A long noncoding RNA at the cortex locus controls adaptive coloration in butterflies.

Evolutionary variation in the wing pigmentation of butterflies and moths offers striking examples of adaptation by crypsis and mimicry. The cortex locus has been independently mapped as the locus controlling color polymorphisms in 15 lepidopteran species, suggesting that it acts as a genomic hotspot for the diversification of wing patterns, but functional validation through protein-coding knockouts has proven difficult to obtain. Our study unveils the role of a long noncoding RNA (lncRNA) which we name ivory, transcribed from the cortex locus, in modulating color patterning in butterflies. Strikingly, ivory expression prefigures most melanic patterns during pupal development, suggesting an early developmental role in specifying scale identity. To test this, we generated CRISPR mosaic knock-outs in five nymphalid butterfly species and show that ivory mutagenesis yields transformations of dark pigmented scales into white or light-colored scales. Genotyping of Vanessa cardui germline mutants associates these phenotypes to small on-target deletions at the conserved first exon of ivory. In contrast, cortex germline mutant butterflies with confirmed null alleles lack any wing phenotype and exclude a color patterning role for this adjacent gene. Overall, these results show that a lncRNA gene acts as a master switch of color pattern specification and played key roles in the adaptive diversification of wing patterns in butterflies.

A butterfly pan-genome reveals that a large amount of structural variation underlies the evolution of chromatin accessibility.

Despite insertions and deletions being the most common structural variants (SVs) found across genomes, not much is known about how much these SVs vary within populations and between closely related species, nor their significance in evolution. To address these questions, we characterized the evolution of indel SVs using genome assemblies of three closely related Heliconius butterfly species. Over the relatively short evolutionary timescales investigated, up to 18.0% of the genome was composed of indels between two haplotypes of an individual Heliconius charithonia butterfly and up to 62.7% included lineage-specific SVs between the genomes of the most distant species (11 Mya). Lineage-specific sequences were mostly characterized as transposable elements (TEs) inserted at random throughout the genome and their overall distribution was similarly affected by linked selection as single nucleotide substitutions. Using chromatin accessibility profiles (i.e., ATAC-seq) of head tissue in caterpillars to identify sequences with potential cis-regulatory function, we found that out of the 31,066 identified differences in chromatin accessibility between species, 30.4% were within lineage-specific SVs and 9.4% were characterized as TE insertions. These TE insertions were localized closer to gene transcription start sites than expected at random and were enriched for sites with significant resemblance to several transcription factor binding sites with known function in neuron development in Drosophila We also identified 24 TE insertions with head-specific chromatin accessibility. Our results show high rates of structural genome evolution that were previously overlooked in comparative genomic studies and suggest a high potential for structural variation to serve as raw material for adaptive evolution.

PIEZO1 regulates leader cell formation and cellular coordination during collective keratinocyte migration.

The collective migration of keratinocytes during wound healing requires both the generation and transmission of mechanical forces for individual cellular locomotion and the coordination of movement across cells. Leader cells along the wound edge transmit mechanical and biochemical cues to ensuing follower cells, ensuring their coordinated direction of migration across multiple cells. Despite the observed importance of mechanical cues in leader cell formation and in controlling coordinated directionality of cell migration, the underlying biophysical mechanisms remain elusive. The mechanically-activated ion channel PIEZO1 was recently identified to play an inhibitory role during the reepithelialization of wounds. Here, through an integrative experimental and mathematical modeling approach, we elucidate PIEZO1's contributions to collective migration. Time-lapse microscopy reveals that PIEZO1 activity inhibits leader cell formation at the wound edge. To probe the relationship between PIEZO1 activity, leader cell formation and inhibition of reepithelialization, we developed an integrative 2D continuum model of wound closure that links observations at the single cell and collective cell migration scales. Through numerical simulations and subsequent experimental validation, we found that coordinated directionality plays a key role during wound closure and is inhibited by upregulated PIEZO1 activity. We propose that PIEZO1-mediated retraction suppresses leader cell formation which inhibits coordinated directionality between cells during collective migration.

Furthering Scientific Inquiry for Weight Loss Maintenance: Assessing the Psychological Processes Impacted by a Low intensity Technology-Assisted Intervention (NULevel Trial).

