Template switching between the leading and lagging strands at replication forks generates inverted copy number variants through hairpin-capped extrachromosomal DNA.

Inherited and germ-line de novo copy number variants (CNVs) are increasingly found to be correlated with human developmental and cancerous phenotypes. Several models for template switching during replication have been proposed to explain the generation of these gross chromosomal rearrangements. We proposed a model of template switching (ODIRA-origin dependent inverted repeat amplification) in which simultaneous ligation of the leading and lagging strands at diverging replication forks could generate segmental inverted triplications through an extrachromosomal inverted circular intermediate. Here, we created a genetic assay using split-ura3 cassettes to trap the proposed inverted intermediate. However, instead of recovering circular inverted intermediates, we found inverted linear chromosomal fragments ending in native telomeres-suggesting that a template switch had occurred at the centromere-proximal fork of a replication bubble. As telomeric inverted hairpin fragments can also be created through double strand breaks we tested whether replication errors or repair of double stranded DNA breaks were the most likely initiating event. The results from CRISPR/Cas9 cleavage experiments and growth in the replication inhibitor hydroxyurea indicate that it is a replication error, not a double stranded break that creates the inverted junctions. Since inverted amplicons of the SUL1 gene occur during long-term growth in sulfate-limited chemostats, we sequenced evolved populations to look for evidence of linear intermediates formed by an error in replication. All of the data are compatible with a two-step version of the ODIRA model in which sequential template switching at short inverted repeats between the leading and lagging strands at a replication fork, followed by integration via homologous recombination, generates inverted interstitial triplications.

Genetic rescue remains underused for aiding recovery of federally listed vertebrates in the United States.

Restoring gene flow among fragmented populations is discussed as a potentially powerful management strategy that could reduce inbreeding depression and cause genetic rescue. Yet, examples of assisted migration for genetic rescue remain sparse in conservation, prompting several outspoken calls for its increased use in genetic management of fragmented populations. We set out to evaluate the extent to which this strategy is underused and to determine how many imperiled species would realistically stand to benefit from genetic rescue, focusing on federally threatened or endangered vertebrate species in the United States. We developed a "genetic rescue suitability index (GR index)" based on concerns about small population problems relative to risks associated with outbreeding depression and surveyed the literature for 222 species. We found that two-thirds of these species were good candidates for consideration of assisted migration for the purpose of genetic rescue according to our suitability index. Good candidate species spanned all taxonomic groups and geographic regions, though species with more missing data tended to score lower on the suitability index. While we do not recommend a prescriptive interpretation of our GR index, we used it here to establish that assisted migration for genetic rescue is an underused strategy. For example, we found in total, "genetic rescue" was only mentioned in 11 recovery plans and has only been implemented in 3 of the species we surveyed. A potential way forward for implementation of this strategy is incorporating genetic rescue as a priority in USFWS recovery documentation. In general, our results suggest that although not appropriate for all imperiled species, many more species stand to benefit from a conservation strategy of assisted migration for genetic rescue than those for which it has previously been considered or implemented.

Sex-specific transgenerational effects of preconception exposure to arsenite: metabolic phenotypes of C57BL/6 offspring.

Chronic exposure to inorganic arsenic (iAs) has been linked to diabetes in both humans and mice, but the role of iAs exposure prior to conception and its transgenerational effects are understudied. The present study investigated transgenerational effects of preconception iAs exposure in C57BL/6J mice, focusing on metabolic phenotypes of G1 and G2 offspring. Body composition and diabetes indicators, including fasting blood glucose, fasting plasma insulin, glucose tolerance, and indicators of insulin resistance and beta cell function, were examined in both generations. The results suggest that the preconception iAs exposure in the parental (G0) generation induced diabetic phenotypes in G1 and G2 offspring in a sex-dependent manner. G1 females from iAs-exposed parents developed insulin resistance while no significant effects were found in G1 males. In the G2 generation, insulin resistance was observed only in males from iAs-exposed grandparents and was associated with higher bodyweights and adiposity. Similar trends were observed in G2 females from iAs-exposed grandparents, but these did not reach statistical significance. Thus, preconception iAs exposure altered metabolic phenotype across two generations of mouse offspring. Future research will investigate the molecular mechanisms underlying these transgenerational effects, including epigenomic and transcriptomic profiles of germ cells and tissues from G0, G1 and G2 generations.

