Tumor-infiltrating lymphocytes in necrotic tumors after melanoma neoadjuvant anti-PD1 therapy correlate with pathological response and recurrence-free survival.

PURPOSE: Neoadjuvant anti-PD1 therapy in melanoma may increase tumor-infiltrating lymphocytes (TILs), and more TILs are associated with better treatment response. A major pathological response (MPR) in melanoma after neoadjuvant anti-PD1 therapy usually comprises tumor necrosis and fibrosis. The role of TILs in necrotic tumor necrosis (nTILs) has not been explored. EXPERIMENTAL DESIGN: We performed CD3 and CD8 immunohistochemical stains on 41 melanomas with geographic necrosis. 14 were immunotherapy-naïve, and 27 had been treated with one dose of neoadjuvant anti-PD-1 in two clinical trials. CD3+ and CD8+ nTILs were graded as absent/minimal or moderate/brisk. The percentage of necrotic areas in the tumor bed before and after treatment was quantified. Endpoints were MPR and 5-year recurrence-free survival (RFS). RESULTS: In the immunotherapy-naïve cohort, 3/14 (21%) specimens had moderate/brisk CD3+, and 2/14 (14%) had moderate/brisk CD8+ nTILs. In the treated cohort, 16/27 (59%) specimens had moderate/brisk CD3+, and 15/27 (56%) had moderate/brisk CD8+ nTILs, higher than the naïve cohort (CD3, p=0.046; CD8, p=0.018). Tumor necrosis was significantly increased after anti-PD1 therapy (p=0.007). In the treated cohort, moderate/brisk CD3+ and CD8+ nTILs correlated with MPR (p=0.042, p=0.019, respectively). Treated patients with moderate/brisk CD3+ nTILs had higher 5-year RFS than those with absent/minimal nTILs (69% versus 0%; p=0.006). This persisted on multivariate analysis (HR 0.16, 95% CI 0.03-0.84, p=0.03), adjusted for pathologic response, which was borderline significant (HR 0.26, 95% CI 0.07-1.01, p=0.051). CONCLUSIONS: CD3+ and CD8+ nTILs are associated with pathological response and 5-year RFS in melanoma patients after neoadjuvant anti-PD1 therapy.

Review of skin grafting in equine wounds: indications and techniques.

Skin grafting is a simple technique that can be performed by equine practitioners to improve cosmetic outcomes in wounds with large skin defects that would not heal functionally or cosmetically with standard wound therapy interventions. Successful skin grafting is not difficult but relies upon appropriate preparation of the wound bed and effective immobilisation of the grafted area after skin graft placement. Prior to grafting, the wound bed should be treated with a moist wound healing dressing to prepare the granulation tissue bed to receive the graft. For best results, skin grafts should be placed in wounds free of infection with healthy granulation tissue, and motion should be reduced in the graft region in the early postoperative period. When successful, skin grafts cover granulation tissue and encourage wound contraction and epithelialisation while decreasing exuberant granulation tissue resulting in a more cosmetic result. This review will advance practitioners' understanding of skin grafting in horses, including graft classification and techniques, donor site selection, recipient site preparation, postoperative management strategies to optimise graft retention and ongoing research in this field.

Post-Dobbs Abortion Restrictions and the Families They Leave Behind.

The June 24, 2022 US Supreme Court decision in Dobbs v Jackson Women's Health Organization resulted in an expansive restriction on abortion access that had been constitutionally guaranteed for nearly half a century. Currently, 14 states have implemented complete bans on abortion with very limited exceptions, and an additional 7 states have implemented abortion bans at 6 to 18 weeks' gestation. It has been well demonstrated that restrictive policies disproportionately limit abortion access for minoritized people and people of low socioeconomic status; the financial and geographic barriers of these post-Dobbs restrictions will only exacerbate this disparity. Proponents of abortion restrictions, who identify as pro-life, assert that these policies are essential to protect children, women, and families. We examine whether the protection of these groups extends past conception by evaluating the association between state abortion legislation and state-based policies and programs designed to provide medical and social support for children, women, and families. We found that states with the most restrictive post-Dobbs abortion policies in fact have the least comprehensive and inclusive public infrastructure to support these groups. We suggest further opportunities for advocacy. (Am J Public Health. 2024;114(10):1043-1050. https://doi.org/10.2105/AJPH.2024.307792).

