#Health and science reporting

[religion-is-a-mental-illness]

By: Jesse Singal

Published: Jun 27, 2024

In April Hilary Cass, a British paediatrician, published her review of gender-identity services for children and young people, commissioned by NHS England. It cast doubt on the evidence base for youth gender medicine. This prompted the World Professional Association for Transgender Health (WPATH), the leading professional organisation for the doctors and practitioners who provide services to trans people, to release a blistering rejoinder. WPATH said that its own guidelines were sturdier, in part because they were “based on far more systematic reviews”.

Systematic reviews should evaluate the evidence for a given medical question in a careful, rigorous manner. Such efforts are particularly important at the moment, given the feverish state of the American debate on youth gender medicine, which is soon to culminate in a Supreme Court case challenging a ban in Tennessee. The case turns, in part, on questions of evidence and expert authority.

Court documents recently released as part of the discovery process in a case involving youth gender medicine in Alabama reveal that WPATH's claim was built on shaky foundations. The documents show that the organisation’s leaders interfered with the production of systematic reviews that it had commissioned from the Johns Hopkins University Evidence-Based Practice Centre (EPC) in 2018.

From early on in the contract negotiations, WPATH expressed a desire to control the results of the Hopkins team’s work. In December 2017, for example, Donna Kelly, an executive director at PATH, told Karen Robinson, the EPC's director, that the WPATH board felt the EPC researchers “cannot publish their findings independently”. A couple of weeks later, Ms Kelly emphasised that, “the [WPATH] board wants it to be clear that the data cannot be used without WPATH approval”.

Ms Robinson saw this as an attempt to exert undue influence over what was supposed to be an independent process. John Ioannidis of Stanford University, who co-authored guidelines for systematic reviews, says that if sponsors interfere or are allowed to veto results, this can lead to either biased summaries or suppression of unfavourable evidence. Ms Robinson sought to avoid such an outcome. “In general, my understanding is that the university will not sign off on a contract that allows a sponsor to stop an academic publication,” she wrote to Ms Kelly.

Months later, with the issue still apparently unresolved, Ms Robinson adopted a sterner tone. She noted in an email in March 2018 that, “Hopkins as an academic institution, and I as a faculty member therein, will not sign something that limits academic freedom in this manner,” nor “language that goes against current standards in systematic reviews and in guideline development”.

Not to reason XY

Eventually WPATH relented, and in May 2018 Ms Robinson signed a contract granting WPATH power to review and offer feedback on her team’s work, but not to meddle in any substantive way. After WPATH leaders saw two manuscripts submitted for review in July 2020, however, the parties’ disagreements flared up again. In August the WPATH executive committee wrote to Ms Robinson that WPATH had “many concerns” about these papers, and that it was implementing a new policy in which WPATH would have authority to influence the EPC team’s output—including the power to nip papers in the bud on the basis of their conclusions.

Ms Robinson protested that the new policy did not reflect the contract she had signed and violated basic principles of unfettered scientific inquiry she had emphasised repeatedly in her dealings with WPATH. The Hopkins team published only one paper after WPATH implemented its new policy: a 2021 meta-analysis on the effects of hormone therapy on transgender people. Among the recently released court documents is a WPATH checklist confirming that an individual from WPATH was involved “in the design, drafting of the article and final approval of [that] article”. (The article itself explicitly claims the opposite.) Now, more than six years after signing the agreement, the EPC team does not appear to have published anything else, despite having provided WPATH with the material for six systematic reviews, according to the documents.

No one at WPATH or Johns Hopkins has responded to multiple inquiries, so there are still gaps in this timeline. But an email in October 2020 from WPATH figures, including its incoming president at the time, Walter Bouman, to the working group on guidelines, made clear what sort of science WPATH did (and did not) want published. Research must be “thoroughly scrutinised and reviewed to ensure that publication does not negatively affect the provision of transgender health care in the broadest sense,” it stated. Mr Bouman and one other coauthor of that email have been named to a World Health Organisation advisory board tasked with developing best practices for transgender medicine.

Another document recently unsealed shows that Rachel Levine, a transwoman who is assistant secretary for health, succeeded in pressing WPATH to remove minimum ages for the treatment of children from its 2022 standards of care. Dr Levine’s office has not commented. Questions remain unanswered, but none of this helps WPATH’s claim to be an organisation that bases its recommendations on science. 

[ Via: https://archive.today/wJCI7 ]

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So, there are 6 completed reviews sitting somewhere, that WPATH knows shows undesirable (to them) results. And they know it. And despite - or perhaps, because of - that, they wrote the insane SOC8 anyway. And then, at the behest of Rachel Levine, went back and took out the age limits, making it even more insane.

This isn't how science works, it's how a cult works.

When John Templeton Foundation commissioned a study on the efficacy of intercessory prayer, a study which unsurprisingly found that it's completely ineffective, it was forced to publish the negative results.

So, even the religious are more ethical than gender ideologues when it comes to science. This is outright scientific corruption.

[jcsmicasereports]

Obsessive Compulsive Disorder in Palestine: A Literature Review by Israa M.Sawalha in Journal of Clinical Case Reports Medical Images and Health Sciences

Abstract

Methods A computerized literature searches (Google Scholar, PubMed, Science Direct, Springer Link, Elsevier, Semantic Scholar, and HINARI) was used to collect studies addressing the OCD in Palestine.

Results and Conclusion OCD in Palestine is widely presented in adolescence and children at a young age. The most common type of OCD in Palestine is checking type. Set of risk factors increases developing OCD, including sexual abuse at any age as well as anxiety, depression, phobia and somatization disorders. In addition, the family incomes play a big role in presenting OCD, especially low income families. Most of the patients who have OCD were depressed and complaining of stigma and ignorance. Recommendations include getting rid of the stigma, creating a chance for low income families, further studies into OCD in Palestine, ending of the occupation and preventing children from following TV programs and war results.

Key words OCD, Obsessive compulsive disorder, Palestinians Mental Health, Palestine, Gaza Strip, West Bank

Background

In this section the researchers highlighted the meaning of health, mental health and mental illness. Also, they showed the impact of Israeli occupation on Palestinians people since 1948 and lastly in 2019. Besides, the state of mental health services in Palestine. A complete condition of physical, social and mental well-being and not purely disability or disease absence are the definition of the health, according to World Health Organization (WHO)(1). According to American Psychiatric Association (APA) the mental health is the foundation for learning, communication, emotions, thinking, self-esteem and resilience, also, it is the key to personal and emotional well-being, relationships, personal and contributing to the community or society(2). Therefore, the combination of behavioral, emotional or thinking process changes, or involving a change in one of them is called a mental health illness which is common and can be treatable(3). Historically, Palestinians health affected because of the Israeli occupation of Palestine, which was divided into two areas (West Bank and Gaza Strip)(4). Those two areas were occupied by Israel in 1948, related to that about 60 percent of the Palestinians living in villages with 27 percent of them in refugee camps(5). Accordingly, Israel attacks the civilians in their places and they experience infringement of their human rights which impact their health(6). Because of affection on the civilian health, especially the mental health, there is a need to develop mental health services(7). Therefore, in 2004 the mental health policy officially adopted for West Bank and Gaza Strip by Palestinian Ministry of Health (MoH) and in 2002-2003 it was formulated(5). As a result, Palestinians need to meet them human rights and develop the mental health policies and services(8). In summary, the history that the researchers mentioned above about Palestine’s political condition, clearly showed that there are major challenges faced the civilians’ mental health, as well as, their social and economic state.

Methodology

A computerized literature searches (Google Scholar, PubMed, Science Direct, Springer Link, Elsevier, Semantic Scholar, and HINARI) was used to collect studies addressing the OCD in Palestine. Search terms included “obsessive-compulsive disorder,” “obsessive compulsive” “OCD Palestine” “Palestinians mental health” “Health in Palestine” “Mental health Palestine” in both Arabic and English languages. Additional papers, which did not appear clearly in the electronic database while searching, were obtained via an examination of reference lists of published papers. Relevant empirical studies are summarized and presented hither. This study included all studies about OCD in Palestine and excluded the studies talked about anxiety, PTSD, or other disorders. The search identified 33 articles. Duplicates and irrelevant articles were removed. Nine articles related to OCD in a Worldwide, fifteen in Arabic countries and nine articles related to OCD in West Bank and Gaza Strip in Palestine. Also the researcher used some Arabic studies and translated them to English language. Studies selected after critically appraised.

An overview of OCD

In this following section the researchers explained the origin of Obsessive Compulsive Disorder (OCD) by writing its definition and clarified main class of OCD and from where it came. Also, this review showed studies about mental health in a worldwide then Arabic world later in Palestine. Moreover, the following sections focused on OCD in Palestine.

Definition of Obsessive Compulsive Disorder This part of the study focused on the definition of Obsessive Compulsive Disorder as both of the International Statistical Classification of Diseases and Related Health Problems 10th Revision (ICD-10) and Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) defined it. According to ICD-10, the essential feature of OCD is recurrent Obsessional thoughts and Compulsive act(9), but according to DSM-5, OCD is the presence of obsessions, compulsions, or both of them(10). Obsessional thoughts are images, impulses, or ideas that enter the patient's mind repeatedly in a vulgar form. They are almost fixedly distressing and the patient often tries, unsuccessfully, to endure them, this definition according to ICD-10(9). But DSM-5 defined the Obsessional thoughts as an intruder, unwanted and recurrent thoughts or impulses that most patients cause marked anxiety or distress and the patient trials to ignore such thoughts or images by performing a Compulsion(10). Additionally, ICD-10 about Compulsive, an acts or rituals are stereotyped behaviors that are repeated over and over, these acts are not enjoyable, nor do they result in the completion of useful tasks(9). Also, the repetitive behaviors (e.g., hand washing, ordering, checking) or mental acts (e.g., praying, counting, repeating words silently) is aimed at preventing or reducing anxiety or distress, or preventing some dreaded event or situation, this definition according to DSM-5(10). As the researchers mentioned above, the OCD is a mental health disorder associated with a change in behaviors and acts, as well as with thoughts changes.