Disparities in fertility preservation among patients diagnosed with female breast cancer.

PURPOSE: To investigate the association of specific patient factors with disparities in fertility preservation counseling and utilization of fertility preservation among patients ≤ 40 years old diagnosed with female breast cancer. METHODS: A retrospective chart review was conducted investigating patients diagnosed with breast cancer between January 2012 and December 2020 in a multi-site health system. Rates of fertility counseling and utilization of preservation services were compared based on age, race/ethnicity, parity, insurance type, and treatment site. RESULTS: Of the 6,783 patients diagnosed with female breast cancer, 306 (4.5%) were ≤ 40 years old at the time of diagnosis. There was no significant difference between Black or African American and White patients in rates of fertility counseling (12.1% vs 17.4%; p = 0.285) or pursuit of fertility preservation (3.3% vs 4.2%; p = 0.508), nor was a difference observed when compared by insurance type. However, younger patients (< 30 years of age), patients with 1 or no children, and patients treated in the more affluent county were more likely to undergo counseling and pursue fertility preservation than their matched counterparts. CONCLUSION: Age, parity, and location of breast cancer care may impact rates of fertility counseling and preservation among reproductive age women diagnosed with breast cancer. Thus, further attention to age discrimination, a patient's desire for future fertility, need for standardization in fertility preservation counseling, and perhaps implementation of comprehensive fertility coverage mandates across all states could help to improve gaps in fertility counseling and fertility preservation.

Fertility and Pregnancy Outcomes After Conservative Management of Adenocarcinoma In Situ of the Cervix.

OBJECTIVE: The aim of the study was to evaluate the pregnancy outcomes of women who underwent conservative management of adenocarcinoma in situ (AIS). MATERIALS AND METHODS: We conducted a retrospective chart review of patients diagnosed with AIS at a single tertiary institution between January 1, 1991, and December 31, 2019. We collected demographic data, AIS-specific information, and fertility outcomes and performed bivariate analyses to compare demographic characteristics and AIS-specific information between patients with and without hysterectomy after diagnosis. Patients with conservative management who achieved pregnancy were described. RESULTS: Among 87 patients with AIS, 38 (44%) underwent a hysterectomy within 6 months of diagnosis and 49 (56%) underwent conservative management. Six of 19 patients (32%) had residual AIS despite undergoing definitive management after an excisional procedure with negative margins and negative endocervical curettage (ECC). Nine of 19 patients (47%) had residual AIS after an excisional procedure with positive margins and/or a positive ECC. Patients who opted for conservative management were younger (median = 31.6 [interquartile range = 27.4-34.9] vs 38.5 y [32.3-44.8 y], p < .001) and nulligravid. Among patients with conservative management, there were 15 pregnancies and 14 live births (29%). Seven were preterm, although 2 were for medical indications. CONCLUSIONS: Residual AIS in patients with negative margins and ECC leading to definitive hysterectomy (32%) and the rate of preterm birth (36%) were higher than previous reports and nationally reported rates. However, only 1 patient had a preterm birth before 34 weeks. These findings reflect important information for counseling patients who elect for conservative management of AIS.

Transforming gastrointestinal helminth parasite identification in vertebrate hosts with metabarcoding: a systematic review.

