4 classes of MM) and embedded cases (12 individual MMs). Major Findings: An interim conceptual model emerged from analyzing the data with main concepts that included; key performance indicators (KPI’s), HEI effectiveness and outlook, practices, processes and procedures, support mechanisms, student events, rules, regulations and policies, career progression, reporting/accountability, changes and challenges, and lastly skills and attributes. Conclusion: Dynamic elements affecting MM includes; increase in government pressures, student numbers, irrelevant development programmes, bureaucratic structures, transparency and accountability, organization policies, skills sets… can only be confronted by employing structured development programmes originated by HR that are not provided generically. Future Work: Stage 2 (Quantitative method) of the study plans to validate the interim conceptual model externally through fully completed online survey questionnaire (Bram Oppenheim) from external HEIs (n=150). The total sample targeted is 1500 MM. Author contribution focuses on enhancing management theory and narrow the gap between by HR and MM development programme provision.

Keywords: development needs (DN), higher education institutions (HEIs), human resources (HR), middle managers (MM)

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Authors: P. C. Kutschera, Elena C. Tesoro, Mary Grace Talamera-Sandico, Jose Maria G. Pelayo III

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Second generation military Filipino Amerasians comprise a formidable contemporary segment of the estimated 250,000-plus biracial Amerasians in the Philippines today. Overall, they are a stigmatized and socioeconomically marginalized diaspora, historically; they were abandoned or estranged by U.S. military personnel fathers assigned during the century-long Colonial, Post-World War II and Cold War Era of permanent military basing (1898-1992). Indeed, U.S. military personnel remain stationed in smaller numbers in the Philippines today. This inquiry is an outgrowth of two recent small sample studies. The first surfaced the impact of the U.S. military prostitution system on formation of the ‘Derivative Amerasian Family Construct’ on first generation Amerasians; a second, qualitative case study suggested the continued effect of the prostitution systems' destructive impetuous on second generation Amerasians. The intent of this current qualitative, multiple-case study was to actively seek out second generation sex industry toilers. The purpose was to focus further on this human phenomenon in the post-basing and post-military prostitution system eras. As background, the former military prostitution apparatus has transformed into a modern dynamic of rampant sex tourism and prostitution nationwide. This is characterized by hotel and resorts offering unrestricted carnal access, urban and provincial brothels (casas), discos, bars and pickup clubs, massage parlors, local barrio karaoke bars and street prostitution. A small case study sample (N = 4) of female and male second generation Amerasians were selected. Sample formation employed a non-probability ‘snowball’ technique drawing respondents from the notorious Angeles, Metro Manila, Olongapo City ‘AMO Amerasian Triangle’ where most former U.S. military installations were sited and modern sex tourism thrives. A six-month study and analysis of in-depth interviews of female and male sex laborers, their families and peers revealed a litany of disturbing, and troublesome experiences. Results showed profiles of debilitating human poverty, history of family disorganization, stigmatization, social marginalization and the ghost of the military prostitution system and its harmful legacy on Amerasian family units. Emerging were testimonials of wayward young people ensnared in a maelstrom of deep economic deprivation, familial dysfunction, psychological desperation and societal indifference. The paper recommends that more study is needed and implications of unstudied psychosocial and socioeconomic experiences of distressed younger generations of military Amerasians require specific research. Heretofore apathetic or disengaged U.S. institutions need to confront the issue and formulate activist and solution-oriented social welfare, human services and immigration easement policies and alternatives. These institutions specifically include academic and social science research agencies, corporate foundations, the U.S. Congress, and Departments of State, Defense and Health and Human Services, and Homeland Security (i.e. Citizen and Immigration Services) It is them who continue to endorse a laissez-faire policy of non-involvement over the entire Filipino Amerasian question. Such apathy, the paper concludes, relegates this consequential but neglected blood progeny to the status of humiliating destitution and exploitation. Amerasians; thus, remain entrapped in their former colonial, and neo-colonial habitat. Ironically, they are unwitting victims of a U.S. American homeland that fancies itself geo-politically as a strong and strategic military treaty ally of the Philippines in the Western Pacific.