History of Obsessive Compulsive Disorder

In this part the researchers showed the historical sequence of Obsessive Compulsive Disorder. Al-Balakhi was the first one in the world mentioned a mental illness and he put the differentiation of OCD from other forms of mental illnesses nearly a millennium earlier(11). Historically, as with any mental health condition, over time the conceptualization and treatment of OCD has changed(12). In the centuries sixteenth, seventeenth, eighteenth, nineteenth and the first half of the twentieth century the OCD passed through different conceptualizations. Religious melancholy was in seventeenth century the description of Obsession and Compulsion(13), but they have likely been around since humans first roved the earth(12). OCD was associated with moral and spiritual issue in the seventeenth century. Later, in eighteenth century many doctors saw that the Obsessions and Compulsions were caused by intellectual disordered(12).After this view, in the nineteenth century a modern concepts of OCD began to evolved(14),which is ‘neurosis’ implied a neuropathological condition. In the last quarter of the nineteenth century OCD was engulfed along with numerous other disorders(13). Supplementally, in the twentieth century the OCD became with a new concept. Sigmund Freud (1856-1939) and Pierre Janet (1859-1947) isolated OCD from neurasthenia(14).Freud’s view highlighted that this mental health disorder related to subconscious problems, and he sawed that both of obsessions and compulsions were often treated via psychoanalysis(14). Throughout the first half of the twentieth century Freud’s view dominated the mental health field(13). Finally, the researchers back in the time since the appearance of Obsessive Compulsive Disorder until the new concept were appeared.

OCD in a worldwide

In this section the researchers showed a review of OCD from the worldwide view by showing the prevalence of OCD in a worldwide, also the effect of it on the patient’s life, as well as its types and the prevalence of each one. Later the researchers showed risk factors. In the world, at some points in peoples’ lives, they have obsessive thoughts with or without compulsive behaviors, but that does not mean that all of them suffer from Obsessive Compulsive Disorder(15). Approximately 2% is the prevalence of in the general population in a worldwide(16). During the past year, OCD in the U.S affected 1.2% of adults. But now it affects approximately 1 in 40 adults and 1 in 100 children in the U.S. According to the National Institute of Mental Health (NIMH)(17). In Australia around 2% of people have OCD(18). But in the UK population, OCD affects about 12 in every 1,000 people (1.2% of the population) from young children to adults, regardless of social, cultural background or gender(19). In China the prevalence of OCD is 3.17%, according to a study done by Guo et al., its title is “Meta-analysis of the prevalence of anxiety disorders in mainland China from 2000 to 2015”(20). In this condition the patient has an obsessive need to repeatedly do certain things and may have unwanted ideas, impulses or images(21). People with OCD are usually aware that their symptoms are illogical and excessive, but they find the obsessions ungovernable and the compulsions unattainable to resist(18). There are many forms of OCD, Checking, Contamination/Mental Contamination, Symmetry and ordering, Ruminations/Intrusive thoughts and Hording(22). About the prevalence of each type the checking obsessive has the highest prevalence which is 79.3%, the second high prevalence is Hoarding obsessive which has 62.3%, later Ordering 3%, Morality 5%, Sexual/Religious 2%, Contamination/Washing 3%, Harming/Aggression 5% and Illness ratios 8% to 10% (23). A study done by J. Henderson and C. Pollard in greater ST. Louis showed that the overall prevalence rate of OCD was 2.8%. The most prevalent type of Obsessive Compulsive Disorder involved checking (1.6%), followed by a multiple category that included counting, repeating and collecting rituals (1.0%) and, finally, washing compulsions (0.8%)(24) According to National Comorbidity Survey Replication (NCS-R), many people with Obsessive Compulsive Disorder have more than one OCD form(23). The risk factors which may increase the incidence of getting an OCD are divided into three ranks, factors that the person born with, factors outside human control and modifiable risk factors(25). Factors person born with like genetics 50%, gender male at more risk to develop childhood OCD than female, brain structure and socioeconomic status as a study showed that there is an association between OCD and low socioeconomic status(25). But about the factors outside human control are included age life events and mental illness. The risk of OCD drops with age and the late adolescence has the greater risk(25). Those who have stressful life and suffer from physical or sexual abuse are a major risk factor to get OCD, also having another mental illness such as anxiety or depression increase the risk of having OCD (26). According to Owen and Adrian, the third rank is the modifiable risk factors such as drugs, marital status and employment. Drug uses cans causing a neurotransmitter changes in the brain, which create a chance for developing OCD, and being unmarried increase the risk too as well as being unemployed. However, there are many risk factors may increase the incidence to develop an OCD. OCD at higher risk to present comorbid major depression or another anxiety disorder across all areas(27). Peoples suffering from OCD also end up suffering from a lack of self-esteem and self-confidence, relationship problems, very weak willpower, and social withdrawal(28).

OCD in the Arabic countries

In this section the researchers showed a review about OCD in Arabic countries. From one hand, they pointed out that the first one highlighted the OCD was an Arabian psychiatrist and he wrote about it since 1000 years ago. And from other hand, they reviewed different studies about OCD prevalence, Islamic view, culture view and stigma in the Arabic world. Statistics mentioned that the frequency of most mental disorders does not have much difference from country to country around the world(32). The prevalence of OCD in Egyptian adolescent population is 2.2%(33). Also, 0.1 % in Lebanon(34). In Iraq, the peak age for OCD was from 21 to 30 years old, females were predominating (63.2%), singles were (47.3%) and the family history of OCD and any mental illness was observed in 20.5% and 52.9%, respectively(35). The few statistics coming out of certain Arab countries assert the reality of having no difference from country to country in the frequency of mental disorders specially OCD(32). The issue in the Arab world is more to do with stigma and ignorance than it is lack of mental health problems(32). Despite the complication and the importance of the mental health problems, the Arab world still shows a lack of awareness; patients in Arab countries tend to express their psychological issues in terms of physical symptoms, thereby avoiding the stigma attached to mental illness(36). A study done by Mohamed et al., 2015 in Egypt showed the following result: “Religious patients receiving religious psychotherapy showed significantly more rapid improvement and required lower dosage of medications and for periods less than others. The role of religion as CBT could be significant in the Islamic culture.”(37). Recently, the relationship between mental health, religiosity, and personal beliefs (Such as magical ideation) has been studied Psychiatry is depending on culture more than any other medical discipline, therefore, it is not well known in developing countries the frequency of mental illness such as anxiety, OCD or depression, even doctors themselves may not know the problem size, on the contrary of the developed countries which are well characterized in determining mental diseases(32).

An overview of OCD in Palestine

In this section the researchers showed a review of OCD in Palestine. They mentioned the prevalence of OCD in Palestine, and showed the all available studies about OCD. A 15.3% is the prevalence of Obsessive Compulsive Disorder among Palestinian university students in Gaza Strip, in assessing OCD and sociodemographic variables such as family income and type of college, study showed that the OCD is more in students coming from families earning 250$ and leases more than students from families earning 500-750$ and there is no statistical significant in OCD and type of college. In addition to that, this study showed there is no statistically significant correlation between OCD and age and grade average of the students. Also, this study clarifies that the OCD correlate with anxiety (R=0.63), with depression (R=0.66, P=0.001), with Phobic anxiety (R=0.44) and with Somatization (R=0.51). However, in assessing the OCD statue with sex, the T independent test according to the same study showed statistically significant in female than in male (Mean 15.39 vs. 15.20) (T= -50)(39). Additionally, a descriptive study done by Amira Abu Shaban in Jerusalem zone by using self-reported questionnaire and the Yale-Brown Obsessive Compulsive Scale (CY-BOCS) among Palestinian school children grade 11 (public and private), this study showed that the prevalence of OCD among Palestinian school students is 15.6%: 19.1 for females and 10.2 for males. Also, the study showed significant associations among OCD and females, students with low academic level, school achievements and less educated parents. Moreover, this study showed a strong relationship between OCD and social-demographic variables and a weak relationship with social environmental factors(40). 20.6%, according to Spence anxiety scale reported Obsessive Compulsive Disorder problems among children working due to low family income. This study, which was done by Mater et al (2007), aimed to identify the impact of work on children general mental health and anxiety in a total number of 789 children in the Gaza Strip. Also, it showed that 79.2% of children rating themselves as a psychiatric patient(42). The study sample included 99 women and their ages ranged between 16 years to 42 years with mean age 25.5. In this study pre and post assessment for women who got counseling and vocational training. Accordingly, the study showed that there was improvement in Obsessive Compulsive Disorder for the women(45). In the summary for the OCD in Palestine, the OCD is higher in women than men, in adolescent and children than older ages. The risk factors that increase the OCD separation between Palestinians are low income families, stigma, and Israeli occupation, and violence, sexual abuse of the children, depression disorder and anxiety disorder.

Discussion

In this section the researchers discussed the reviewed studies about OCD worldwide, in Arabic countries, and in Palestine by showing the differences in prevalence, stigma, and risk factors.

Prevalence

The studies showed that the prevalence of OCD in a worldwide is 2%-3% (16) Convergent to the prevalence in Arabic countries 2.2% (32), but there is no general prevalence of OCD in Palestine because of lack in studies. But some studies showed 15.3% the prevalence of Obsessive Compulsive Disorder among Palestinian university students in Gaza Strip (16, 32). Checking Obsessive is the most common type in the world, 79.3% of the OCD patients are checking obsessively and 62.3% suffer from Hording Obsessive (23). The studies in Arabic countries also support this prevalence of checking obsessive 1.6%, then hording then contamination obsessions (23, 22), after that the contamination obsessions in Arabic countries and in Palestine (22, 34).

Stigma

The issue in the Arab world is more to do with stigma and ignorance than it is lack of mental health problems and the stigma attached to the illness (34, 35). Also the Palestinians studies showed that the patients suffer from community view to them and their mental health (38). The Arab world still shows a lack of awareness; patients in Arab countries tend to express their psychological issues in terms of physical symptoms, thereby avoiding the stigma attached to mental illness (36).

The risk factors

The risk factor which may increase the incidence of getting an OCD are divided into three ranks, factors that the person born with, factors outside human control and modifiable risk factors (26). The genetic factor prevalence is 50% and the male more than female in childhood (25, 28) in the world view, but in comparison with Arabic countries view the risk factors were in female more than in male in ages between 21 to 30 years old (34, 31) . Finally, in Palestine the low family income earning 250$ and less were the basis for having an OCD among Palestinians, also the studies in Palestine showed that the female more than male with mean age 15.39 for female Verses 15.20 for male(38, 31). In addition to the OCD risk factor in Palestine the sexual abuse at any age play a major role in having OCD as well as Anxiety, depression, Phobic anxiety and Somatization disorders (31, 38, 40, 44).