BACKGROUND: Gastrointestinal helminths are a very widespread group of intestinal parasites that can cause major health issues in their hosts, including severe illness or death. Traditional methods of helminth parasite identification using microscopy are time-consuming and poor in terms of taxonomic resolution, and require skilled observers. DNA metabarcoding has emerged as a powerful alternative for assessing community composition in a variety of sample types over the last few decades. While metabarcoding approaches have been reviewed for use in other research areas, the use of metabarcoding for parasites has only recently become widespread. As such, there is a need to synthesize parasite metabarcoding methodology and highlight the considerations to be taken into account when developing a protocol. METHODS: We reviewed published literature that utilized DNA metabarcoding to identify gastrointestinal helminth parasites in vertebrate hosts. We extracted information from 62 peer-reviewed papers published between 2014 and 2023 and created a stepwise guide to the metabarcoding process. RESULTS: We found that studies in our review varied in technique and methodology, such as the sample type utilized, genetic marker regions targeted and bioinformatic databases used. The main limitations of metabarcoding are that parasite abundance data may not be reliably attained from sequence read numbers, metabarcoding data may not be representative of the species present in the host and the cost and bioinformatic expertise required to utilize this method may be prohibitive to some groups. CONCLUSIONS: Overall, using metabarcoding to assess gastrointestinal parasite communities is preferable to traditional methods, yielding higher taxonomic resolution, higher throughput and increased versatility due to its utility in any geographical location, with a variety of sample types, and with virtually any vertebrate host species. Additionally, metabarcoding has the potential for exciting new discoveries regarding host and parasite evolution.

A Retrospective Study of Fertility Counseling and Preservation Rates for Women of Reproductive Age With Breast Care After Integrating a Fertility Specialist Into a Multidisciplinary Tumor Board.

INTRODUCTION: Many breast centers have adopted multidisciplinary tumor boards to discuss and develop treatment plans for patients diagnosed with breast cancer. This study aims to determine whether adding a fertility specialist to tumor board will improve fertility counseling and utilization in breast cancer patients METHODS: A retrospective study of reproductive age patients diagnosed with breast cancer between January 1, 2012, and January 31, 2020, before and after integrating a designated fertility specialist into a comprehensive multidisciplinary care (cMDC) tumor board. Rates of fertility counseling and preservation were assessed for patients treated before (pre-cMDC) and after (post-cMDC) tumor board enhancement. Associations of race/ethnicity, age, chemotherapy, hormone receptor status, insurance type, parity, stage, site of treatment, and home county with fertility care rates were assessed in the post-cMDC group. RESULTS: Of 306 patients diagnosed with breast cancer, 117 (38%) were in the pre-cMDC and 189 (62%) were in the post-cMDC tumor board group. Significantly more patients in the post-cMDC tumor board group were offered fertility counseling than patients in the pre-cMDC tumor board group (23.3% (44) vs. 0.9% (1); P < .001). However, rate of fertility preservation did not differ significantly between groups. CONCLUSION: Integrating a fertility specialist within a cMDC tumor board may help improve rates of fertility counseling among breast cancer patients but may not improve preservation rates.

Management of small bowel obstruction in the third trimester.

Small bowel obstruction (SBO) in pregnancy is exceedingly rare. Management of SBO in the third trimester may pose particular challenges, as clinicians must determine whether or not the delivery of the fetus is indicated. In this report, we review the case of a patient in her mid-20's with no prior surgical history who presented with nausea and vomiting at 34 weeks of gestation and was ultimately diagnosed with an SBO. Following expectant management during the initial 4 days of inpatient admission, the patient subsequently underwent an exploratory laparotomy at 35 weeks without concurrent delivery. She was monitored for the remainder of her pregnancy with non-stress tests to evaluate fetal status and eventually underwent induction of labour at 39 weeks, resulting in a successful vaginal delivery. Herein, we review the challenges related to the diagnosis and management of SBO in pregnancy, as well as the maternal-fetal outcomes in the setting of SBO in the third trimester.

How medical students' trauma histories affect their clinical clerkship experiences.

