Health and social consequences for survivors of genocidal rape: A systematic scoping review.

The unique forms of trauma experienced by survivors of genocidal rape are not well understood. Hence, we conducted a systematic scoping review regarding the consequences for survivors of rape during genocide. Searches conducted in PubMed, Global Health, Scopus, PyscInfo, and Embase produced a total of 783 articles. After completing the screening process, 34 articles were eligible for inclusion in the review. The included articles focus on survivors from six different genocides, with most focusing on either the genocide of the Tutsis in Rwanda or the Yazidis in Iraq. The study findings consistently show that survivors deal with stigmatization as well as a lack of both financial and psychological social support. This lack of support is partly due to social ostracization and shame but is also attributed to the fact that many survivors' families and other providers of social support were murdered during the violence. Many survivors, particularly young girls, reported dealing with intense forms of trauma both as a direct result of sexual violence and due to witnessing the death of their community members during the period of genocide. A notable proportion of survivors became pregnant from genocidal rape and contracted HIV. Group therapy was shown to improve mental health outcomes across numerous studies. These findings have important implications and can inform recovery process efforts. Psychosocial supports, stigma reduction campaigns, community reestablishment, and financial assistance are integral in facilitating recovery. These findings can also play an important role in shaping refugee support programs.

Risk Factors for COVID-19 Mortality Among People Living with HIV: A Scoping Review.

People living with HIV (PLWH) are particularly vulnerable to worsened outcomes of COVID-19. Therefore, the purpose of this work was to provide a scoping review of the literature to assess the risk factors for COVID-19 mortality among PLWH. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews (PRISMA-ScR), searches were conducted in PubMed, Scopus, Global Health, and WHO Coronavirus Database. Articles were eligible for inclusion if they were in English, included PLWH who died after COVID-19 infection, and described risk factors for mortality. Results were descriptively synthesized and pooled thereafter. Study quality was assessed using the Joanna Brigg Institute's critical appraisal tools. 20 studies were eligible for inclusion, with the pooled death rate being 11.7%. Age was a major risk factor, especially after 50 (23.2%) and after 70 (41.8%), and males had a death rate nearly double that of females. As total comorbidities increased, the death rate also greatly increased; among those with comorbidities, the highest fatality rates were those with cardiovascular disease (30.2%), chronic kidney disease (23.5%), obesity (22.4%), and diabetes (18.4%). Other risk factors for mortality among PLWH included having a Black racial background, being an injection drug user, being a smoker, and having a CD4 cell count below 200. There is a need to better study confounding factors, and to understand how vaccination influences mortality risk. Overall, the findings highlight a need to ensure that focus is placed on the varying demographics of PLWH amidst COVID-19 control efforts.

Regulation of PRMT5-MDM4 axis is critical in the response to CDK4/6 inhibitors in melanoma.

Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors are an established treatment in estrogen receptor-positive breast cancer and are currently in clinical development in melanoma, a tumor that exhibits high rates of CDK4 activation. We analyzed melanoma cells with acquired resistance to the CDK4/6 inhibitor palbociclib and demonstrate that the activity of PRMT5, a protein arginine methyltransferase and indirect target of CDK4, is essential for CDK4/6 inhibitor sensitivity. By indirectly suppressing PRMT5 activity, palbociclib alters the pre-mRNA splicing of MDM4, a negative regulator of p53, leading to decreased MDM4 protein expression and subsequent p53 activation. In turn, p53 induces p21, leading to inhibition of CDK2, the main kinase substituting for CDK4/6 and a key driver of resistance to palbociclib. Loss of the ability of palbociclib to regulate the PRMT5-MDM4 axis leads to resistance. Importantly, combining palbociclib with the PRMT5 inhibitor GSK3326595 enhances the efficacy of palbociclib in treating naive and resistant models and also delays the emergence of resistance. Our studies have uncovered a mechanism of action of CDK4/6 inhibitors in regulating the MDM4 oncogene and the tumor suppressor, p53. Furthermore, we have established that palbociclib inhibition of the PRMT5-MDM4 axis is essential for robust melanoma cell sensitivity and provide preclinical evidence that coinhibition of CDK4/6 and PRMT5 is an effective and well-tolerated therapeutic strategy. Overall, our data provide a strong rationale for further investigation of novel combinations of CDK4/6 and PRMT5 inhibitors, not only in melanoma but other tumor types, including breast, pancreatic, and esophageal carcinoma.