Definition

They are almost fixedly distressing and the patient often tries, unsuccessfully, to endure them while DSM-5 defined the Obsessional thoughts as an intruder, unwanted and recurrent thoughts or impulses that most patients cause marked anxiety or distress and the patient trials to ignore such thoughts or images by performing a Compulsion (15).

Results and Conclusion

In this section, the researchers conclude the results of this review. According to the studies that the researchers reviewed and discussed above, they found that there is a difference between the prevalence of OCD in Palestine in comparing with Arabic countries as well as with a worldwide. Also, they discovered that there is a lack of studies about OCD in Palestine especially in West Bank. The most common type of OCD in Palestine is checking type; in addition to that, OCD patients suffer from the stigma so the prevalence of it was significantly high related to fear from the community. However, there is a religious view about OCD as well as cultural view. Palestinians because of Israel occupation faced a lot of barriers standing in front of their mental health status. OCD in Palestine is widely presented in adolescence and children at a young age. The family incomes play a big role in present of OCD, especially low income families as well as a stigma. In concluding, Palestinians with OCD have a related disorder, the most common one is depressed. Also the researchers found that there was a lack in studies about OCD in Palestine and other mental health disorders, and they discovered that there is a study in specific areas of Palestine such as Gaza Strip

Recommendations

Recommendations include get rid of the stigma and create a work chances for a low income family, apply more and more studies about OCD in Palestine, ending of the occupation and prevent the children from following TV programs and war.

Limitations

The literature review has discussed an Obsessive Compulsive Disorder in Palestine. Palestine is a state that is seeking independence with a scare of resources; therefore, the research is underdeveloped. As a result, there is a lack of detailed data regarding Obsessive Compulsive Disorder in Palestine. Due to lack the complete data, all literature that was found, including a thesis study done in Al-Quds Open University about the OCD among school students in 11 grade was included.

Acknowledgments

Special thanks to all authors in the field of mental health in Palestine who equipped us with the relevant information for this literature.

This case represents an unusual example of extrinsic esophageal compression due to lymphoma1,2 leading to severe pill- induced esophagitis3.

[myrawjcsmicasereports]

 Inhibition of EIF4E Downregulates VEGFA and CCND1 Expression to Suppress Ovarian Cancer Tumor Progression by Jing Wang in Journal of Clinical Case Reports Medical Images and Health Sciences

Abstract

This study investigates the role of EIF4E in ovarian cancer and its influence on the expression of VEGFA and CCND1. Differential expression analysis of VEGFA, CCND1, and EIF4E was conducted using SKOV3 cells in ovarian cancer patients and controls. Correlations between EIF4E and VEGFA/CCND1 were assessed, and three-dimensional cell culture experiments were performed. Comparisons of EIF4E, VEGFA, and CCND1 mRNA and protein expression between the EIF4E inhibitor 4EGI-1-treated group and controls were carried out through RT-PCR and Western blot. Our findings demonstrate elevated expression of EIF4E, VEGFA, and CCND1 in ovarian cancer patients, with positive correlations. The inhibition of EIF4E by 4EGI-1 led to decreased SKOV3 cell clustering and reduced mRNA and protein levels of VEGFA and CCND1. These results suggest that EIF4E plays a crucial role in ovarian cancer and its inhibition may modulate VEGFA and CCND1 expression, underscoring EIF4E as a potential therapeutic target for ovarian cancer treatment.

Keywords: Ovarian cancer; Eukaryotic translation initiation factor 4E; Vascular endothelial growth factor A; Cyclin D1

Introduction

Ovarian cancer ranks high among gynecological malignancies in terms of mortality, necessitating innovative therapeutic strategies [1]. Vascular endothelial growth factor (VEGF) plays a pivotal role in angiogenesis, influencing endothelial cell proliferation, migration, vascular permeability, and apoptosis regulation [2, 3]. While anti-VEGF therapies are prominent in malignancy treatment [4], the significance of cyclin D1 (CCND1) amplification in cancers, including ovarian, cannot be overlooked, as it disrupts the cell cycle, fostering tumorigenesis [5, 6]. Eukaryotic translation initiation factor 4E (EIF4E), central to translation initiation, correlates with poor prognoses in various cancers due to its dysregulated expression and activation, particularly in driving translation of growth-promoting genes like VEGF [7, 8]. Remarkably, elevated EIF4E protein levels have been observed in ovarian cancer tissue, suggesting a potential role in enhancing CCND1 translation, thereby facilitating cell cycle progression and proliferation [9]. Hence, a novel conjecture emerges: by modulating EIF4E expression, a dual impact on VEGF and CCND1 expression might be achieved. This approach introduces an innovative perspective to impede the onset and progression of ovarian cancer, distinct from existing literature, and potentially offering a unique therapeutic avenue.

Materials and Methods

Cell Culture

Human ovarian serous carcinoma cell line SKOV3 (obtained from the Cell Resource Center, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences) was cultured in DMEM medium containing 10% fetal bovine serum. Cells were maintained at 37°C with 5% CO2 in a cell culture incubator and subcultured every 2-3 days.

Three-Dimensional Spheroid Culture

SKOV3 cells were prepared as single-cell suspensions and adjusted to a concentration of 5×10^5 cells/mL. A volume of 0.5 mL of single-cell suspension was added to Corning Ultra-Low Attachment 24-well microplates and cultured at 37°C with 5% CO2 for 24 hours. Subsequently, 0.5 mL of culture medium or 0.5 mL of EIF4E inhibitor 4EGI-1 (Selleck, 40 μM) was added. After 48 hours, images were captured randomly from five different fields—upper, lower, left, right, and center—using an inverted phase-contrast microscope. The experiment was repeated three times.

GEPIA Online Analysis

The GEPIA online analysis tool (http://gepia.cancer-pku.cn/index.html) was utilized to assess the expression of VEGFA, CCND1, and EIF4E in ovarian cancer tumor samples from TCGA and normal samples from GTEx. Additionally, Pearson correlation coefficient analysis was employed to determine the correlation between VEGF and CCND1 with EIF4E.

RT-PCR

RT-PCR was employed to assess the mRNA expression levels of EIF4E, VEGF, and CCND1 in treatment and control group samples. Total RNA was extracted using the RNA extraction kit from Vazyme, followed by reverse transcription to obtain cDNA using their reverse transcription kit. Amplification was carried out using SYBR qPCR Master Mix as per the recommended conditions from Vazyme. GAPDH was used as an internal reference, and the primer sequences for PCR are shown in Table 1.

Amplification was carried out under the following conditions: an initial denaturation step at 95°C for 60 seconds, followed by cycling conditions of denaturation at 95°C for 10 seconds, annealing at 60°C for 30 seconds, repeated for a total of 40 cycles. Melting curves were determined under the corresponding conditions. Each sample was subjected to triplicate experiments. The reference gene GAPDH was used for normalization. The relative expression levels of the target genes were calculated using the 2-ΔΔCt method.

Western Blot

Western Blot technique was employed to assess the protein expression levels of EIF4E, VEGF, and CCND1 in the treatment and control groups. Initially, cell samples collected using RIPA lysis buffer were lysed, and the total protein concentration was determined using the BCA assay kit (Shanghai Biyuntian Biotechnology, Product No.: P0012S). Based on the detected concentration, 20 μg of total protein was loaded per well. Electrophoresis was carried out using 5% stacking gel and 10% separating gel. Subsequently, the following primary antibodies were used for immune reactions: rabbit anti-human polyclonal antibody against phospho-EIF4E (Beijing Boao Sen Biotechnology, Product No.: bs-2446R, dilution 1:1000), mouse anti-human monoclonal antibody against EIF4E (Wuhan Sanying Biotechnology, Product No.: 66655-1-Ig, dilution 1:5000), mouse anti-human monoclonal antibody against VEGFA (Wuhan Sanying Biotechnology, Product No.: 66828-1-Ig, dilution 1:1000), mouse anti-human monoclonal antibody against CCND1 (Wuhan Sanying Biotechnology, Product No.: 60186-1-Ig, dilution 1:5000), and mouse anti-human monoclonal antibody against GAPDH (Shanghai Biyuntian Biotechnology, Product No.: AF0006, dilution 1:1000). Subsequently, secondary antibodies conjugated with horseradish peroxidase (Shanghai Biyuntian Biotechnology, Product No.: A0216, dilution 1:1000) were used for immune reactions. Finally, super-sensitive ECL chemiluminescence reagent (Shanghai Biyuntian Biotechnology, Product No.: P0018S) was employed for visualization, and the ChemiDocTM Imaging System (Bio-Rad Laboratories, USA) was used for image analysis.

Statistical Analysis

GraphPad software was used for statistical analysis. Data were presented as (x ± s) and analyzed using the t-test for quantitative data. Pearson correlation analysis was performed for assessing correlations. A significance level of P < 0.05 was considered statistically significant.

Results

3D Cell Culture of SKOV3 Cells and Inhibitory Effect of 4EGI-1 on Aggregation

In this experiment, SKOV3 cells were subjected to 3D cell culture, and the impact of the EIF4E inhibitor 4EGI-1 on ovarian cancer cell aggregation was investigated. As depicted in Figure 1, compared to the control group (Figure 1A), the diameter of the SKOV3 cell spheres significantly decreased in the treatment group (Figure 1B) when exposed to 4EGI-1 under identical culture conditions. This observation indicates that inhibiting EIF4E expression effectively suppresses tumor aggregation.