Clinical characteristics associated with problematic pornography use among individuals seeking treatment for opioid use disorder.

Background and Aims: Many jurisdictions are experiencing opioid epidemics. Opioid use disorder (OUD) often co-occurs with other psychiatric disorders including behavioral addictions like gambling disorder. However, little is known regarding the frequency and correlates of problematic pornography use (PPU) among people seeking treatment for OUD. Here we aimed to investigate PPU and its correlates in people seeking OUD treatment. Method: From October 2018 to March 2020, 1,272 individuals seeking OUD treatment were screened for PPU by completing the Brief Pornography Screen (BPS), a 5-item instrument validated for assessing PPU. Self-reported data were used. Results: Among the sample there were 707 (60%) males and 565 (40%) females. The mean age of participants was 37.9 ± 10.5 years (range 18-73), there were 707 (60%) males and 565 (40%) females, 14.4% (n = 183) exhibited low positive BPS scores (1 ≤ score ≤4), and 4.5% of the sample (n = 57) screened positive for PPU (BPS score ≥4). Individuals screening positive for PPU versus negative were mostly male (77%), scored higher on measures of impulsivity in the domains of positive urgency, negative urgency, and sensation-seeking and demonstrated more psychopathology on measures of substance use, psychotic symptoms, emotional lability, depression/functioning and self-harm. Discussion and Conclusion: A minority of individuals seeking treatment for OUD screened positive for PPU. Among individuals with OUD, those screening positive (versus negative) for PPU were more impulsive and experienced more psychiatric symptoms, suggesting the need for additional investigation and screening for and addressing PPU in people with OUD.

Design and implementation of a Type-2 hybrid, prospective randomized trial of opioid agonist therapies integration into primary care clinics in Ukraine.

INTRODUCTION: Ukraine has high HIV prevalence, concentrated among people who inject drugs (PWID), mostly of opioids. Maintenance on opioid agonist therapies (OAT) is the most effective evidence-based treatment for opioid use disorder. As PWID experience high morbidity and mortality from preventable and treatable non-communicable diseases, international agencies recommend integrating OAT into primary care centers (PCC). METHODS: A randomized, type-2 hybrid implementation trial was carried out to compare outcomes of OAT integration in PCC to OAT delivery at specialty treatment centers (STC) - standard-of-care. Tele-education supporting PCC providers in managing OAT, HIV, tuberculosis and non-communicable diseases along with pay-for-performance incentives were used to facilitate implementation. Consenting patients underwent 1:2 randomization to either STC or PCC. Quality health indicators (QHIs), a composite percentage of recommended primary and specialty services accessed by patients (blood/urine tests, cancer screenings, etc.), were defined as efficacy outcomes and were assessed by participant self-report at baseline and every 6 months over 24 months and electronic chart reviews after the completion of the follow-up. The primary outcome is defined as the difference in composite QHI scores at 24 months, in which a repeated measures likelihood-based mixed model with missing at random assumptions will be used. Providers at PCC completed surveys at baseline, 12 and 24 months to assess implementation outcomes including changes in stigma and attitudes towards OAT and PWID. PRELIMINARY RESULTS: Among the 1459 participants allocated to STC (N = 509) or PCC (N = 950), there were no differences in clinical and demographic characteristics. Self-reported prevalences were available for HIV (42 %), HCV (57 %), and prior tuberculosis (17 %). Study retention at 6, 12, 18, and 24 months was as 91 %, 85 %, 80 %, and 74 %, respectively. CONCLUSION: PWID have a high prevalence of medical comorbidities and integrating OAT into primary care settings has the potential to improve the health of PWID. Findings from this study can help guide implementation of integrated care in Ukraine and throughout similar low-resource, high-burden countries in the Eastern European and Central Asian region.

Design and Pilot Implementation of an ECHO Module on Hepatitis C Virus Infection During Pregnancy.

We developed a Project ECHO® module to offer prenatal providers training on engaging in shared decision-making about hepatitis C virus (HCV) treatment during pregnancy. In this pilot program, the ECHO module addressing HCV during pregnancy and the potential benefits of treatment was associated with increases in self-efficacy scores among participants.