BACKGROUND: As the gender demographics of medical students have evolved over the past decades, it is important to understand potential stressors and challenges that may affect clinical learning experiences. This study investigated the prevalence of prior sexual assault (SA) and interpersonal violence (IPV) in medical students and how these affect their clinical clerkship experiences. METHODS: A survey was distributed to third- and fourth-year medical students at a single institution in August 2022 querying respondents on demographics and prior experiences with SA/IPV at any point in their lives. Respondents who indicated they had previously experienced SA/IPV were directed to questions about how these experiences affected clerkships. FINDINGS: Of 419 students, 125 responded to the survey (30.8% response rate). Forty (31.1%) reported a history of SA/IPV-32 (80.0%) women, five (12.5%) men, and three (7.5%) who did not report gender or identified as non-binary. Of the 40 respondents with a history of SA/IPV, 20 (50.0%) reported that their prior history affected their overall clinical experience, and nine (22.5%) felt that it affected their performance. Only seven (17.5%) reported using any resources, such as counselling, during their clerkships. Narrative responses discussed significant effects on performing physical exams, taking a history, interacting with team members, and engaging during clerkships. DISCUSSION: This work demonstrates the high number of students affected by SA/IPV and how these prior experiences affected core components of their clerkship experiences. CONCLUSIONS: Institutions must be proactive to create better supports for learners with histories of trauma, including SA/IPV.

White-tailed deer detection rates increase when coyotes are present.

Predator species can indirectly affect prey species through the cost of anti-predator behavior responses, which may involve shifts in occupancy, space use, or movement. Quantifying the various strategies implemented by prey species to avoid adverse interactions with predators can lead to a better understanding of potential population-level repercussions. Therefore, the purpose of this study was to examine predator-prey interactions by quantifying the effect of predator species presence on detection rates of prey species, using coyotes (Canis latrans) and white-tailed deer (Odocoileus virginianus) in Central Appalachian forests of the eastern United States as a model predator-prey system. To test two competing hypotheses related to interspecific interactions, we modeled species detections from 319 camera traps with a two-species occupancy model that incorporated a continuous-time detection process. We found that white-tailed deer occupancy was independent of coyote occupancy, but white-tailed deer were more frequently detectable and had greater detection intensity at sites where coyotes were present, regardless of vegetation-related covariates. In addition, white-tailed deer detection rates at sites with coyotes were highest when presumed forage availability was relatively low. These findings suggest that white-tailed deer may be exhibiting an active avoidance behavioral response to predators by increasing movement rates when coyotes are present in an area, perhaps due to reactive evasive maneuvers and/or proactive attempts to reduce adverse encounters with them. Concurrently, coyotes could be occupying sites with higher white-tailed deer densities. Because white-tailed deer did not exhibit significant shifts in daily activity patterns based on coyote occupancy, we further suggest that white-tailed deer in our study system generally do not use temporal partitioning as their primary strategy for avoiding encounters with coyotes. Overall, our study implements a recently developed analytical approach for modeling multi-species occupancy from camera traps and provides novel ecological insight into the complex relationships between predator and prey species.

Processability of Thermoelectric Ultrafine Fibers via Electrospinning for Wearable Electronics.

Polymer-based thermoelectric generators hold great appeal in the realm of wearable electronics as they enable the utilization of body heat for power generation. Fibers produced from conducting polymers for use in thermoelectric generators have high porosity and good flexibility, providing comfort-based performance advantages over thin films for wearable electronics. Some fiber processing techniques have been explored to produce textile-based thermoelectric generators; however, they fail to approach the conductivities of polymeric thin films. Ultrafine fibers solution processed through electrospinning yield fiber diameters on the nanoscale, allowing for high surface area to volume ratios and thus low thermal conductivity; however, a number of processing challenges in electrospinning conducting polymers limit the success of preparing high performing thermoelectric textiles. In this work, the specific processing challenges inherent to electrospinning conducting polymers are addressed for both n- and p-type materials. For the p-type polymer, 63 wt % PEDOT:PSS fibers are fabricated through solution formulation improvements yielding a conductivity of 3 S/cm and a power factor of 0.1 µW/mK2. The first of their kind n-type poly(NiETT)/PVA electrospun fibers were created yielding a conductivity of 0.11 S/cm and a power factor of 0.0036 µW/mK2. These nonwoven ultrafine fiber mats show progress toward achieving textile-based thermoelectric materials with equivalent performance of comparable polymeric thin films. This work shows the feasibility of creating ultrafine fibers for use in thermoelectric generators through electrospinning including the first demonstration of poly(NiETT)/PVA fibers.