Expression and Correlation Analysis of VEGFA, CCND1, and EIF4E in Ovarian Cancer Samples

To investigate the expression of VEGFA, CCND1, and EIF4E in ovarian cancer, we utilized the GEPIA online analysis tool and employed the Pearson correlation analysis method to compare expression differences between tumor and normal groups. As depicted in Figures 2A-C, the results indicate significantly elevated expression levels of VEGFA, CCND1, and EIF4E in the tumor group compared to the normal control group. Notably, the expression differences of VEGFA and CCND1 were statistically significant (p < 0.05). Furthermore, the correlation analysis revealed a positive correlation between VEGFA and CCND1 with EIF4E (Figures 2D-E), and this correlation exhibited significant statistical differences (p < 0.001). These findings suggest a potential pivotal role of VEGFA, CCND1, and EIF4E in the initiation and progression of ovarian cancer, indicating the presence of intricate interrelationships among them.

EIF4E, VEGFA, and CCND1 mRNA Expression in SKOV3 Cells

To investigate the function of EIF4E in SKOV3 cells, we conducted RT-PCR experiments comparing EIF4E inhibition group with the control group. As illustrated in Figure 3, treatment with 4EGI-1 significantly reduced EIF4E expression (0.58±0.09 vs. control, p < 0.01). Concurrently, mRNA expression of VEGFA (0.76±0.15 vs. control, p < 0.05) and CCND1 (0.81±0.11 vs. control, p < 0.05) also displayed a substantial decrease. These findings underscore the significant impact of EIF4E inhibition on the expression of VEGFA and CCND1, indicating statistically significant differences.

Protein Expression Profiles in SKOV3 Cells with EIF4E Inhibition and Control Group

Protein expression of EIF4E, VEGFA, and CCND1 was assessed using Western Blot in the 4EGI-1 treatment group and the control group. As presented in Figure 4, the expression of p-EIF4E was significantly lower in the 4EGI-1 treatment group compared to the control group (0.33±0.14 vs. control, p < 0.001). Simultaneously, the expression of VEGFA (0.53±0.18 vs. control, p < 0.01) and CCND1 (0.44±0.16 vs. control, p < 0.001) in the 4EGI-1 treatment group exhibited a marked reduction compared to the control group.

Discussion

EIF4E is a post-transcriptional modification factor that plays a pivotal role in protein synthesis. Recent studies have underscored its critical involvement in various cancers [10]. In the context of ovarian cancer research, elevated EIF4E expression has been observed in late-stage ovarian cancer tissues, with low EIF4E expression correlating to higher survival rates [9]. Suppression of EIF4E expression or function has been shown to inhibit ovarian cancer cell proliferation, invasion, and promote apoptosis. Various compounds and drugs that inhibit EIF4E have been identified, rendering them potential candidates for ovarian cancer treatment [11]. Based on the progressing understanding of EIF4E's role in ovarian cancer, inhibiting EIF4E has emerged as a novel therapeutic avenue for the disease. 4EGI-1, a cap-dependent translation small molecule inhibitor, has been suggested to disrupt the formation of the eIF4E complex [12]. In this study, our analysis of public databases revealed elevated EIF4E expression in ovarian cancer patients compared to normal controls. Furthermore, through treatment with 4EGI-1 in the SKOV3 ovarian cancer cell line, we observed a capacity for 4EGI-1 to inhibit SKOV3 cell spheroid formation. Concurrently, results from PCR and Western Blot analyses demonstrated effective EIF4E inhibition by 4EGI-1. Collectively, 4EGI-1 effectively suppresses EIF4E expression and may exert its effects on ovarian cancer therapy by modulating EIF4E.

Vascular Endothelial Growth Factor (VEGF) is a protein that stimulates angiogenesis and increases vascular permeability, playing a crucial role in tumor growth and metastasis [13]. In ovarian cancer, excessive release of VEGF by tumor cells leads to increased angiogenesis, forming a new vascular network to provide nutrients and oxygen to tumor cells. The formation of new blood vessels enables tumor growth, proliferation, and facilitates tumor cell dissemination into the bloodstream, contributing to distant metastasis [14]. As a significant member of the VEGF family, VEGFA has been extensively studied, and it has been reported that VEGFA expression is notably higher in ovarian cancer tumors [15], consistent with our public database analysis. Furthermore, elevated EIF4E levels have been associated with increased malignant tumor VEGF mRNA translation [16]. Through the use of the EIF4E inhibitor 4EGI-1 in ovarian cancer cell lines, we observed a downregulation in both mRNA and protein expression levels of VEGFA. This suggests that EIF4E inhibition might affect ovarian cancer cell angiogenesis capability through downregulation of VEGF expression.

Cyclin D1 (CCND1) is a cell cycle regulatory protein that participates in controlling cell entry into the S phase and the cell division process. In ovarian cancer, overexpression of CCND1 is associated with increased tumor proliferation activity and poor prognosis [17]. Elevated CCND1 levels promote cell cycle progression, leading to uncontrolled cell proliferation [18]. Additionally, CCND1 can activate cell cycle-related signaling pathways, promoting cancer cell growth and invasion capabilities [19]. Studies have shown that CCND1 gene expression is significantly higher in ovarian cancer tissues compared to normal ovarian tissues [20], potentially promoting proliferation and cell cycle progression through enhanced cyclin D1 translation [9]. Our public database analysis results confirm these observations. Furthermore, treatment with the EIF4E inhibitor 4EGI-1 in ovarian cancer cell lines resulted in varying degrees of downregulation in CCND1 mRNA and protein levels. This indicates that EIF4E inhibition might affect ovarian cancer cell proliferation and cell cycle progression through regulation of CCND1 expression.

In conclusion, overexpression of EIF4E appears to be closely associated with the clinical and pathological characteristics of ovarian cancer patients. In various tumors, EIF4E is significantly correlated with VEGF and cyclin D1, suggesting its role in the regulation of protein translation related to angiogenesis and growth [9, 21]. The correlation analysis results in our study further confirmed the positive correlation among EIF4E, VEGFA, and CCND1 in ovarian cancer. Simultaneous inhibition of EIF4E also led to downregulation of VEGFA and CCND1 expression, validating their interconnectedness. Thus, targeted therapy against EIF4E may prove to be an effective strategy for treating ovarian cancer. However, further research and clinical trials are necessary to assess the safety and efficacy of targeted EIF4E therapy, offering more effective treatment options for ovarian cancer patients.

Acknowledgments:

Funding: This study was supported by the Joint Project of Southwest Medical University and the Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University (Grant No. 2020XYLH-043).

Conflict of Interest: The authors declare no conflicts of interest.

[dreaminginthedeepsouth]

 In a development that should give hope to all Americans, a group of Montana youth secured a court victory that invalidated a state law prohibiting the consideration of climate effects in the approval process for new energy projects. The victory is a watershed moment, even though the ruling is narrow. The Montana constitution guarantees its citizens the right to a “clean and healthful environment.” Prohibiting the consideration of climate effects of new energy projects is plainly antagonistic to that guarantee. A state court judge correctly granted judgment in favor of the young people of Montana. See Washington Post, Judge rules in favor of Montana youths in landmark climate decision.

          The decision faces ongoing opposition from Montana’s attorney general, who called the decision “absurd” and promised an appeal that will end up in the Montana Supreme Court. No matter. The dam has broken and the victory by sixteen young citizens of Montana will inspire hundreds (or thousands) of additional suits. Some of those suits will succeed, encouraging more such suits. Fossil fuel lobbyists have ruled supreme in state legislatures for more than a century. The victory today is a very small step forward, but it is significant, nonetheless. It is particularly impactful because the plaintiffs were youths ranging in age from 5 to 22 years old.

          The Montana litigation is part of a global litigation strategy to challenge climate change. The Sabin Center for Climate Change Law at Columbia Law School has published a report on climate change litigation across the world.  See Global Climate  Litigation Report | 2023 Review. Amidst the noise of the Trump indictment watch, good things are happening in the background.

[Robert B. Hubbell newsletter]

+

In 1972, after a century of mining, ranching, and farming had taken a toll on Montana, voters in that state added to their constitution an amendment saying that “[t]he state and each person shall maintain and improve a clean and healthful environment in Montana for present and future generations,” and that the state legislature must make rules to prevent the degradation of the environment. 

In March 2020 the nonprofit public interest law firm Our Children’s Trust filed a lawsuit on behalf of sixteen young Montana residents, arguing that the state’s support for coal, oil, and gas violated their constitutional rights because it created the pollution fueling climate change, thus depriving them of their right to a healthy environment. They pointed to a Montana law forbidding the state and its agents from taking the impact of greenhouse gas emissions or climate change into consideration in their environmental reviews, as well as the state’s fossil fuel–based state energy policy. 

That lawsuit is named Held v. Montana after the oldest plaintiff, Rikki Held, whose family’s 7,000-acre ranch was threatened by a dwindling water supply, and both the state and a number of officers of Montana. The state of Montana contested the lawsuit by denying that the burning of fossil fuels causes climate change—despite the scientific consensus that it does—and denied that Montana has experienced changing weather patterns. Through a spokesperson, the governor said: “We must focus on American innovation and ingenuity, not costly, expansive government mandates, to address our changing climate.”

Today, U.S. District Court Judge Kathy Seeley found for the young Montana residents, agreeing that they have “experienced past and ongoing injuries resulting from the State’s failure to consider [greenhouse gas emissions] and climate change, including injuries to their physical and mental health, homes and property, recreational, spiritual, and aesthetic interests, tribal and cultural traditions, economic security, and happiness.” She found that their “injuries will grow increasingly severe and irreversible without science-based actions to address climate change.”  

The plaintiffs sought an acknowledgement of the relationship of fossil fuels to climate change and a declaration that the state’s support for fossil fuel industries is unconstitutional. Such a declaration would create a foundation for other lawsuits in other states. 

[Heather Cox Richardson :: Letters From An American]

[synechd0che]

.

[ferritins]

Thought u might appreciate me saying but as a nurse ur latest fic didn’t raise any red flags medicine wise. (For me anyway but my area is more gerontology than emergency) ALSO the whole fic had me feral and foaming at the mouth it was so good 🖤

hello anon! you thought absolutely right, and that is a MASSIVE relief.

General histology, clinical microbiology, antimicrobial resistance and current clinical trials for new therapies for AMR staph? I’m your guy! Actual patient facing medicine? fuck no. I’m gonna be so for real if you’re bleeding all I have is a three years out of date first aid cert and vibes 😭 and yet I’m out here writing medical fic with chest 🥴

I’m really glad you enjoyed the fic!! Thank you for your encouragement and feedback, it really means a lot.