Keywords: Asian Americans, diaspora, Filipino Amerasians, military prostitution, stigmatization

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Authors: Claire Harrison, Raajit K. Rampal, Vikas Gupta, Srdan Verstovsek, Moshe Talpaz, Jean-Jacques Kiladjian, Ruben Mesa, Andrew Kuykendall, Alessandro Vannucchi, Francesca Palandri, Sebastian Grosicki, Timothy Devos, Eric Jourdan, Marielle J. Wondergem, Haifa Kathrin Al-Ali, Veronika Buxhofer-Ausch, Alberto Alvarez-Larrán, Sanjay Akhani, Rafael Muñoz-Carerras, Yury Sheykin, Gozde Colak, Morgan Harris, John Mascarenhas

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Myelofibrosis (MF) is characterized by bone marrow fibrosis, anemia, splenomegaly and constitutional symptoms. Progressive bone marrow fibrosis results from aberrant megakaryopoeisis and expression of proinflammatory cytokines, both of which are heavily influenced by bromodomain and extraterminal domain (BET)-mediated gene regulation and lead to myeloproliferation and cytopenias. Pelabresib (CPI-0610) is an oral small-molecule investigational inhibitor of BET protein bromodomains currently being developed for the treatment of patients with MF. It is designed to downregulate BET target genes and modify nuclear factor kappa B (NF-κB) signaling. MANIFEST-2 was initiated based on data from Arm 3 of the ongoing Phase 2 MANIFEST study (NCT02158858), which is evaluating the combination of pelabresib and ruxolitinib in Janus kinase inhibitor (JAKi) treatment-naïve patients with MF. Primary endpoint analyses showed splenic and symptom responses in 68% and 56% of 84 enrolled patients, respectively. MANIFEST-2 (NCT04603495) is a global, Phase 3, randomized, double-blind, active-control study of pelabresib and ruxolitinib versus placebo and ruxolitinib in JAKi treatment-naïve patients with primary MF, post-polycythemia vera MF or post-essential thrombocythemia MF. The aim of this study is to evaluate the efficacy and safety of pelabresib in combination with ruxolitinib. Here we report updates from a recent protocol amendment. The MANIFEST-2 study schema is shown in Figure 1. Key eligibility criteria include a Dynamic International Prognostic Scoring System (DIPSS) score of Intermediate-1 or higher, platelet count ≥100 × 10^9/L, spleen volume ≥450 cc by computerized tomography or magnetic resonance imaging, ≥2 symptoms with an average score ≥3 or a Total Symptom Score (TSS) of ≥10 using the Myelofibrosis Symptom Assessment Form v4.0, peripheral blast count <5% and Eastern Cooperative Oncology Group performance status ≤2. Patient randomization will be stratified by DIPSS risk category (Intermediate-1 vs Intermediate-2 vs High), platelet count (>200 × 10^9/L vs 100–200 × 10^9/L) and spleen volume (≥1800 cm^3 vs <1800 cm^3). Double-blind treatment (pelabresib or matching placebo) will be administered once daily for 14 consecutive days, followed by a 7 day break, which is considered one cycle of treatment. Ruxolitinib will be administered twice daily for all 21 days of the cycle. The primary endpoint is SVR35 response (≥35% reduction in spleen volume from baseline) at Week 24, and the key secondary endpoint is TSS50 response (≥50% reduction in TSS from baseline) at Week 24. Other secondary endpoints include safety, pharmacokinetics, changes in bone marrow fibrosis, duration of SVR35 response, duration of TSS50 response, progression-free survival, overall survival, conversion from transfusion dependence to independence and rate of red blood cell transfusion for the first 24 weeks. Study recruitment is ongoing; 400 patients (200 per arm) from North America, Europe, Asia and Australia will be enrolled. The study opened for enrollment in November 2020. MANIFEST-2 was initiated based on data from the ongoing Phase 2 MANIFEST study with the aim of assessing the efficacy and safety of pelabresib and ruxolitinib in JAKi treatment-naïve patients with MF. MANIFEST-2 is currently open for enrollment.

Keywords: CPI-0610, JAKi treatment-naïve, MANIFEST-2, myelofibrosis, pelabresib

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