A Computational Approach in the Systematic Search of the Interaction Partners of Alternatively Spliced TREM2 Isoforms.

Alzheimer's disease is the most common form of dementia, characterized by the pathological accumulation of amyloid-beta (Aß) plaques and tau neurofibrillary tangles. Triggering receptor expressed on myeloid cells 2 (TREM2) is increasingly recognized as playing a central role in Aß clearance and microglia activation in AD. The TREM2 gene transcriptional product is alternatively spliced to produce three different protein isoforms. The canonical TREM2 isoform binds to DAP12 to activate downstream pathways. However, little is known about the function or interaction partners of the alternative TREM2 isoforms. The present study utilized a computational approach in a systematic search for new interaction partners of the TREM2 isoforms by integrating several state-of-the-art structural bioinformatics tools from initial large-scale screening to one-on-one corroborative modeling and eventual all-atom visualization. CD9, a cell surface glycoprotein involved in cell-cell adhesion and migration, was identified as a new interaction partner for two TREM2 isoforms, and CALM, a calcium-binding protein involved in calcium signaling, was identified as an interaction partner for a third TREM2 isoform, highlighting the potential role of cell adhesion and calcium regulation in AD.

E. coli-expressed SECRET AGENT O-GlcNAc modifies threonine 829 of GIGANTEA.

The Arabidopsis thaliana glycosyl transferases SPINDLY (SPY) and SECRET AGENT (SEC) modify nuclear and cytosolic proteins with O-linked fucose or O-linked N-acetylglucosamine (O-GlcNAc), respectively. O-fucose and O-GlcNAc modifications can occur at the same sites. SPY interacts physically and genetically with GIGANTEA (GI), suggesting that it could be modified by both enzymes. Previously, we found that, when co-expressed in Escherichia coli, SEC modifies GI; however, the modification site was not determined. By analyzing the overlapping sub-fragments of GI, we identified a region that was modified by SEC in E. coli. Modification was undetectable when threonine 829 (T829) was mutated to alanine, while the T834A and T837A mutations reduced the modification, suggesting that T829 was the primary or the only modification site. Mapping using mass spectrometry detected only the modification of T829. Previous studies have shown that the positions modified by SEC in E. coli are modified in planta, suggesting that T829 is O-GlcNAc modified in planta.

No evidence of Bartonella infections in host-seeking Ixodes scapularis and Ixodes pacificus ticks in the United States.

BACKGROUND: Bartonella spp. infect a variety of vertebrates throughout the world, with generally high prevalence. Several Bartonella spp. are known to cause diverse clinical manifestations in humans and have been recognized as emerging pathogens. These bacteria are mainly transmitted by blood-sucking arthropods, such as fleas and lice. The role of ticks in the transmission of Bartonella spp. is unclear. METHODS: A recently developed quadruplex polymerase chain reaction (PCR) amplicon next-generation sequencing approach that targets Bartonella-specific fragments on gltA, ssrA, rpoB, and groEL was applied to test host-seeking Ixodes scapularis ticks (n = 1641; consisting of 886 nymphs and 755 adults) collected in 23 states of the eastern half of the United States and Ixodes pacificus ticks (n = 966; all nymphs) collected in California in the western United States for the presence of Bartonella DNA. These species were selected because they are common human biters and serve as vectors of pathogens causing the greatest number of vector-borne diseases in the United States. RESULTS: No Bartonella DNA was detected in any of the ticks tested by any target. CONCLUSIONS: Owing to the lack of Bartonella detection in a large number of host-seeking Ixodes spp. ticks tested across a broad geographical region, our results strongly suggest that I. scapularis and I. pacificus are unlikely to contribute more than minimally, if at all, to the transmission of Bartonella spp.

The Impact of Lunch Timing on Nap Quality.