False-Positive Human Immunodeficiency Virus Screening Results in Pregnancy During the Coronavirus Disease 2019 (COVID-19) Pandemic.

False-positive human immunodeficiency virus (HIV) test results are rare but have been documented in the setting of certain underlying conditions such as Epstein-Barr virus, metastatic cancer, and certain autoimmune conditions. A retrospective cohort study in a large hospital system was conducted to compare the occurrence of false-positive HIV fourth-generation test results before and after the coronavirus disease 2019 (COVID-19) pandemic in a population of pregnant patients (N=44,187; 22,073 pre-COVID and 22,114 during COVID). The COVID cohort had a significantly higher frequency of false-positive HIV test results compared with the pre-COVID cohort (0.381 vs 0.676, P =.002). Within the COVID cohort, 25% of patients had a positive polymerase chain reaction test result for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) preceding their false-positive HIV test results. When this subgroup was excluded, the difference in frequency of false-positive HIV test results between the cohorts was no longer significant (0.381 vs 0.507, P =.348). Our findings suggest that SARS-CoV-2 seropositivity was associated with an increased frequency of false-positive HIV test results in the pregnant population.

Does lower use of academic affiliation by university faculty in top U.S. newspapers contribute to misinformation about abortion?

BACKGROUND: University faculty are considered trusted sources of information to disseminate accurate information to the public that abortion is a common, safe and necessary medical health care service. However, misinformation persists about abortion's alleged dangers, commonality, and medical necessity. METHODS: Systematic review of popular media articles related to abortion, gun control (an equally controversial topic), and cigarette use (a more neutral topic) published in top U.S. newspapers between January 2015 and July 2020 using bivariate analysis and logistic regression to compare disclosure of university affiliation among experts in each topic area. RESULTS: We included 41 abortion, 102 gun control, and 130 smoking articles, which consisted of 304 distinct media mentions of university-affiliated faculty. Articles with smoking and gun control faculty experts had statistically more affiliations mentioned (90%, n = 195 and 88%, n = 159, respectively) than abortion faculty experts (77%, n = 54) (p = 0.02). The probability of faculty disclosing university affiliation was similar between smoking and gun control (p = 0.73), but between smoking and abortion was significantly less (Ave Marginal Effects - 0.13, p = 0.02). CONCLUSIONS: Fewer faculty members disclose their university affiliation in top U.S. newspapers when discussing abortion. Lack of academic disclosure may paradoxically make these faculty appear less 'legitimate.' This leads to misinformation, branding abortion as a 'choice,' suggesting it is an unessential medical service. With the recent U.S. Supreme Court landmark decision, Dobbs v. Jackson Women's Health Organization, and subsequent banning of abortion in many U.S. states, faculty will probably be even less likely to disclose their university affiliation in the media than in the past.

RACCOONS (PROCYON LOTOR) SHOW HIGHER TRYPANOSOMA CRUZI DETECTION RATES THAN VIRGINIA OPOSSUMS (DIDELPHIS VIRGINIANA) IN SOUTH CAROLINA, USA.