BACKGROUND: NULevel was a randomized control trial to evaluate a technology-assisted weight loss maintenance (WLM) program in the UK. The program included: (a) a face-to-face goal-setting session; (b) an internet platform, a pedometer, and wirelessly connected scales to monitor and report diet, physical activity, and weight, and; (c) regular automated feedback delivered by mobile phone, tailored to participants' progress. Components were designed to target psychological processes linked to weight-related behavior. Though intervention participants showed increased physical activity, there was no difference in WLM between the intervention and control groups after 12 months (Sniehotta FF, Evans EH, Sainsbury K, et al. Behavioural intervention for weight loss maintenance versus standard weight advice in adults with obesity: A randomized controlled trial in the UK (NULevel Trial). PLoS Med. 2019; 16(5):e1002793. doi:10.1371/journal.pmed.1002793). It is unclear whether the program failed to alter targeted psychological processes, or whether changes in these processes failed to influence WLM. PURPOSE: We evaluate whether the program influenced 16 prespecified psychological processes (e.g., self-efficacy and automaticity toward diet and physical activity), and whether these processes (at 6 months) were associated with successful WLM (at 12 months). METHODS: 288 adults who had previously lost weight were randomized to the intervention or control groups. The control group received wireless scales and standard advice via newsletters. Assessments occurred in person at 0, 6, and 12 months. RESULTS: The intervention significantly altered 10 of the 16 psychological processes, compared with the control group. However, few processes were associated with WLM, leading to no significant indirect effects of the intervention via the processes on WLM. CONCLUSIONS: Changes in targeted processes were insufficient to support WLM. Future efforts may more closely examine the sequence of effects between processes, behavior, and WLM.

Many tools exist to help people lose weight, but it is common for people to regain that weight over time. Thus, understanding how to support the maintenance of weight loss remains a priority. The NULevel program was a 12-month weight loss maintenance (WLM) intervention for individuals who had recently lost weight. It promoted psychological factors, shown to be tied to weight-related behaviors, using face-to-face and technology-based (e.g., mobile phone feedback) elements. For example, the program encouraged making plans to improve lifestyles (e.g., exercise, better diet) and promoted people's confidence in these behaviors. However, the program was not more successful than a control condition in maintaining weight loss. We sought to understand why this occurred. We found that the program was indeed successful in influencing most of the psychological factors it targeted. Instead, it was the psychological factors that failed to predict WLM. Were the psychological factors insufficient to impact behavior? Or did the promoted behaviors fail to aid WLM? Future research should focus on answering such questions. Doing so would inform whether interventions should target different psychological factors to change behaviors, or choose different sets of behaviors to support WLM.

A phase 1/2 study of pepinemab in children, adolescents, or young adults with recurrent or refractory solid tumors: A children's oncology group consortium report (ADVL1614).

PURPOSE: Pepinemab, a humanized IgG4 monoclonal antibody, targets the SEMA4D (CD100) antigen to inhibit binding to its high-affinity receptors (plexin B1/PLXNB1, plexin B2/PLXNB2) and low-affinity receptor (CD72). SEMA4D blockade leads to increased cytotoxic T-cell infiltration, delayed tumor growth, and durable tumor rejection in murine tumor models. Pepinemab was well tolerated and improved T cell infiltration in clinical studies in adults with refractory tumors. SEMA4D was identified as a strong candidate proto-oncogene in a model of osteosarcoma. Based on these preclinical and clinical data, we conducted a phase 1/2 study to determine the recommended phase 2 dose (RP2D), pharmacokinetics, pharmacodynamics, and immunogenicity, of pepinemab in pediatric patients with recurrent/refractory solid tumors, and activity in osteosarcoma. EXPERIMENTAL DESIGN: Pepinemab was administered intravenously on Days 1 and 15 of a 28-day cycle at 20 mg/kg, the adult RP2D. Part A (phase 1) used a Rolling 6 design; Part B (phase 2) used a Simon 2-stage design in patients with osteosarcoma. Pharmacokinetics and target saturation were evaluated in peripheral blood. RESULTS: Pepinemab (20 mg/kg) was well tolerated and no dose-limiting toxicities were observed during Part A. There were no objective responses. Two patients with osteosarcoma achieved disease control and prolonged stable disease. Pepinemab pharmacokinetics were similar to adults. CONCLUSIONS: Pepinemab (20 mg/kg) is safe, well tolerated and resulted in adequate and sustained target saturation in pediatric patients. Encouraging disease control in two patients with osteosarcoma warrants further investigation with novel combination strategies to modulate the tumor microenvironment and antitumor immune response. CLINICAL TRIAL REGISTRY: This trial is registered as NCT03320330 at Clinicaltrials.gov. DISCLAIMER: The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Gender identity, stimulant drug use, and criminal justice history on internalized stigma among a nationally representative sample of adults who misuse opioids.