M x

[tornadoquest]

Tornado Quest Top Science Links For June 1 - 8, 2024 #science #weather #climate #tornado #hurricane #drought #okwx

Greetings everybody! Thanks so much for stopping by. This has been an above average year to date for tornado activity so we’ll continue with our overview of tornado safety. With the Atlantic hurricane season now officially upon us, I’ve got a review of this years hurricane outlook and a link on hurricane safety. Don’t miss our weekly look at the latest US Drought Monitor update. There’s plenty of…

[omg-erika]

Does Alternative Medicine Have a Future?

by Dr.Harald Wiesendanger– Klartext What the mainstream media is hiding The more effective alternative medicine is, the more popular it is and the more likely it is to threaten its continued existence. Because their success endangers the profits of an overpowering opponent who can destroy them. Their humble future lies in the health economics niche where word of mouth leads – under the radar of…

[religion-is-a-mental-illness]

By: Benjamin Ryan

Published: Jun , 2024

NEWS: Alabama Attorney General submits motion for summary judgment in District Court case over ban on pediatric gender-transition treatment.

The document offers a scathing @WPATH's credibility, based on subpoenaed documents, dismissing it as an "activist interest group." 🧵

This summarizes the Alabama Attorney General's assessment of @WPATH, based on a trove of subpoenaed internal communications that have been unsealed this week, plus more yet to be unsealed: "In short, neither the Court nor Alabama need treat WPATH as anything other than the activist interest group it has shown itself to be. The Constitution allows States to reject WPATH’s model of “care” and protect vulnerable minors from life-altering transitioning “treatments.” The Court should grant Defendants summary judgment."

The AL AG's motion for summary judgment borrows liberally from the UK Cass Review to portray the scientific literature on gender-transition treatment as weak and unreliable. It also relies on the words of @WPATH's president, Dr. Marci Bowers: "Asked whether 'reasonable people could conclude that there is not enough evidence to support the safety or clinical effectiveness of puberty blockers,' Bowers replied: 'There’s not enough high level evidence. Yes, you can – you can – you can say that.'”

The AL AG also points to Dr. Eli Coleman, the chair of @WPATH's Standards of Care 8 trans-care guidelines, when arguing that a 12-year-old cannot assent to gender-transition treatment that may make them infertile: “at their age – they would not know what they want."

The Alabama AG posits what has become a highly contested argument that most gender dysphoric young children will desist and stop identifying as transgender during adolescence.

The Alabama Attorney General argues in its motion for summary judgment in District Court regarding suit over the state's pediatric gender-transition ban: “Minors, and often their parents, are unable to comprehend and fully appreciate the risk and life implications, including permanent sterility, that result from the use of puberty blockers, cross-sex hormones, and surgical procedures." Thus, “the decision to pursue a course of hormonal and surgical interventions to address a discordance between the individual’s sex and sense of identity should not be presented to or determined for minors who are incapable of comprehending the negative implications and life-course difficulties attending to these interventions.”

The plaintiffs suing Alabama over its ban of pediatric gender-transition treatment rely on guidelines by @WPATH and the Endocrine Society. The AL Attorney General points to the Cass Review to characterize them as "unreliable and methodologically unrigorous."

The Alabama AG again refers to the Cass Review when characterizing what Cass called "circularity" in the WPATH and Endocrine Society's pediatric gender-transition treatment guidelines, but which the AG refers to as laundering.

The Alabama AG argues that the major medical associations that back the gender-affirming care model for children do not, in fact, explicitly endorse @WPATH or the Endocrine Society's treatment guidelines per se. 

When @WPATH's Dr. Eli Coleman couldn't get the @AmerMedicalAssn to back WPATH's Standards of Care 8 guidelines for trans care, he emailed his colleagues in a fury and said the AMA is run by “white cisgender heterosexual hillbillies from nowhere."

The Alabama AG criticizes @WPATH for not seeking to prevent intellectual conflicts of interest from biasing its Standards of Care 8, meaning the guidelines were made by those "professionally engaged in performing, researching, or advocating for the practices under review."

Activists have made much of the fact that Hilary Cass was appointed by the NHS to conduct a review of pediatric care for gender dysphoric children despite no experience with such patients. But that is why she was chosen, because she lacked that intellectual conflict of interest. 

WPATH, the AL AG asserts, leaned into intellectual conflicts of interest when crafting the SoC8. Its president, Dr Marci Bowers, says she made more than $1 million from such surgeries last year and said it was "absolutely...important for someone to be an advocate" for gender-transition treatment to sit on the guideline committee.

Despite the fact that the head of WPATH's Standards of Care 8 trans treatment guidelines, Dr. Eli Coleman, said that most of those who contributed to them had financial and/or nonfinancial conflicts of interest, WPATH denied this in public.

Despite asserting that they were creating the Standards of Care 8 according to evidence-based medicine principles, WPATH did not do so. Dr. Eli Coleman, who headed the effort, said, "we were not able to be as systematic as we could have been (e.g. we did not use GRADE explicitly)

WPATH admitted using the term "recommend," which per the principles of evidence-based medicine is reserved for treatments backed by strong evidence with few downsides and a high degree of acceptance among providers and patients, to describe treatments with low-quality evidence.

The systematic literature reviews that @WPATH commissioned from Johns Hopkins and that it subsequently largely buried found "little to no evidence about children and adolescents" with respect to gender-transition treatment. HHS acknowledged this in Sept 2020.

WPATH denied Johns Hopkins the requisite independence for conducting and publishing the systematic literature reviews on trans care that the organization commissioned.

Social justice lawyers told @WPATH that evidence-based reviews of the science behind gender transition treatment for children would put the organization "in an untenable position in terms of affecting policy or winning lawsuits."

WPATH, the Alabama AG alleges, were "explicit in their desire to tailor SOC-8 to ensure cover-age for practically any 'embodiment goal' a patient has by labelling it 'medically necessary.' That label was given to a staggeringly broad list of treatments, seemingly without regard to the evidence base."

Biden Admin health official Rachel Levine put political pressure on WPATH to remove the age restrictions for gender-transition treatments in the Standards of Care 8.

After the @AmerAcadPeds threatened to withhold support for the SoC8 and to come out against it if @WPATH didn't remove the age limits on gender-transition treatment, WPATH relented and then fabricated a story for the public about why they did so.

WPATH's Dr. Eli Coleman said trans health care is "not only under attack by politicians, but by:” (1) “academics and scientists who are naturally skeptical,” (2) “parents of youth who are caught in the middle of this controversy,” (3) “increasing number of regret cases” who “blame clinicians for allowing them[] to transition,” and (4) “continuing pres-sure in health care to provide evidence-based care.”

Erica Anderson, former USPATH head, told me how she locked horns with her WPATH colleagues after telling @AbigailShrier that some care of gender dysphoric kids was "sloppy." Anderson wanted more openness with journalists, USPATH wanted a moratorium on talking to the press. Anderson lost that battle.

One author of the SoC8 adolescent chapter said: "My fear is that if WPATH continues to muzzle clinicians and relay the message to the public that they have no right to know about the debate, WPATH will become the bad guy and not the trusted source."

In public, WPATH denies that social contagion may contribute to gender dysphoria in minors and that rapid-onset gender dysphoria may be a real phenomenon, but in private they are more circumspect, the Alabama Attorney General asserts.

--

==

Having all of this corruption, coverups, ideological capture, and violation of medical ethics on the legal record heralds the coming end of WPATH.

[myrawjcsmicasereports]

Retinal and choroidal vascular drop out in a case of severe phenotype of Flammer Syndrome. Rescue of the ischemic-preconditioning mimicking action of endogenous Erythropoietin (EPO) by off-label intra vitreal injection of recombinant human EPO (rhEPO) by Claude Boscher in Journal of Clinical Case Reports Medical Images and Health Sciences

Abstract

Background: Erythropoietin (EPO) is a pleiotropic anti-apoptotic, neurotrophic, anti-inflammatory, and pro-angiogenic endogenous agent, in addition to its effect on erythropoiesis. Exogenous EPO is currently used notably in human spinal cord trauma, and pilot studies in ocular diseases have been reported. Its action has been shown in all (neurons, glia, retinal pigment epithelium, and endothelial) retinal cells. Patients affected by the Flammer Syndrome (FS) (secondary to Endothelin (ET)-related endothelial dysfunction) are exposed to ischemic accidents in the microcirculation, notably the retina and optic nerve.

Case Presentation: A 54 years old female patient with a diagnosis of venous occlusion OR since three weeks presented on March 3, 2019. A severe Flammer phenotype and underlying non arteritic ischemic optic neuropathy; retinal and choroidal drop-out were obviated. Investigation and follow-up were performed for 36 months with Retinal Multimodal Imaging (Visual field, SD-OCT, OCT- Angiography, Indo Cyanin Green Cine-Video Angiography). Recombinant human EPO (rhEPO)(EPREX®)(2000 units, 0.05 cc) off-label intravitreal injection was performed twice at one month interval. Visual acuity rapidly improved from 20/200 to 20/63 with disparition of the initial altitudinal scotoma after the first rhEPO injection, to 20/40 after the second injection, and gradually up to 20/32, by month 5 to month 36. Secondary cystoid macular edema developed ten days after the first injection, that was not treated via anti-VEGF therapy, and resolved after the second rhEPO injection. PR1 layer integrity, as well as protective macular gliosis were fully restored. Some level of ischemia persisted in the deep capillary plexus and at the optic disc.

Conclusion: Patients with FS are submitted to chronic ischemia and paroxystic ischemia/reperfusion injury that drive survival physiological adaptations via  the hypoxic-preconditioning mimicking effect of endogenous EPO, that becomes overwhelmed in case of acute hypoxic stress threshold above resilience limits. Intra vitreal exogenous rhEPO injection restores retinal hypoxic-preconditioning adaptation capacity, provided it is timely administrated. Intra vitreal rhEPO might be beneficial in other retinal diseases of ischemic and inflammatory nature.

Key words : Erythropoietin, retinal vein occlusion, anterior ischemic optic neuropathy, Flammer syndrome, Primary Vascular Dysfunction, anti-VEGF therapy, Endothelin, microcirculation, off-label therapy.