Chagas disease, a significant public health concern in the Americas, is caused by a protozoan parasite, Trypanosoma cruzi. The life cycle of T. cruzi involves kissing bugs (Triatoma spp.) functioning as vectors and mammalian species serving as hosts. Raccoons (Procyon lotor) and opossums (Didelphis virginiana) have been identified as important reservoir species in the life cycle of T. cruzi, but prevalence in both species in the southeastern US is currently understudied. We quantified T. cruzi prevalence in these two key reservoir species across our study area in South Carolina, US, and identified factors that may influence parasite detection. We collected whole blood from 183 raccoons and 126 opossums and used PCR to detect the presence of T. cruzi. We then used generalized linear models with parasite detection status as a binary response variable and predictor variables of land cover, distance to water, sex, season, and species. Our analysis indicated that raccoons experienced significantly higher parasite detection rates than Virginia opossums, with T. cruzi prevalence found to be 26.5% (95% confidence interval [CI], 20.0-33.8) in raccoons and 10.5% (95% CI, 5.51-17.5) in opossums. Overall, our results concur with previous studies, in that T. cruzi is established in reservoir host populations in natural areas of the southeastern US.

Raccoon spatial ecology in the rural southeastern United States.

The movement ecology of raccoons varies widely across habitats with important implications for the management of zoonotic diseases such as rabies. However, the spatial ecology of raccoons remains poorly understood in many regions of the United States, particularly in the southeast. To better understand the spatial ecology of raccoons in the southeastern US, we investigated the role of sex, season, and habitat on monthly raccoon home range and core area sizes in three common rural habitats (bottomland hardwood, upland pine, and riparian forest) in South Carolina, USA. From 2018-2022, we obtained 264 monthly home ranges from 46 raccoons. Mean monthly 95% utilization distribution (UD) sizes ranged from 1.05 ± 0.48 km2 (breeding bottomland females) to 5.69 ± 3.37 km2 (fall riparian males) and mean monthly 60% UD sizes ranged from 0.25 ± 0.15 km2 (breeding bottomland females) to 1.59 ± 1.02 km2 (summer riparian males). Males maintained home range and core areas ~2-5 times larger than females in upland pine and riparian habitat throughout the year, whereas those of bottomland males were only larger than females during the breeding season. Home ranges and core areas of females did not vary across habitats, whereas male raccoons had home ranges and core areas ~2-3 times larger in upland pine and riparian compared to bottomland hardwood throughout much of the year. The home ranges of males in upland pine and riparian are among the largest recorded for raccoons in the United States. Such large and variable home ranges likely contribute to elevated risk of zoonotic disease spread by males in these habitats. These results can be used to inform disease mitigation strategies in the southeastern United States.

Fate of arsenicals in mice carrying the human AS3MT gene exposed to environmentally relevant levels of arsenite in drinking water.

Although mice are widely used to study adverse effects of inorganic arsenic (iAs), higher rates of iAs methylation in mice than in humans may limit their utility as a model organism. A recently created 129S6 mouse strain in which the Borcs7/As3mt locus replaces the human BORCS7/AS3MT locus exhibits a human-like pattern of iAs metabolism. Here, we evaluate dosage dependency of iAs metabolism in humanized (Hs) mice. We determined tissue and urinary concentrations and proportions of iAs, methylarsenic (MAs), and dimethylarsenic (DMAs) in male and female Hs and wild-type (WT) mice that received 25- or 400-ppb iAs in drinking water. At both exposure levels, Hs mice excrete less total arsenic (tAs) in urine and retain more tAs in tissues than WT mice. Tissue tAs levels are higher in Hs females than in Hs males, particularly after exposure to 400-ppb iAs. Tissue and urinary fractions of tAs present as iAs and MAs are significantly greater in Hs mice than in WT mice. Notably, tissue tAs dosimetry in Hs mice resembles human tissue dosimetry predicted by a physiologically based pharmacokinetic model. These data provide additional support for use of Hs mice in laboratory studies examining effects of iAs exposure in target tissues or cells.

Ribosomal DNA replication time coordinates completion of genome replication and anaphase in yeast.