PURPOSE: The rise of fatal stimulant use among adults who use opioids is a public health problem. Internalized stigma is a barrier to substance use treatment, which is greater for women and populations with criminal justice involvement. METHODS: Using a nationally representative sample of adults in the United States from a probability-based survey on household opinions in 2021, we examined characteristics of women (n = 289) and men (n = 416) who misuse opioids. In gender-stratified multivariable linear regression, we investigated factors associated with internalized stigma, and tested for the interaction of stimulant use and criminal justice involvement. RESULTS: Compared to men, women reported greater mental health symptom severity (3.2 vs. 2.7 on a 1 to 6 scale, p < 0.001). Internalized stigma was similar between women (2.3 ± 1.1) and men (2.2 ± 0.1). Among women and not men, however, stimulant use was positively associated with internalized stigma (0.36, 95% CI [0.07, 0.65]; p = 0.02). Interaction between stimulant use and criminal justice involvement was negatively associated with internalized stigma among women (- 0.60, 95% CI [- 1.16, -0.04]; p = 0.04); among men, the interaction was not significant. Predictive margins illustrate among women, stimulant use eliminated the gap in internalized stigma such that women with no criminal justice involvement had a similar level of internalized stigma as women with criminal justice involvement. CONCLUSION: Internalized stigma between women and men who misuse opioids differed based on stimulant use and criminal justice involvement. Future research should assess whether internalized stigma influences treatment utilization among women with criminal justice involvement.

"Expected to happen": perspectives on post-release overdose from recently incarcerated people with opioid use disorder.

BACKGROUND: Opioid-related overdose is the leading cause of death for people recently released from incarceration, however treatment with medications for opioid use disorder (MOUD) during incarceration can reduce the mortality risk. This study seeks to qualitatively analyze perceptions of post-release overdose risk from the perspectives of people who received MOUD while incarcerated in one of eight Massachusetts jails during 2021-2022 using the Risk Environment Framework to guide analyses. METHODS: N = 38 participants with lived experience of MOUD treatment during incarceration who are now living in the community were interviewed on factors that may contribute to or protect against post-release overdose risk. Themes were identified inductively and deductively using the Risk Environment Framework and its domains, which organizes themes along physical, social, economic, and policy environments on both the micro- and macro- scales. RESULTS: The physical risk environment included loss of opioid tolerance during incarceration, polysubstance use, and the toxicity of the regional drug supply as key producers of increased risk for post-release overdose. Social drivers of risk included peer group risk norms-including peer-driven harm reduction practices and interpersonal relationships between drug sellers and buyers-as well as macro-level social determinants of health such as housing insecurity and availability of mental health services. Economic drivers of post-release overdose risk included lack of income generation during incarceration and employment challenges. Participants discussed several aspects of policy that contribute to post-release overdose risk, including availability of harm reduction supplies, public health services, and broader policy around MOUD. CONCLUSIONS: The perspectives of people with lived experience are vital to understanding the disproportionate risks of overdose for those recently released from incarceration. Our results highlight the intersectional factors that produce and reproduce the post-release overdose risk environment, providing support for interventions across each domain of the Risk Environment Framework. By capturing perspectives from people with lived experience of OUD and incarceration during this critical period of risk, we can better identify interventions that target and mitigate overdose-related harm in this population.

Lessons Learned from Implementation of a Post-opioid Overdose Outreach Program in a Rural Massachusetts Community.

