Exploring the impact of therapeutic advances in HIV-related mortality in the United States.

Objectives: Mortality from HIV has significantly declined with the introduction of highly active antiretroviral therapy (HAART). This study sought to examine the longitudinal trends in mortality from HIV-related diseases by race, sex, geographical region, and over time as HAART trends changed. Methods: We queried the Centers for Disease Control and Prevention's Wide-Ranging Online Data for Epidemiologic Research database and performed serial cross-sectional analyses of national death certificate data for all-cause mortality with comorbid HIV from 1999 to 2020. HIV diseases (International Classification of Diseases, Tenth Revision codes B20-B24, O98.7, R75) were listed as the contributing cause of death. We calculated the age-adjusted mortality ratio (AAMR) per 1,000,000 individuals and determined mortality trends using the Joinpoint Regression Program. Subgroup analyses were performed by sex, race, region, and organ system. The study period was further stratified into three groups when specific drug regimens were more prevalent. Results: In the 22-year study period, 251,759 all-cause mortalities with comorbid HIV were identified. The leading cause of death was infectious disease (84.0%, N = 211,438). Men recorded a higher AAMR than women (4.66 vs 1.65, P < 0.01). African American individuals had the highest AAMR (13.46) compared to White, American Indian, and Asian individuals (1.70 vs 1.65 vs 0.47). The South region had the highest AAMR (4.32) and urban areas had a higher AAMR compared to rural areas (1.77 vs 0.88). Conclusions: More than 80% of deaths occurred because of infectious disease over the last 2 decades with a decreasing trend over time when stratified by race, sex, and geographical region. Despite advances in HAART, mortality disparities persist which emphasizes the need for targeted interventions in these populations.

Traumatic atlantoaxial rotatory fixation in adults: a systematic review of published cases.

Atlantoaxial rotatory fixation (AARF) in adults is a rare and clinically challenging condition characterized by a spectrum of etiological factors, predominantly attributed to traumatic and inflammatory pathologies within the craniovertebral region. Trauma is the most frequently identified cause within the adult population, with the first case report published in 1907. This study aims to conduct a systematic review that addresses the clinical presentations and management strategies relating to traumatic atlantoaxial rotatory fixation in adults. A comprehensive search of the PubMed database was executed, adhering to the PRISMA guidelines. The inclusion criteria encompassed case reports and series documenting AARF cases in individuals aged 18 and above, spanning database inception to July 2022. Studies not published in the English language were excluded. A total of 61 articles reporting cases of AARF in the adult population were included in the study. The mean age of affected individuals was 36.1 years (± 15.6), with a distribution of 46% females and 54% males. Predominant mechanisms of injury included motor vehicle accidents and falls, constituting 38% and 22% of cases, respectively. Among the classification systems employed, Fielding and Hawkins type I accounted for the majority at 63%, followed by type II at 10%, and type III at 4%. Conservative management was used for treatment in 65% of acute (65%) cases and 29% of chronic cases. Traumatic AARF is a rare phenomenon in the adult population, is more common in younger adults, and does not often present with neurologic deficits. Patients diagnosed acutely are more likely to be successfully treated with conservative management, while patients diagnosed chronically are less likely to be reduced with conservatively and often require surgical treatment. Surgery should be considered for patients with irreducible dislocations, ligamentous injuries, unstable associated fractures, and persistent pain resistant to conservative management.

A Survey of Transcription Factors in Cell Fate Control.

Transcription factors (TFs) play a cardinal role in the development and maintenance of human physiology by acting as mediators of gene expression and cell state control. Recent advancements have broadened our knowledge on the potency of TFs in governing cell physiology and have deepened our understanding of the mechanisms through which they exert this control. The ability of TFs to program cell fates has gathered significant interest in recent decades, and high-throughput technologies now allow for the systematic discovery of forward programming factors to convert pluripotent stem cells into numerous differentiated cell types. The next generation of these technologies has the potential to improve our understanding and control of cell fates and states and provide advanced therapeutic modalities to address many medical conditions.

Cell therapy strategies for COVID-19: Current approaches and potential applications.

Coronavirus disease 2019 (COVID-19) continues to burden society worldwide. Despite most patients having a mild course, severe presentations have limited treatment options. COVID-19 manifestations extend beyond the lungs and may affect the cardiovascular, nervous, and other organ systems. Current treatments are nonspecific and do not address potential long-term consequences such as pulmonary fibrosis, demyelination, and ischemic organ damage. Cell therapies offer great potential in treating severe COVID-19 presentations due to their customizability and regenerative function. This review summarizes COVID-19 pathogenesis, respective areas where cell therapies have potential, and the ongoing 89 cell therapy trials in COVID-19 as of 1 January 2021.

Extensive germline genome engineering in pigs.

The clinical applicability of porcine xenotransplantation-a long-investigated alternative to the scarce availability of human organs for patients with organ failure-is limited by molecular incompatibilities between the immune systems of pigs and humans as well as by the risk of transmitting porcine endogenous retroviruses (PERVs). We recently showed the production of pigs with genomically inactivated PERVs. Here, using a combination of CRISPR-Cas9 and transposon technologies, we show that pigs with all PERVs inactivated can also be genetically engineered to eliminate three xenoantigens and to express nine human transgenes that enhance the pigs' immunological compatibility and blood-coagulation compatibility with humans. The engineered pigs exhibit normal physiology, fertility and germline transmission of the 13 genes and 42 alleles edited. Using in vitro assays, we show that cells from the engineered pigs are resistant to human humoral rejection, cell-mediated damage and pathogenesis associated with dysregulated coagulation. The extensive genome engineering of pigs for greater compatibility with the human immune system may eventually enable safe and effective porcine xenotransplantation.

Inactivation of porcine endogenous retrovirus in pigs using CRISPR-Cas9.

Xenotransplantation is a promising strategy to alleviate the shortage of organs for human transplantation. In addition to the concerns about pig-to-human immunological compatibility, the risk of cross-species transmission of porcine endogenous retroviruses (PERVs) has impeded the clinical application of this approach. We previously demonstrated the feasibility of inactivating PERV activity in an immortalized pig cell line. We now confirm that PERVs infect human cells, and we observe the horizontal transfer of PERVs among human cells. Using CRISPR-Cas9, we inactivated all of the PERVs in a porcine primary cell line and generated PERV-inactivated pigs via somatic cell nuclear transfer. Our study highlights the value of PERV inactivation to prevent cross-species viral transmission and demonstrates the successful production of PERV-inactivated animals to address the safety concern in clinical xenotransplantation.

Genome-wide inactivation of porcine endogenous retroviruses (PERVs).

The shortage of organs for transplantation is a major barrier to the treatment of organ failure. Although porcine organs are considered promising, their use has been checked by concerns about the transmission of porcine endogenous retroviruses (PERVs) to humans. Here we describe the eradication of all PERVs in a porcine kidney epithelial cell line (PK15). We first determined the PK15 PERV copy number to be 62. Using CRISPR-Cas9, we disrupted all copies of the PERV pol gene and demonstrated a >1000-fold reduction in PERV transmission to human cells, using our engineered cells. Our study shows that CRISPR-Cas9 multiplexability can be as high as 62 and demonstrates the possibility that PERVs can be inactivated for clinical application of porcine-to-human xenotransplantation.