Introduction

Retinal Venous Occlusion (RVO) treatment still carries insufficiencies and contradictions (1) due to the incomplete deciphering of the pathophysiology and of its complex multifactorial nature, with overlooking of factors other than VEGF up-regulation, notably the roles of  retinal venous tone and Endothelin-1 (ET) (2-5), and of endothelial caspase-9 activation (6). Flammer Syndrome (FS)( (Primary Vascular Dysfunction) is related to a non atherosclerotic ET-related endothelial dysfunction in a context of frequent hypotension and increased oxidative stress (OS), that alienates organs perfusion, with notably changeable functional altered regulation of blood flow (7-9), but the pathophysiology remains uncompletely  elucidated (8). FS is more frequent in females, and does not seem to be expressed among outdoors workers, implying an influence of sex hormons and light (7)(9). ET is the most potent pro-proliferative, pro-fibrotic, pro-oxidative and pro-inflammatory vasoconstrictor, currently considered involved in many diseases other than cardio-vascular ones, and is notably an inducer of neuronal apoptosis (10). It is produced by endothelial (EC), smooth vascular muscles (SVMC) and kidney medullar cells,  and binds the surface Receptors  ET-A on SVMC and ET-B on EC,  in an autocrine and paracrine fashion. Schematically, binding on SVMC Receptors (i.e. through local diffusion in fenestrated capillaries or dysfunctioning EC) and on EC ones (i.e. by circulating ET) induce respectively arterial and venous vasoconstriction, and vasodilation, the latter via Nitrite oxide (NO) synthesis. ET production is stimulated notably by Angiotensin 2, insulin, cortisol, hypoxia, and antagonized by endothelial gaseous NO, itself induced by flow shear stress. Schematically but not exclusively, vascular tone is maintained by a complex regulation of ET-NO balance (8) (10-11).  Both decrease of NO and increase of ET production are both a cause and consequence of inflammation, OS  and endothelial dysfunction, that accordingly favour vasoconstriction; in addition ET competes for L-arginine substrate with NO synthase, thereby reducing NO bioavailability, a mechanism obviated notably in carotid plaques and amaurosis fugax (reviewed in 11).

Severe FS phenotypes are rare. Within the eye, circulating ET reaches retinal VSMC in case of Blood-Retinal-Barrier (BRB) rupture and diffuses freely via the fenestrated choroidal circulation, notably around the optic nerve (ON) head behind the lamina cribrosa, and may induce all pathologies related to acute ocular blood flow decrease (2-3)(5)(7-9). We previously reported two severe cases with rapid onset of monocular cecity and low vision, of respectively RVO in altitude and non arteritic  ischemic optic neuropathy (NAION) (Boscher et al, Société Francaise d'Ophtalmologie and Retina Society, 2015 annual meetings).

Exogenous Recombinant human EPO (rhEPO) has been shown  effective in humans for spinal cord injury (12), neurodegenerative and chronic kidney diseases (CKD) (reviewed in 13). Endogenous EPO is released physiologically in the circulation by the kidney and liver; it may be secreted in addition by all cells in response to hypoxic stress, and it is the prevailing pathway induced via genes up-regulation by the transcription factor Hypoxia Inducible Factor 1 alpha, among angiogenesis (VEGF pathway), vasomotor regulation (inducible NO synthase), antioxidation, and energy metabolism (14). EPO Receptor signaling induces cell proliferation, survival and differentiation (reviewed in 13), and targets multiple non hematopoietic pathways as well as the long-known effect on erythropoiesis (reviewed in 15). Of particular interest here, are its synergistic anti-inflammatory, neural antiapoptotic (16) pro-survival and  pro-regenerative (17) actions upon hypoxic injury, that were long-suggested to be also indirect, via blockade of ET release by astrocytes, and assimilated to ET-A blockers action (18). Quite interestingly, endogenous EPO’s pleiotropic effects were long-summarized (back to 2002), as “mimicking hypoxic-preconditioning” by Dawson (19), a concept applied to the retina (20). EPO Receptors are present in all retinal cells and their rescue activation targets all retinal cells, i.e. retinal EC, neurons (photoreceptors (PR), ganglion (RGG) and  bipolar cells), retinal pigment epithelium (RPE) osmotic function through restoration of the BRB, and  glial cells (reviewed in 21), and the optic nerve (reviewed in 22).  RhEPO has been tested experimentally in animal models of glaucoma, retinal ischemia-reperfusion (I/R) and light phototoxicity, via multiple routes (systemic, subconjunctival, retrobulbar and intravitreal injection (IVI) (reviewed in 23), and used successfully via IVI in human pilot studies, notably first in diabetic macular edema (24) (reviewed in 25 and 26). It failed to improve neuroprotection in association to corticosteroids in optic neuritis, likely for bias reasons (reviewed in 22). Of specific relation to the current case, it has been reported in NAION (27) (reviewed in 28) and traumatic ON injury (29 Rashad), and in one case of acute severe central RVO (CRVO) (Luscan and Roche, Société Francaise d’Ophtalmologie 2017 annual meeting). In addition EPO RPE gene therapy was recently suggested to prevent retinal degeneration induced by OS in a rodent model of dry Age Macular Degeneration (AMD) (30).

Case Report Presentation

This 54 years female patient was first visited on March 2019 4th, seeking for second opinion for ongoing vision deterioration OR on a daily basis, since around 3 weeks. Sub-central RVO (CRVO) OR had been diagnosed on February 27th; available SD-OCT macular volume was increased with  epiretinal marked hyperreflectivity, one available Fluorescein angiography picture showed a non-filled superior CRVO, and a vast central ischemia involving the macular and paraoptic territories. Of note there was ON edema with a para-papillary hemorrage nasal to the disc on the available colour fundus picture.

At presentation on March 4, Best Corrected Visual Acuity (BCVA) was reduced at 20/100 OR (20/25 OS). The patient described periods of acutely excruciating retro-orbital pain in the OR. Intraocular pressure was normal, at 12 OR and 18 OS (pachymetry was at 490 microns in both eyes). The dilated fundus examination was similar to the previous color picture and  did not disclose peripheral hemorrages recalling extended peripheral retinal ischemia. Humphrey Visual Field disclosed an altitudinal inferior scotoma and a peripheral inferior scotoma OR and was in the normal range OS, i.e. did not recall normal tension glaucoma OS . There were no papillary drusen on the autofluorescence picture, ON volume was increased  (11.77 mm3 OR versus 5.75 OS) on SD-OCT (Heidelberg Engineering®) OR,  Retinal Nerve Fiber (RNFL) and RGC layers thicknesses were normal  Marked epimacular hypereflectivity OR with foveolar depression inversion, moderately increased total volume and central foveolar thickness (CFT) (428 microns versus 328 OS), and a whitish aspect of the supero-temporal internal retinal layers recalling ischemic edema, were present . EDI CFT was incresead at 315 microns (versus 273 microns OS), with focal pachyvessels on the video mapping . OCT-Angiography disclosed focal perfusion defects in both the retinal and chorio-capillaris circulations , and central alterations of the PR1 layer on en-face OCT

Altogether the clinical picture evoked a NAION with venous sub-occlusion, recalling Fraenkel’s et al early hypothesis of an ET interstitial diffusion-related venous vasoconstriction behind the lamina cribrosa (2), as much as a rupture of the BRB was present in the optic nerve area (hemorrage along the optic disc). Choroidal vascular drop-out was suggested by the severity and rapidity of the VF impairment (31). The extremely rapid development of a significant “epiretinal membrane”, that we interpreted as a reactive - and protective, in absence of cystoid macular edema (CME) - ET 2-induced astrocytic proliferation (reviewed in 32), was as an additional  sign of severe ischemia.

The mention of the retro-orbital pain evoking a “ciliary angor”, the absence of any inflammatory syndrome and of the usual metabolic syndrome in the emergency blood test, oriented the etiology towards a FS. And indeed anamnesis collected many features of the FS, i.e. hypotension (“non dipper” profile with one symptomatic nocturnal episode of hypotension on the MAPA), migrains, hypersensitivity to cold, stress, noise, smells, and medicines, history of a spontaneously resolutive hydrops six months earlier, and of paroxystic episods of vertigo (which had driven a prior negative brain RMI investigation for Multiple Sclerosis, a frequent record among FS patients (33) and of paroxystic visual field alterations (7)(9), that were actually recorded several times along the follow-up.

The diagnosis of FS was eventually confirmed in the Ophthalmology Department in Basel University on April 10th, with elevated retinal venous pressure (20 to 25mmHg versus 10-15 OS) (4)(7)(9), reduced perfusion in the central retinal artery and veins on ocular Doppler (respectively 8.3 cm/second OR velocity versus 14.1 mmHg OS, and 3.1/second OR versus 5.9 cm OS), and impaired vasodilation upon flicker light-dependant shear stress on the Dynamic Vessel Analyser testing (7-9). In addition atherosclerotic plaques were absent on carotid Doppler.

On March 4th, the patient was at length informed about the FS, a possible off label rhEPO IVI, and a related written informed consent on the ratio risk-benefits was delivered.

By March 7th, she returned on an emergency basis because of vision worsening OR. VA was unchanged, intraocular pressure was at 13, but Visual Field showed a worsening of the central and inferior scotomas with a decreased foveolar threshold, from 33 to 29 decibels. SD-OCT showed a 10% increase in the CFT volume.

On the very same day, an off label rhEPO IVI OR (EPREX® 2000 units, 0,05 cc in a pre-filled syringe) was performed in the operating theater, i.e. the dose reported  by Modarres et al (27), and twenty times inferior to the usual weekly intravenous dose for treatment of chronic anemia secondary to CKD. Intra venous acetazolamide (500 milligrams) was performed prior to the injection, to prevent any increase in intra-ocular pressure. The patient was discharged with a prescription of chlorydrate betaxolol (Betoptic® 0.5 %) two drops a day, and high dose daily magnesium supplementation (600 mgr).

Incidentally the patient developed bradycardia the day after, after altogether instillation of 4 drops of betaxolol only, that was replaced by acetazolamide drops, i.e. a typical hypersensitivity reaction to medications in the FS (7)(9).