Post-overdose outreach programs can play a key role in reducing opioid overdose deaths and increasing access to healthcare services. The design and implementation of these programs, especially in rural communities, remains a gap in knowledge. We aimed to understand the lessons learned from the implementation experiences of the Community, Opportunity, Network, Navigation, Exploration, and Connection Team (CONNECT), a post-overdose outreach program based in a rural community in Massachusetts. We conducted semi-structured focus groups and interviews with 21 community partners after the first year of implementation in 2022. Participants included behavioral health, medical, public health, and public safety personnel involved in the design and implementation of CONNECT. Using a combination of thematic and rapid qualitative analysis methods, we inductively coded transcripts for salient themes. Themes were mapped onto the Health Equity Implementation Framework to better understand implementation and health-equity factors. Facilitators to implementation of this innovation included efficient inter-partner data sharing and coordination, and ability to offer numerous health services to clients to meet their needs. Key partners identified that CONNECT serves clients who use opioids, have previous involvement with the legal system, and reside in low-income areas within this rural region. Unhoused individuals and individuals who do not call 9-11 after an overdose were identified as populations of need that CONNECT was missing due to structural barriers. Partners shared how the context of this rural community came with challenges related to limited access to health services and pervasive stigma towards substance use, while it was also perceived to foster a culture of collaboration and unity among multidisciplinary key partners. Post overdose outreach programs serve clients with complex health needs. The ability to access services for these health needs is shaped by the post overdose outreach program and its key partners, and by the broader community context. As post-overdose outreach programs continue to expand as a promising strategy to address the opioid overdose crisis, there exists a need to contextualize implementation strategies to inform adaptations and develop best-practices.

The Intersection of Social Determinants of Health and Post-stroke Aphasia Outcomes: A Need for Intersectional Analysis.

Aphasia is a disorder that results from damage to portions of the brain that are responsible for language and can vary significantly by type and severity. Differences in aphasia outcomes are influenced by the social determinants of health (SDOH). The SDOH are structural, environmental, and personal determinants that influence health outcomes. Intersectionality, or how one's social and political identities interact to influence individual life outcomes and/or advantage in our society, provides a way to examine the varying levels of the SDOH. However, intersectionality is complex, difficult to measure, and has not yet been explored in post-stroke aphasia outcomes. This article reviews the relationship of race and aphasia outcomes and the SDOH and aphasia outcomes. Additionally, we provide a novel current approach to examine the SDOH and aphasia outcomes. Lastly, we discuss the need for evaluation of intersectionality in aphasia and aim to provide a leveled social-ecological framework to examine aphasia-related outcomes. With notable individual differences among aphasia outcomes, we present a framework to support optimizing research and clinical aphasia care in speech-language pathology.

Evolving roles of activins and inhibins in ovarian cancer pathophysiology.

Activins and inhibins are unique members of the transforming growth factor-ß (TGFß) family of growth factors, with the ability to exert autocrine, endocrine, and paracrine effects in a wide range of complex physiologic and pathologic processes. Although first isolated within the pituitary, emerging evidence suggests broader influence beyond reproductive development and function. Known roles of activin and inhibin in angiogenesis and immunity along with correlations between gene expression and cancer prognosis suggest potential roles in tumorigenesis. Here, we present a review of the current understanding of the biological role of activins and inhibins as it relates to ovarian cancers, summarizing the underlying signaling mechanisms and physiologic influence, followed by detailing their roles in cancer progression, diagnosis, and treatment.

Widespread Gene Expression Divergence in Butterfly Sensory Tissues Plays a Fundamental Role During Reproductive Isolation and Speciation.

Neotropical Heliconius butterflies are well known for their intricate behaviors and multiple instances of incipient speciation. Chemosensing plays a fundamental role in the life history of these groups of butterflies and in the establishment of reproductive isolation. However, chemical communication involves synergistic sensory and accessory functions, and it remains challenging to investigate the molecular mechanisms underlying behavioral differences. Here, we examine the gene expression profiles and genomic divergence of three sensory tissues (antennae, legs, and mouthparts) between sexes (females and males) and life stages (different adult stages) in two hybridizing butterflies, Heliconius melpomene and Heliconius cydno. By integrating comparative transcriptomic and population genomic approaches, we found evidence of widespread gene expression divergence, supporting a crucial role of sensory tissues in the establishment of species barriers. We also show that sensory diversification increases in a manner consistent with evolutionary divergence based on comparison with the more distantly related species Heliconius charithonia. The findings of our study strongly support the unique chemosensory function of antennae in all three species, the importance of the Z chromosome in interspecific divergence, and the nonnegligible role of nonchemosensory genes in the divergence of chemosensory tissues. Collectively, our results provide a genome-wide illustration of diversification in the chemosensory system under incomplete reproductive isolation, revealing strong molecular separation in the early stage of speciation. Here, we provide a unique perspective and relevant view of the genetic architecture (sensory and accessory functions) of chemosensing beyond the classic chemosensory gene families, leading to a better understanding of the magnitude and complexity of molecular changes in sensory tissues that contribute to the establishment of reproductive isolation and speciation.