Timely completion of genome replication is a prerequisite for mitosis, genome integrity, and cell survival. A challenge to this timely completion comes from the need to replicate the hundreds of untranscribed copies of rDNA that organisms maintain in addition to the copies required for ribosome biogenesis. Replication of these rDNA arrays is relegated to late S phase despite their large size, repetitive nature, and essentiality. Here, we show that, in Saccharomyces cerevisiae, reducing the number of rDNA repeats leads to early rDNA replication, which results in delaying replication elsewhere in the genome. Moreover, cells with early-replicating rDNA arrays and delayed genome-wide replication aberrantly release the mitotic phosphatase Cdc14 from the nucleolus and enter anaphase prematurely. We propose that rDNA copy number determines the replication time of the rDNA locus and that the release of Cdc14 upon completion of rDNA replication is a signal for cell cycle progression.

Evaluation of a microperforate hymen leading to the incidental diagnosis of a borderline ovarian tumour.

Microperforate hymens are rare anatomical variants with an unknown incidence and very few reported cases. Borderline ovarian tumours are similarly uncommon, with an incidence of approximately 0.002%-0.006%. The concurrent presence of a microperforate hymen and a borderline ovarian tumour is therefore exceedingly unique with no documented cases to date. In this report, we review the case of a nulliparous woman in her late 20s who initially presented with an inability to have penetrative intercourse. A subocclusive hymenal variant was noted on examination and further imaging work-up resulted in the incidental discovery of a large ovarian mass subsequently noted to be a borderline ovarian tumour. Herein, we review contemporary approaches to the diagnosis and management of both hymenal variants and borderline ovarian tumours, and discuss fertility-sparing strategies for young women diagnosed with ovarian neoplasms.

An epigenetic switch regulates the ontogeny of AXL-positive/EGFR-TKi-resistant cells by modulating miR-335 expression.

Despite current advancements in research and therapeutics, lung cancer remains the leading cause of cancer-related mortality worldwide. This is mainly due to the resistance that patients develop against chemotherapeutic agents over the course of treatment. In the context of non-small cell lung cancers (NSCLC) harboring EGFR-oncogenic mutations, augmented levels of AXL and GAS6 have been found to drive resistance to EGFR tyrosine kinase inhibitors such as Erlotinib and Osimertinib in certain tumors with mesenchymal-like features. By studying the ontogeny of AXL-positive cells, we have identified a novel non-genetic mechanism of drug resistance based on cell-state transition. We demonstrate that AXL-positive cells are already present as a subpopulation of cancer cells in Erlotinib-naïve tumors and tumor-derived cell lines and that the expression of AXL is regulated through a stochastic mechanism centered on the epigenetic regulation of miR-335. The existence of a cell-intrinsic program through which AXL-positive/Erlotinib-resistant cells emerge infers the need of treating tumors harboring EGFR-oncogenic mutations upfront with combinatorial treatments targeting both AXL-negative and AXL-positive cancer cells.

Opioid Use Disorders in People Living with HIV/AIDS: A Review of Implications for Patient Outcomes, Drug Interactions, and Neurocognitive Disorders.

The opioid epidemic has had a significant, negative impact in the United States, and people living with HIV/AIDS (PLWHA) represent a vulnerable sub-population that is at risk for negative sequela from prolonged opioid use or opioid use disorder (OUD). PLWHA are known to suffer from HIV-related pain and are commonly treated with opioids, leading to subsequent addictive disorders. PLWHA and OUD are at an increased risk for attrition in the HIV care continuum, including suboptimal HIV laboratory testing, delayed entry into HIV care, and initiation or adherence to antiretroviral therapy. Barriers to OUD treatment, such as medication-assisted therapy, are also apparent for PLWHA with OUD, particularly those living in rural areas. Additionally, PLWHA and OUD are at a high risk for serious drug-drug interactions through antiretroviral-opioid metabolic pathway-related inhibition/induction, or via the human ether-a-go-go-related gene potassium ion channel pathways. HIV-associated neurocognitive disorders can also be potentiated by the off-target inflammatory effects of opioid use. PLWHA and OUD might require more intensive, individualized protocols to sustain treatment for the underlying opioid addiction, as well as to provide proactive social support to aid in improving patient outcomes. Advancements in the understanding and management of PLWHA and OUD are needed to improve patient care. This review describes the effects of prescription and non-prescription opioid use in PLWHA.