PURPOSE: Previous research has established that food intake is a biological regulator of the human sleep-wake cycle. As such, the timing of eating relative to sleep may influence the quality of sleep, including daytime naps. Here, we examine whether the timing of lunch (1 h vs. 2 h interval between lunch and a napping opportunity) impacts the quality of an afternoon nap. METHODS: Using a randomized within-subject design over two separate experimental sessions (7 days apart), participants (n = 40, mean age = 25.8 years) consumed lunch 1 h and 2 h prior to an afternoon nap opportunity. Polysomnography and subjective self-reports were used to assess sleep architecture, sleepiness levels, and nap quality. RESULTS: Results revealed no significant differences in subjective ratings of sleep quality and sleepiness, or in sleep architecture (total sleep time, sleep efficiency, sleep onset latency, sleep stages) between the 1 h and 2-h lunch conditions. CONCLUSIONS: All sleep measures were similar when napping followed eating by either 1 h or 2 h, suggesting that eating closer to nap onset may not negatively impact sleep architecture and quality. Future research should continue to identify conditions that improve nap quality, given the well-documented benefits of naps to reduce sleep pressure and improve human performance.

Resources to Support Canadian Nurses to Deliver Virtual Care: Environmental Scan.

BACKGROUND: Regulatory and professional nursing associations have an important role in ensuring that nurses provide safe, competent, and ethical care and are capable of adapting to emerging phenomena that influence society and population health needs. Telehealth and more recently virtual care are 2 digital health modalities that have gained momentum during the COVID-19 pandemic. Telehealth refers to telecommunications and digital communication technologies used to deliver health care, support health care provider and patient education, and facilitate self-care. Virtual care facilitates the delivery of health care services via any remote communication between patients and health care providers and among health care providers, either synchronously or asynchronously, through information and communication technologies. Despite nurses' adaptability to delivering virtual care, many have also reported challenges. OBJECTIVE: This study aims to describe resources about virtual care, digital health, and nursing informatics (ie, practice guidelines and fact sheets) available to Canadian nurses through their regulatory and professional associations. METHODS: An environmental scan was conducted between March and July 2023. The websites of nursing regulatory bodies across 13 Canadian provinces and territories and relevant nursing and a few nonnursing professional associations were searched. Data were extracted from the websites of these organizations to map out educational materials, training opportunities, and guidelines made available for nurses to learn and adapt to the ongoing digitalization of the health care system. Information from each source was summarized and analyzed using an inductive content analysis approach to identify categories and themes. The Virtual Health Competency Framework was applied to support the analysis process. RESULTS: Seven themes were identified: (1) types of resources available about virtual care, (2) terminologies used in virtual care resources, (3) currency of virtual care resources identified, (4) requirements for providing virtual care between provinces, (5) resources through professional nursing associations and other relevant organizations, (6) regulatory guidance versus competency in virtual care, and (7) resources about digital health and nursing informatics. Results also revealed that practice guidance for delivering telehealth existed before the COVID-19 pandemic, but it was further expanded during the pandemic. Differences were noted across available resources with respect to terms used (eg, telenursing, telehealth, or virtual care), types of documents (eg, guideline vs fact sheet), and the depth of information shared. Only 2 associations provided comprehensive telenursing practice guidelines. Resources relative to digital health and nursing informatics exist, but variations between provinces were also noted. CONCLUSIONS: The use of telehealth and virtual care services is becoming mainstream in Canadian health care. Despite variations across jurisdictions, the existing nursing practice guidance resources for delivering telehealth and virtual care are substantial and can serve as a beginning step for developing a standardized set of practice requirements or competencies to inform nursing practice and the education of future nurses.

Longitudinal assessment of glymphatic changes following mild traumatic brain injury: Insights from perivascular space burden and DTI-ALPS imaging.