A call to action: Contingency management to improve post-release treatment engagement among people with opioid use disorder who are incarcerated.

People with opioid use disorder (OUD) are overrepresented in US correctional facilities and experience disproportionately high risk for illicit opioid use and overdose after release. A growing number of correctional facilities offer medication for OUD (MOUD), which is effective in reducing these risks. However, a recent evaluation found that <50% of those prescribed MOUD during incarceration continued MOUD within 30 days after release, demonstrating a need to improve post-release continuity of care. We describe available evidence on contingency management (CM), an intervention wherein patients receive incentives contingent on behavior change, to achieve this goal. A prior systematic review reported strong evidence in support of CM for increasing treatment adherence in MOUD programs, but the trials reviewed did not include incarcerated participants. Research on CM to increase treatment adherence among participants in the criminal justice system is limited with mixed findings. However, in comparison to the trials that supported CM's efficacy in the community, CM trials in the criminal justice system provided smaller rewards with greater delays in the delivery of rewards to patients, which likely contributed to null findings. Indeed, a prior meta-analysis demonstrates a dose-response relationship between the magnitude and immediacy of reward and CM effectiveness. Thus, CM involving larger and more immediately delivered rewards are likely necessary to improve MOUD adherence during the critical period following release from incarceration. Future research on the effectiveness and implementation of CM to improve MOUD retention after release from incarceration is warranted.

Use of Big Data and Ethical Issues for Populations With Substance Use Disorder.

With expanding data availability and computing power, health research is increasingly relying on big data from a variety of sources. We describe a state-level effort to address aspects of the opioid epidemic through public health research, which has resulted in an expansive data resource combining dozens of administrative data sources in Massachusetts. The Massachusetts Public Health Data Warehouse is a public health innovation that serves as an example of how to address the complexities of balancing data privacy and access to data for public health and health services research. We discuss issues of data protection and data access, and provide recommendations for ethical data governance. Keeping these issues in mind, the use of this data resource has the potential to allow for transformative research on critical public health issues.

"And Then COVID Hits": A Qualitative Study of How Jails Adapted Services to Treat Opioid Use Disorder During COVID-19.

Background: Jails in Massachusetts are among the first nationwide to provide correctional populations with medications to treat opioid use disorder (MOUD). The COVID-19 pandemic caused jails to pivot and adapt MOUD programming. We aimed to identify adaptations and barriers to MOUD access that COVID-19 exacerbated or created, and document new elements that staff wish to sustain as COVID-19 recedes. Methods: We conducted semi-structured in-depth interviews and focus groups in 2020-2021 with 29 jail staff who implement MOUD programming in two Massachusetts jails. We conducted qualitative data analysis in Atlas.ti 8 using an inductive approach. Results: Participants shared that access to MOUD among correctional populations is understood by jail staff to be an essential health service. Thus, to facilitate continued access to MOUD, both during incarceration and also at community reentry, jail staff quickly implemented changes in MOUD regulations and dosing protocols and established telehealth capacity. Despite these program adaptations, participants identified how COVID-19 increased health and social needs among correctional populations, reduced availability of community-based healthcare and recovery-supportive services, and introduced new factors that could undermine recovery. Innovations that participants wished to sustain as COVID-19 receded included telehealth capacity, smaller-sized therapeutic groups, and application of a public health approach to treat opioid use disorder among correctional populations. Conclusions: During disruptive events, jails can adapt MOUD programming to ensure access for people living in jail and upon release. Findings identify factors for understanding the outcomes of jail-based MOUD programming during COVID-19 and highlight opportunities to improve service delivery after COVID-19.

Predictors of Functioning and Recovery Among Men and Women Veterans with Schizophrenia.