Subjective vision improvement was recorded as early as D1 after injection. By March 18 th, eleven days post rhEPO IVI, BCVA was improved at 20/63, the altitudinal scotoma had resolved (Fig. 5), Posterior Vitreous Detachment had developed with a disturbing marked Weiss ring, optic disc swelling had decreased; vasculogenesis within the retinal plexi and some regression of PR1 alterations  were visible on OCT-en face. Indeed by 11 days post EPO significant functional, neuronal and vascular rescue were observed, while the natural evolution had been seriously vision threatening.

However cystoid ME (CME) had developed . Indo Cyanin Green-Cine Video Angiography (ICG-CVA) OR, performed on March 23, i.e. 16 days after the rhEPO IVI, showed a persistent drop in ocular perfusion: ciliary and central retinal artery perfusion timings were dramatically delayed at respectively 21 and 25 seconds, central retinal vein perfusion initiated by 35 seconds, was pulsatile, and completed by 50 seconds only (video 3). Choroidal pachyveins matching the ones on SD-OCT video mapping were present in the temporal superior and inferior fields, and crossed the macula; capillary exclusion territories were present in the macula and around the optic disc.

By April 1, 23 days after the rhEPO injection, VA was unchanged, but CME and perfusion voids in the superficial deep capillary plexi and choriocapillaris were worsened, and optic disc swelling had recurred back to baseline, in a context of repeated episodes of systemic hypotension; and actually Nifepidin-Ratiopharm® oral drops (34), that had been delivered via a Temporary Use Authorization from the central Pharmacology Department in Assistance Publique Hopitaux de Paris, had had to be stopped because of hypersensitivity.

A second off label rhEPO IVI was performed in the same conditions on April 3, i.e. approximately one month after the first one.

Evolution was favourable as early as the day after EPO injection 2: VA was improved at 20/40, CME was reduced, and perfusion improved in the superficial retinal plexus as well as in the choriocapillaris. By week 4 after EPO injection 2, CME was much decreased, i.e. without anti VEGF injection. On august 19th, by week 18 after EPO 2, perfusion on ICG-CVA was greatly improved , with ciliary timing at 18 seconds, central retinal artery at 20 seconds and venous return from 23 to 36 seconds, still pulsatile. Capillary exclusion territories were visible in the macula and temporal to the macula after the capillary flood time that went on by 20.5 until 22.5 seconds (video 4); they  were no longer persistent at intermediate and late timings.

Last complete follow-up was recorded on January 7, 2021, at 22 months from EPO injection 2. BCVA was at 20/40, ON volume had dropped at 7.46 mm3, a sequaelar superior deficit was present in the RNFL  with some  corresponding residual defects on the inferior para central Visual Field , CFT was at 384 mm3 with an epimacular hyperreflectivity without ME, EDI CFT was dropped at 230 microns. Perfusion on ICG-CVA was not normalized, but even more improved, with ciliary timing at 15 seconds, central retinal artery at 16 seconds and venous return from 22 to 31 seconds, still pulsatile , indicating that VP was still above IOP. OCT-A showed persisting perfusion voids, especially at  the optic disc and within the deep retinal capillary plexus. The latter were present at some degree in the OS as well . Choriocapillaris and PR1 layer were dramatically improved.

Last recorded BCVA was at 20/32 by February 14, 2022, at 34 months from EPO 2. SD-OCT showed stable gliosis hypertrophy and mild alterations of the external layers .

Discussion

What was striking in the initial clinical phenotype of CRVO  was  the contrast between the moderate venous dilation,  and the intensity of ischemia, that were illustrating the pioneer hypothesis of Professor Flammer‘s team regarding the pivotal role of ET in VO (2), recently confirmed (3)(35), i.e. the local venous constriction backwards the lamina cribrosa, induced by diffusion of ET-1 within the vascular interstitium, in reaction to hypoxia. NAION was actually the primary and prevailing alteration, and ocular hypoperfusion was confirmed via ICG-CVA, as well as by the ocular Doppler performed in Basel. ICG-CVA confirmed the choroidal drop-out suggested by the severity of the VF impairment (31) and by OCT-A in the choriocapillaris. Venous pressure measurement, which instrumentation is now available (8), should become part of routine eye examination in case of RVO, as it is key to guide cases analysis and personalized therapeutical options.

Indeed, the endogenous EPO pathway is the dominant one activated by hypoxia and is synergetic with the VEGF pathway, and coherently it is expressed along to VEGF in the vitreous in human RVO (36). Diseases develop when the individual limiting  stress threshold for efficient adaptative reactive capacity gets overwhelmed. In this case by Week 3 after symtoms onset,  neuronal and vascular resilience mechanisms were no longer operative, but the BRB, compromised at the ON, was still maintained in the retina.

As mentioned in the introduction, the scientific rationale for the use of EPO was well demonstrated by that time, as well as the capacities of exogenous EPO to mimic endogenous EPO vasculogenesis, neurogenesis and  synaptogenesis, restoration of  the balance between ET-1 and NO. Improvement of chorioretinal blood flow was actually illustrated by the evolution of the choriocapillaris perfusion on repeated OCT-A and ICG-CVA. The anti-apoptotic effect of EPO (16) seems as much appropriate in case of RVO as the caspase-9 activation is possibly another overlooked co-factor (6).

All the conditions for translation into off label clinical use were present: severe vision loss with daily worsening and  unlikely spontaneous favourable  evolution, absence of toxicity in the human pilot studies, of contradictory comorbidities and co-medications, and of context of intraocular neovascularization that might be exacerbated by EPO (37).

Why didn’t we treat the onset of CME by March 18th, i.e. eleven days after EPO IVI 1, by anti-VEGF therapy, the “standard-of-care” in CME for RVO ?

In addition to the context of functional, neuronal and vascular improvements obviated by rhEPO IVI by that timing in the present case, actually anti VEGF therapy does not address the underlying causative pathology. Coherently, anti-VEGF IVI :  1) may not be efficient in improving vision in RVO, despite its efficiency in resolving/improving CME (usually requiring repeated injections), as shown in the Retain study (56% of eyes with resolved ME continued to loose vision)(quoted in (1) 2) eventually may be followed by serum ET-1 levels increase and VA reduction (in 25% of cases in a series of twenty eyes with BRVO) (38) and by increased areas of non perfusion in OCT-A (39). Rather did we perform a second hrEPO IVI, and actually we consider open the question whether the perfusion improvement, that was progressive, might have been accelerated/improved via repeated rhEPO IVI, on a three to four weeks basis.

The development of CME itself, involving a breakdown of the BRB, i.e. of part of the complex  retinal armentorium resilience to hypoxia, was somewhat paradoxical in the context of improvement after the first EPO injection, as EPO restores the BRB (24), and as much as it was suggested that EPO inhibits glial osmotic swelling, one cause of ME, via VEGF induction (40). Possible explanations were: 1) the vascular hyperpermeability induced by the up-regulation of VEGF gene expression via EPO (41) 2) the ongoing causative disease, of chronic nature, that was obviated by the ICG-CVA and the Basel investigation, responsible for overwhelming the gliosis-dependant capacity of resilience to hypoxia 3) a combination of both. I/R seemed excluded: EPO precisely mimics hypoxic reconditioning as shown in over ten years publications, including in the retina (20), and as EPO therapy is part of the current strategy for stabilization of the endothelial glycocalix against I/R injury (42-43). An additional and not exclusive possible explanation was the potential antagonist action of EPO on GFAP astrocytes proliferation, as mentioned in the introduction (18), that might have counteracted the reactive protective hypertrophic gliosis, still fully operative prior to EPO injection, and that was eventually restored during the follow-up, where epiretinal hyperreflectivity without ME and ongoing chronic ischemia do coincide (Fig. 6 and video 6), as much as it is unlikely that EPO’s effect would exceed one month (cf infra). Inhibition of gliosis by EPO IVI might have been also part of the mechanism of rescue of RGG, compromised by gliosis in hypoxic conditions (44). Whatever the complex balance initially reached, then overwhelmed after EPO IVI 1, the challenge was rapidly overcome by the second EPO IVI without anti-VEGF injection, likely because the former was powerful enough to restore the threshold limit for resilience to hypoxia, that seemed no longer reached again during the relapse-free follow-up. Of note, this “epiretinal membrane “, which association to good vision is a proof of concept of its protective effect, must not be removed surgically, as it would suppress one of the mecanisms of resilience to hypoxia.

To our best knowledge, ICG-CVA was never reported in FS; it allows real time evaluation of the ocular perfusion and illustration of the universal rheological laws that control choroidal blood flow as well. Pachyveins recall a “reverse” veno-arteriolar reflex in the choroidal circulation, that is NO and autonomous nervous system-dependant, and that we suggested to be an adaptative choroidal microcirculation process to hypoxia (45).  Their persistence during follow-up accounts for a persisting state of chronic ischemia.

The optimal timing for reperfusion via rhEPO in a non resolved issue:

in the case reported by Luscan and Roche, rhEPO IVI was performed on the very same day of disease onset, where it induced complete recovery from VA reduced at counting fingers at 1 meter, within 48 hours. This clinical human finding is on line with a recent rodent stroke study that established the timings for non lethal versus lethal ischemia of the neural and vascular lineages, and the optimized ones for beneficial reperfusion: the acute phase - from Day 1 where endothelial and neural cells are still preserved,  to Day 7 where proliferation of pericytes and Progenitor Stem Cells are obtainable - and the chronic stage, up to Day 56, where vasculogenesis, neurogenesis and functional recovery are still possible, but with uncertain efficiency (46). In our particular case, PR rescue after rhEPO IVI 1 indicated that Week 3 was still timely. RhEPO IVI  efficacy was shown to last between one (restoration of the BRB)  and four weeks (antiapoptotic effect) in diabetic rats (24). The relapse after Week 3 post IVI 1 might indicate that it might be  approximately the interval to be followed, should repeated injections be necessary.

The bilateral chronic perfusion defects on OCT-A at last follow-up indicate that both eyes remain in a condition of chronic ischemia and I/R, where endogenous EPO provides efficient ischemic pre-conditioning, but is potentially susceptible to be challenged during episodes of acute hypoxia that overwhelm the resilience threshold.