Introduction: Traumatic brain injury (TBI) even in the mild form may result in long-lasting post-concussion symptoms. TBI is also a known risk to late-life neurodegeneration. Recent studies suggest that dysfunction in the glymphatic system, responsible for clearing protein waste from the brain, may play a pivotal role in the development of dementia following TBI. Given the diverse nature of TBI, longitudinal investigations are essential to comprehending the dynamic changes in the glymphatic system and its implications for recovery. Methods: In this prospective study, we evaluated two promising glymphatic imaging markers, namely the enlarged perivascular space (ePVS) burden and Diffusion Tensor Imaging-based ALPS index, in 44 patients with mTBI at two early post-injury time points: approximately 14 days (14Day) and 6-12 months (6-12Mon) post-injury, while also examining their associations with post-concussion symptoms. Additionally, 37 controls, comprising both orthopedic patients and healthy individuals, were included for comparative analysis. Results: Our key findings include: (1) White matter ePVS burden (WM-ePVS) and ALPS index exhibit significant correlations with age. (2) Elevated WM-ePVS burden in acute mTBI (14Day) is significantly linked to a higher number of post-concussion symptoms, particularly memory problems. (3) The increase in the ALPS index from acute (14Day) to the chronic (6-12Mon) phases in mTBI patients correlates with improvement in sleep measures. Furthermore, incorporating WM-ePVS burden and the ALPS index from acute phase enhances the prediction of chronic memory problems beyond socio-demographic and basic clinical information. Conclusion: ePVS burden and ALPS index offers distinct values in assessing glymphatic structure and activity. Early evaluation of glymphatic function could be crucial for understanding TBI recovery and developing targeted interventions to improve patient outcomes.

Genomic reproducibility in the bioinformatics era.

In biomedical research, validating a scientific discovery hinges on the reproducibility of its experimental results. However, in genomics, the definition and implementation of reproducibility remain imprecise. We argue that genomic reproducibility, defined as the ability of bioinformatics tools to maintain consistent results across technical replicates, is essential for advancing scientific knowledge and medical applications. Initially, we examine different interpretations of reproducibility in genomics to clarify terms. Subsequently, we discuss the impact of bioinformatics tools on genomic reproducibility and explore methods for evaluating these tools regarding their effectiveness in ensuring genomic reproducibility. Finally, we recommend best practices to improve genomic reproducibility.

Combination anti-PD-1 and anti-CTLA-4 therapy generates waves of clonal responses that include progenitor-exhausted CD8+ T cells.

Combination checkpoint blockade with anti-PD-1 and anti-CTLA-4 antibodies has shown promising efficacy in melanoma. However, the underlying mechanism in humans remains unclear. Here, we perform paired single-cell RNA and T cell receptor (TCR) sequencing across time in 36 patients with stage IV melanoma treated with anti-PD-1, anti-CTLA-4, or combination therapy. We develop the algorithm Cyclone to track temporal clonal dynamics and underlying cell states. Checkpoint blockade induces waves of clonal T cell responses that peak at distinct time points. Combination therapy results in greater magnitude of clonal responses at 6 and 9 weeks compared to single-agent therapies, including melanoma-specific CD8+ T cells and exhausted CD8+ T cell (TEX) clones. Focused analyses of TEX identify that anti-CTLA-4 induces robust expansion and proliferation of progenitor TEX, which synergizes with anti-PD-1 to reinvigorate TEX during combination therapy. These next generation immune profiling approaches can guide the selection of drugs, schedule, and dosing for novel combination strategies.

Short-Term Coupling Associations Between State Loneliness and Cognitive Performance in Daily Life Among Older Adults.

OBJECTIVES: Despite extensive efforts to study individual differences in loneliness and neurocognitive health, little is known about how within-person changes in state loneliness relate to cognitive performance. This study addressed this gap by examining the association between within-person variation in state loneliness and cognitive performance assessed objectively in daily life. METHODS: Participants were 313 community-dwelling older adults (70-90 years) who reported momentary feelings of loneliness and completed smartphone-based cognitive tests 5 times daily for 14 consecutive days. Mobile cognitive tests assess visual associative memory, processing speed, and spatial memory. RESULTS: At the day level, average state loneliness levels were negatively related to cognitive performance on the same day and subsequent day. Consistent with the day-level analysis, momentary assessments of increased loneliness were consistently linked to worse cognitive performance on concurrent assessments. However, moments characterized by lower cognitive performance predicted higher levels of loneliness 3-4 hr later (next occasion), but not vice versa. DISCUSSION: The findings suggest a prospective association between loneliness and cognitive performance, with higher daily loneliness negatively associated with cognitive performance on the same day and predicting worse performance the following day. Notably, within a single day, lower cognitive performance at a given moment predicted elevated loneliness later in the day. This highlights a complex, reciprocal relationship-loneliness predicting and being predicted by cognitive performance depending on timescale.

The cascade of care for commercially-insured persons with opioid use disorder and comorbid HIV and HCV infections.