Gender differences may play a role in functional outcomes for individuals with schizophrenia. To better understand differences, an exploratory secondary analysis was conducted using data from a large, multi-site study of individuals with schizophrenia in treatment at Veterans Affairs medical centers. Participants completed surveys at baseline (n = 801; 734 men, 67 women) to assess demographics, symptoms, social supports, and recovery; and one year (n = 662; 604 men, 58 women) to assess quality of life and functioning. Hierarchical linear regressions examined interactions of baseline factors with functioning and quality of life. Women and men did not differ significantly in baseline social support, psychiatric symptoms, or recovery. Female gender predicted higher occupational functioning, while social functioning in men was inversely related to baseline symptom severity. Being married predicted higher quality of life for women, but not men. These findings may inform gender tailoring of services for schizophrenia.

Holyoke Early Access to Recovery and Treatment (HEART): A case study of a court-based intervention to reduce opioid overdose.

The District Court in Holyoke, Massachusetts, is among the first courts nationwide to provide access to medications for opioid use disorder (MOUD) and other treatment. The program uses an innovative multisectoral approach to serve a primarily Latinx population living in communities of concentrated poverty with high opioid overdose rates. We document the origins, adaptations, and current status of program operations, including the use of on-site peer recovery specialists and robust data collection efforts. From August 16, 2021, to February 28, 2022, of the 1040 individuals who entered the court for an arraignment, 47.9% (n = 498) were eligible for program participation. Of those 498 individuals, 54.2% (n = 270) spoke with a recovery specialist. Many self-identified as Latinx (53.0%) and male (69.3%). Over one-fourth (27.0%) were connected to a long-term peer recovery specialist and 11.5% were directly connected to a MOUD provider. Semi-structured interviews with key implementers and participants revealed a shared appreciation for the life-saving efforts of the program. We conclude with practical and theoretical considerations required to offer linkage to MOUD in court-based contexts. Future efforts will assess participant outcomes to determine whether the program is an effective and feasible intervention that can be adopted by other court-based settings.

Semaphorin 4D is upregulated in neurons of diseased brains and triggers astrocyte reactivity.

BACKGROUND: The close interaction and interdependence of astrocytes and neurons allows for the possibility that astrocyte dysfunction contributes to and amplifies neurodegenerative pathology. Molecular pathways that trigger reactive astrocytes may represent important targets to preserve normal homeostatic maintenance and modify disease progression. METHODS: Semaphorin 4D (SEMA4D) expression in the context of disease-associated neuropathology was assessed in postmortem brain sections of patients with Huntington's (HD) and Alzheimer's disease (AD), as well as in mouse models of HD (zQ175) and AD (CVN; APPSwDI/NOS2-/-) by immunohistochemistry. Effects of SEMA4D antibody blockade were assessed in purified astrocyte cultures and in the CVN mouse AD model. CVN mice were treated weekly from 26 to 38 weeks of age; thereafter mice underwent cognitive assessment and brains were collected for histopathology. RESULTS: We report here that SEMA4D is upregulated in neurons during progression of neurodegenerative diseases and is a trigger of reactive astrocytes. Evidence of reactive astrocytes in close proximity to neurons expressing SEMA4D is detected in brain sections of patients and mouse models of HD and AD. We further report that SEMA4D-blockade prevents characteristic loss of GABAergic synapses and restores spatial memory and learning in CVN mice, a disease model that appears to reproduce many features of AD-like pathology including neuroinflammation. In vitro mechanistic studies demonstrate that astrocytes express cognate receptors for SEMA4D and that ligand binding triggers morphological variations, and changes in expression of key membrane receptors and enzymes characteristic of reactive astrocytes. These changes include reductions in EAAT-2 glutamate transporter and glutamine synthetase, key enzymes in neurotransmitter recycling, as well as reduced GLUT-1 glucose and MCT-4 lactate transporters, that allow astrocytes to couple energy metabolism with synaptic activity. Antibody blockade of SEMA4D prevented these changes and reversed functional deficits in glucose uptake. CONCLUSIONS: Collectively, these results suggest that SEMA4D blockade may ameliorate disease pathology by preserving normal astrocyte function and reducing the negative consequences of reactive astrogliosis.

Development of Delivery Systems for Local Administration of Cytokines/Cytokine Gene-Directed Therapeutics: Modern Oncologic Implications.