Conclusion

The present case advocates for individualized medicine with careful recording of the medical history, investigation of the systemic context, and exploiting of the available retinal multimodal imaging for accurate analytical interpretation of retinal diseases and their complex pathophysiology. The Flammer Syndrome is unfortunately overlooked in case of RVO; it should be suspected clinically in case of absence of the usual vascular and metabolic context, and in case  of elevated RVP. RhEPO therapy is able to restore the beneficial endogenous EPO ischemic pre-conditioning in eyes submitted to challenging acute hypoxia episodes in addition to chronic ischemic stress, as in the Flammer Syndrome and fluctuating ocular blood flow, when it becomes compromised by the overwhelming of the hypoxic stress resilience threshold. The latter physiopathological explanation illuminates the cases of RVO where anti-VEGF therapy proved functionally inefficient, and/or worsened retinal ischemia. RhEPO therapy might be applied to other chronic ischemia and I/R conditions, as non neo-vascular Age Macular Degeneration (AMD), and actually EPO was listed in 2020 among the nineteen promising molecules in AMD in a pooling of four thousands (47).

[literaturepublishersjournal]

Psychiatry Case Reports Journal publishes case reports in Psychiatry journal, case reports on Mental Health journal, case reports in Addictive Behaviours, case reports in Behavioural Science, case reports in Stress Disorders etc. Psychiatry case reports journal deals with the study, diagnosis, prevention and cure of mental disorders, which includes cognitive, behavioural, affective and perceptual mental disorders.

[worldinyourpalm]

जलवायु परिवर्तन के खिलाफ त्वरित कार्रवाई की जरूरत: संयुक्त राष्ट्र पैनल | UN Panel: Urgent Climate Change Action Is Required;

पारिस्थितिक तंत्रों पर अपरिवर्तनीय प्रभाव

आईपीसीसी की एक रिपोर्ट में कहा गया है कि ग्लोबल वार्मिंग को 1.5 डिग्री सेल्सियस तक सीमित करने में विफल रहने से कुछ पारिस्थितिक तंत्रों पर अपरिवर्तनीय प्रभाव पड़ेगा; 'तेजी से बंद होने वाले अवसर की खिड़की' की चेतावनी दी।

जलवायु परिवर्तन पर अंतर सरकारी पैनल (आईपीसीसी) ने सोमवार को एक रिपोर्ट में कहा कि जलवायु परिवर्तन मानव कल्याण और ग्रहों के स्वास्थ्य के लिए एक खतरा है और सभी के लिए रहने योग्य और टिकाऊ भविष्य को सुरक्षित करने के अवसर की तेजी से समाप्ति खिड़की है।

IPCC की भविष्य की रिपोर्ट

संयुक्त राष्ट्र का पैनल स्वयं वैज्ञानिक मूल्यांकन नहीं करता है बल्कि जलवायु परिवर्तन के विभिन्न पहलुओं पर वैज्ञानिक साक्ष्य की स्थिति का मूल्यांकन करता है। वर्तमान रिपोर्ट में नए वैज्ञानिक प्रमाणों पर ध्यान नहीं दिया गया है, लेकिन तीन कार्य समूहों के निष्कर्षों का संश्ले��ण किया गया है। यह छठे मूल्यांकन चक्र के दौरान तीन विशेष रिपोर्टों के साक्ष्य को भी एकीकृत करता है।

IPCC की भविष्य की रिपोर्ट 2030 तक अपेक्षित नहीं हैं और इसे पहले से ही एक सीमा बिंदु वर्ष के रूप में चिह्नित किया गया है - यदि उत्सर्जन में कटौती करने के लिए महत्वपूर्ण कार्रवाई नहीं की जाती है - तो पृथ्वी को 1. 5 डिग्री सेल्सियस ऊपर गर्म होने से रोकना असंभव होगा पूर्व-औद्योगिक स्तर।

"1.5 डिग्री सेल्सियस से अधिक तापमान कम लचीलेपन के साथ कुछ पारिस्थितिक तंत्रों पर अपरिवर्तनीय प्रतिकूल प्रभाव का परिणाम होगा, जैसे कि ध्रुवीय, पर्वतीय और तटीय पारिस्थितिक तंत्र, बर्फ की चादर, ग्लेशियर के पिघलने, या तेजी से और उच्च प्रतिबद्ध समुद्र स्तर की वृद्धि से प्रभावित," आईपीसीसी ने रिपोर्ट में कहा।

अपरिहार्य और/या अपरिवर्तनीय

इसमें कहा गया है कि भविष्य में होने वाले कुछ परिवर्तन "अपरिहार्य और/या अपरिवर्तनीय" हैं, लेकिन गहन, तीव्र और निरंतर वैश्विक ग्रीनहाउस गैस उत्सर्जन में कमी से इसे सीमित किया जा सकता है।

आईपीसीसी के अध्यक्ष होसुंग ली ने एक बयान में कहा, "प्रभावी और न्यायसंगत जलवायु कार्रवाई को मुख्यधारा में लाने से न केवल प्रकृति और लोगों के लिए नुकसान और क्षति कम होगी, बल्कि यह व्यापक लाभ भी प्रदान करेगी.......

[novy2sirius]

𝐇𝐎𝐖 𝐘𝐎𝐔 𝐂𝐀𝐍 𝐆𝐀𝐈𝐍 𝐅𝐀𝐌𝐄

𝐓𝐡𝐞 𝐬𝐮𝐧 𝐫𝐞𝐩𝐫𝐞𝐬𝐞𝐧𝐭𝐬 𝐟𝐚𝐦𝐞

Sun in Aries/1H

Athletics, fighting/boxing, modeling, fashion designing, makeup related things (ex: being a makeup artist), sex symbol, racing (ex: being a race car driver)

Sun in Taurus/2H

Singing, modeling, your material achievements/financial status, cooking (ex: being on a cooking competition show or having your own)

Sun in Gemini/3H

Social media, your siblings, podcasting, politics, gossiping (ex: gossip page), blogging, writing (ex: author), journalist, comedy, streaming, driver (ex: being a race car driver), teaching, mental health advocating

Sun in Cancer/4H

Your family, cooking/baking (ex: being on a baking/cooking show or having your own), real estate/houses (ex: being on a show like house hunters)

Sun in Leo/5H

Acting, your love interests, your children, any type of entertainment, gamer, only fans, your hobbies (ex: if one of your hobbies is playing the piano you could gain fame from that)

Sun in Virgo/6H

Social media, fitness/health, writing (ex: author), journalist, judge (ex: judge judy), comedy, animals/pets (ex: being on a show similar to animal planet)

Sun in Libra/7H

Dancing, your love interests/relationships/spouses, makeup related things (ex: being a makeup artist), beauty symbol, stylist, judge (ex: judge judy)

Sun in Scorpio/8H

Athletics, psychology, inheritance, sex symbol, death/mystery, conspiracies, surgery (ex: being on a show similar to botched), owning your own famous business

Sun in Sagittarius/9H

Television, interviewing, news reporting, the law (ex: being on a show similar to law and order), your grandparents, your in-laws, religion, blogging, photography, comedy, teaching

Sun in Capricorn/10H

Owning a famous business, directing films, your status, your father, your success, industry plant, historian, this is also a big indication of fame in general from anything

Sun in Aquarius/11H

Social media, DJing, film, your connections/friends, wealth, science, inventing, humanitarian, streaming, vlogging, manifesting, this is also an indication of accumulating lots of loyal supporters/fans in general

Sun in Pisces/12H

Singing/music, modeling, acting, astrology, tarot, psychic, spirituality, fantasy/sci-fi film producer, conspiracies, hypnotism, impersonator, mental health advocating

© novy2sirius

[cognitivejustice]

Agroecology—a science, practice, and movement that seeks social, political, economic, and environmental sustainability in the global food system—is gaining momentum in the U.S., according to a new Dartmouth-led commentary in Nature Food. As the co-authors report, the approach requires coordination among scientists, farmers, and activists.

"Agroecology is different, as it strives to achieve both ecological and social sustainability of food systems without sacrificing one for the other. We cannot save biodiversity and ecosystem integrity without also preserving farmer livelihoods and ensuring that the food systems we create provide food that is culturally relevant to local communities, and not simply meeting a calorie quota," says Ong.

Supporters of agroecology say the U.S. food system is dominated by industrial agriculture, which is characterized by monoculture production, reliance on agrochemicals like pesticides and fertilizers, and advanced technology and machinery that depend heavily on fossil fuels.

Prior research has found that challenges facing global food systems—which include food insecurity, public health crises, biodiversity loss, and climate change—are perpetuated in part by the U.S. food system and the political influence of its big players.

//Granny's comment: Agroecology is solarpunk AF

[incorrectbatfam]

I know we already have retail Steph, but could we also have substitute teacher Jason? (how did he get this job? he's a bat), the reason? he really enjoys the idea and the bonus of annoying his younger siblings and keeps the eyes on them

[art class] 

Jason: What'cha sculpting?

Damian: Your updated tombstone.

———————

[English class] 

Jason: Jon, can I talk to you for a sec?

Jon: Is it about my book report?

Jason: Yes. You were supposed to write a report on The Outsiders, but instead, you wrote about the menu at Outback Steakhouse. However, since it's really well-written, I'm giving you a B. 

———————

[math class] 

Colin: *raises his hand*

Jason: Yes?

Colin: Can I go to the bathroom?

Jason: What do I look like, your handler? Just go. 

Colin: *leaves with his backpack*

Colin: *walks out the school to patrol while Jason watches from the window*

———————

[health class] 

Jason: Can anyone tell me the most important food group?

Billy: Your mom.

———————

[social studies class]

Jason: Who can tell me Nanda Parbat's biggest export?

Suren: Assassins. 

Jason: Other than that.

Suren: Zombie assassins. 

———————

[science class]

Jason: Today we're going to learn about the circle of life.

Maya: You would know a lot about that, wouldn't you?

———————

[music class]

Jason: Girls' side, can I hear that first verse from you again?

The girls: *singing*

Maps: *inhuman screeching*

———————

[gym class]

Jason: Where are your gym clothes?

Kathy: At home.

Jason: M'kay, go get some extras from the lost and found.

Kathy: No thanks, black's not my color.

———————

[recess]

Jason, on the phone: I think my first day's going pretty well—

Jason: *gets hit by mud*

Jason: ...I'm gonna have to call you back.