BACKGROUND: Opioid use disorder (OUD) significantly impacts individual and public health and exacerbated further by concurrent infectious diseases. A syndemic approach is needed to address the intertwined OUD, HIV, and HCV epidemics, including the expanded use of medications for opioid use disorder (MOUD). METHODS: To identify MOUD scale-up opportunities, we conducted a retrospective cohort study, representing commercially insured persons, and created the OUD care continuum, including HIV and HCV influences in adults (18-64 years) newly diagnosed with OUD in 2019 using Merative MarketSan data. RESULTS: Among 124,467,633 individuals, the prevalence of OUD was 0.4 % (95 % CI: 0.36 %-0.46 %; N = 497,871), with 327,277 (65.7 %, 95 % CI: 65.60 %-65.87 %) newly diagnosed in 2019. Among these newly diagnosed individuals (54 % men, mean age 44±0.01), 53,568 (27.0 %, 95 % CI: 26.4 %-27.5 %) were prescribed MOUD, with retention rates at 1, 3, and 6 months being 89.0 % (95 % CI: 88.2 %-89.8 %), 66.0 % (95 % CI: 64.8 %-67.2 %), and 50.3 % (95 % CI: 48.3 %-51.6 %), respectively. Buprenorphine was the most prescribed MOUD (79.6 %, 95 % CI: 78.6 %-80.7 %), followed by XR-NTX (14.9 %, 95 % CI:14.0 %-15.8 %) and methadone (5.5 %, 95 % CI: 4.9 %-6.1 %). Six-month retention was highest for methadone (73.4 %, 95 % CI: 73.0 %-73.8 %), however, followed by buprenorphine (55.7 %, 95 % CI: 55.3 %-57.1 %) and substantially lower for XR-NTX (12.6 %, 95 % CI: 10.6 %-14.6 %). Screening for HIV and HCV was low among OUD enrollees (11.1 %, 14.4 %), slightly higher for MOUD initiators (18.0 %, 21.6 %). Being prescribed MOUD was correlated with HCV infection (AOR: 2.54; 95 % CI: 2.41-2.68), HCV/HIV coinfection (AOR: 1.89; 95 % CI: 1.41-2.53), and hospitalization for OUD-related services (AOR: 1.14; 95 % CI: 1.11-1.17), yet hospitalization for OUD-related services was positively correlated with XR-NTX (AOR: 2.72; 95 % CI: 2.56-2.85) prescription and negatively with methadone (AOR: 0.19; 95 % CI: 0.16-0.23) prescription. Having HIV was negatively correlated with being prescribed methadone (AOR: 0.33; 95 % CI: 0.13-0.86). CONCLUSIONS: Substantial gaps in the OUD cascade persist, underscoring better implementation opportunities for MOUD prescription in hospital-based settings and expanding access to methadone beyond highly regulated sites given its low coverage yet high treatment retention.

Newly Qualified Canadian Nurses' Experiences With Digital Health in the Workplace: Comparative Qualitative Analysis.

BACKGROUND: Clinical practice settings have increasingly become dependent on the use of digital or eHealth technologies such as electronic health records. It is vitally important to support nurses in adapting to digitalized health care systems; however, little is known about nursing graduates' experiences as they transition to the workplace. OBJECTIVE: This study aims to (1) describe newly qualified nurses' experiences with digital health in the workplace, and (2) identify strategies that could help support new graduates' transition and practice with digital health. METHODS: An exploratory descriptive qualitative design was used. A total of 14 nurses from Eastern and Western Canada participated in semistructured interviews and data were analyzed using inductive content analysis. RESULTS: Three themes were identified: (1) experiences before becoming a registered nurse, (2) experiences upon joining the workplace, and (3) suggestions for bridging the gap in transition to digital health practice. Findings revealed more similarities than differences between participants with respect to gaps in digital health education, technology-related challenges, and their influence on nursing practice. CONCLUSIONS: Digital health is the foundation of contemporary health care; therefore, comprehensive education during nursing school and throughout professional nursing practice, as well as organizational support and policy, are critical pillars. Health systems investing in digital health technologies must create supportive work environments for nurses to thrive in technologically rich environments and increase their capacity to deliver the digital health future.