PURPOSE OF REVIEW: In this review, we discuss modern cytokine delivery systems in oncologic care, focusing on modalities being developed in the clinical trials or currently in use. These include pegylation, immune-cytokine drug conjugates, cytokine-expressing plasmid nanoparticles, nonviral cytokine nanoparticles, viral systems, and AcTakines. RECENT FINDINGS: Cytokine therapy has the potential to contribute to cancer treatment options by modulating the immune system towards an improved antitumor response and has shown promise both independently and in combination with other immunotherapy agents. Despite promising preliminary studies, systemic toxicities and challenges with administration have limited the impact of unmodified cytokine therapy. In the last decade, novel delivery systems have been developed to address these challenges and facilitate cytokine-based oncologic treatments. Novel delivery systems provide potential solutions to decrease dose-limiting side effects, facilitate administration, and increase the therapeutic activity of cytokine treatments in oncology care. The expanding clinical and translational research in these systems provides an opportunity to augment the armamentarium of immune oncology and may represent the next frontier of cytokine-based immuno-oncology.

Laser in situ Fenestration in Thoracic Endovascular Aortic Repair: A Single-Center Analysis.

BACKGROUND: Laser in situ fenestration (LISF) is an expanding technique for arch vessel revascularization in thoracic endovascular aortic repair (TEVAR). We present a single center's early and midterm outcomes using adjunctive LISF with TEVAR for treatment of various arch pathologies. METHODS: 24 patients underwent TEVAR with LISF (2017-2020). Patients were evaluated by an Aortic Team consisting of cardiothoracic and vascular surgeons and were deemed unfit for open surgical repair. Informed consent emphasized the procedure's off-label nature. Thoracic stent-grafts were sized by preoperative Computed Tomography Angiogram and intraoperative Intravascular Ultrasound, with oversizing determined by pathology. Extra-anatomic debranching was performed in staged or concurrent fashion based on urgency of repair and access site options for branch fenestration. A 2.3 mm Spectranetics laser was used, with access site determined at surgeon discretion. Covered balloon expandable stent-grafts were deployed with 0-10% oversizing. RESULTS: In 24 patients, a total of 30 fenestrations were created (LSA N = 19, LCCA N = 3, Innominate N = 7, RSA N = 1) with 1 (N = 18) or 2 (N = 6) fenestrations/patient. Indications included aneurysm (8), chronic dissection with aneurysmal degeneration (8), acute dissection (4), intramural hematoma (2), and pseudoaneurysm (2). 13 cases were elective, and 11 were emergent. Technical success was 100%. 12 patients underwent concurrent (N = 8) or staged (N = 4) extra-anatomic bypass. The major complication rate was 21%, including stroke (N = 3) and 30-day mortality (N = 2). The overall complication rate was 58%. Over a mean follow up of 261 days (15-864 days), 7 patients (32%) have required reinterventions. CONCLUSIONS: LISF for branch revascularization in TEVAR is technically feasible for treating various aortic arch pathologies, demonstrating practicality in both elective and emergent settings. With a morbidity and mortality profile that is favorable compared to that of open repair, LISF with TEVAR is a promising potential option for patients with complex arch pathology and prohibitive open surgical risk.

A unique presentation of Colovesical fistula.

A colovesical fistula (CVF) is a pathological connection between the colon and the urinary bladder. Although they are uncommon, consequences can severely affect quality of life and mortality. Diverticula are the most common cause of CVF. This case details a patient's CVF diagnosis in the emergency department with unremitting gastrointestinal and urinary symptoms. A 78-year-old male patient with recent hospitalization for stroke and left carotid endarterectomy complicated by urinary retention treated with a Foley catheter presented to the Emergency Department with a chief complaint of hematuria and unremitting diarrhea. Foley exchange resulted in improved urinary retention and diarrhea during hospitalization. One day following hospital discharge, the patient presented again with a blocked Foley catheter and diarrhea. Foley irrigations resulting in near immediate diarrhea and lack of bladder filling on bladder scan portended to a diagnosis of colovesical fistula despite no history diverticula or colon malignancy. An abdominal/pelvic computed tomography scan and cystogram confirmed a colovesical fistula. This case highlights the need for consideration of colovesical fistula in a seemingly simple ED complaint of urinary retention. It is prudent to closely follow bladder scan volumes when flushing a Foley catheter. Given the significant comorbidities such as urosepsis and health care impact of repeat ED visits and hospitalizations, CVF can and should be entertained and rapidly diagnosed in the emergency department. Our case highlights the need for consideration of a vesico-colic fistula despite the absence of initial relevant risk factors.