Cancer Immunotherapy Trials Network 12: Pembrolizumab in HIV-Associated Kaposi Sarcoma.

PURPOSE: Cancer Immunotherapy Trials Network 12 demonstrated safety of pembrolizumab in treating advanced cancer in people with HIV. Here, we report results of the Kaposi sarcoma (KS) cohort. METHODS: In this multicenter phase I trial, we enrolled participants with HIV-associated KS on antiretroviral therapy with CD4+ ≥50 cells/µL and HIV plasma RNA <200 copies/mL. Pembrolizumab 200 mg intravenously was administered once every 3 weeks for up to 35 cycles. The primary end point was safety, and the secondary end point was KS response by modified AIDS Clinical Trials Group Criteria. RESULTS: Thirty-two cisgender men enrolled with baseline median CD4+ T-cell count of 274 cells/µL. All but nine participants had received previous systemic KS therapy. Participants received a median of 11 cycles of pembrolizumab (range, 1-35). Sixty-six percent had grade ≥1 treatment-emergent adverse events, including one death from polyclonal KS herpesvirus-related B-cell lymphoproliferation. Thirty-one percent had ≥one immune-mediated AEs (imAEs) with 25% requiring systemic steroids. In 29 participants with evaluable KS, the overall response rate (ORR) was 62.1% (95% CI, 42.3 to 79.3) and did not differ by CD4+ T-cell count. ORR in the eight participants with evaluable disease without previous KS therapy was 87.5% (95% CI, 47.3 to 99.7). Median duration of response (DOR) was not reached, and the Kaplan-Meier estimate of DOR of ≥12 months was 92.3% (95% CI, 56.6 to 98.8). Median progression-free survival was 28.2 months (95% CI, 4.2 to noncalculable). CONCLUSION: Pembrolizumab yielded a high rate of durable responses in HIV-associated KS. imAEs were successfully managed with standard guidelines.

Richter's Hernia Unveiled: The Danger of High Pain Tolerance and Lack of Systemic Symptoms.

Hernia repairs are among the most common surgical procedures performed by general surgeons annually in the United States, defined as the abnormal protrusion of tissue and/or organs through an anatomical defect in the surrounding wall at various locations in the human body. While some hernias can remain asymptomatic and seemingly harmless, some may lead to intestinal obstruction, ischemic bowel from strangulation of blood supply, or septic shock if not diagnosed and addressed within a short period of time. This case report is about an elderly woman who presented with a Richter's. A Richter's hernia is an atypical type of strangulation where only a portion of the bowel, the antimesenteric border, is trapped within the anatomical defect. Given the limited extent of entrapped bowel, numerous different presentations can be seen, including but not limited to signs of obstruction without signs of ischemia or, in some instances, lack of either sign of obstruction or ischemia. Within this report, we will discuss the need for high clinical suspicion for Richter's hernias when evaluating strangulated hernias without systemic signs of sepsis.

AAV dose-dependent transduction efficiency in retinal ganglion cells and functional efficacy of optogenetic vision restoration.

Optogenetics is a promising approach for restoring vision to the blind after photoreceptor degeneration. The ability to restore vision through AAV-mediated delivery of light-sensitive proteins, especially channelrhodopsins, into retinal ganglion cells has been extensively demonstrated in animal models. For clinical application, knowledge of viral dose-dependent functional efficacy is desired. In this study, using a triple-knockout blind mouse model and a highly light-sensitive channelrhodopsin variant, we evaluated viral dose-dependent vision restoration through retinal ganglion cell expression by using optomotor behavioral assays. Our results show that both the restored light sensitivity and visual acuity reached peak levels at a medial viral dose of 108 vg. With increasing dose, transduction efficiency continued to increase while protein expression peaked at the dose of ~109 vg and declined at higher doses. Also, a significant increase in retinal gliosis and inflammatory responses started at the dose of ~109 vg, and a marked increase was observed at the dose of ~1010. These results provide valuable insights into viral dose design for clinical studies.

Exploring the Features of the Self-Regulatory Environment in Kindergarten Classrooms.

Self-regulatory skills are increasingly recognized as critical early education goals, but few efforts have been made to identify all the features of the classroom that actually promote such skills. This study experiments with a new observational measure capturing three dimensions of the classroom environment hypothesized to influence self-regulation: classroom management, emotionally supportive interactions, and direct promotion of self-regulatory skills. These classroom dimensions were tested as predictors of change over the kindergarten year in both self-regulatory and academic skills in a sample of racially/ethnically-diverse low-income children in Tulsa, OK. Results showed that classroom management was associated with small gains in one of four measures of self-regulation, and four of six measures of academic skills. The other dimensions of the environment had weak or no associations with outcomes. These results indicate that further work is needed to refine both models and measures of the self-regulatory environment.

Multi-omic profiling reveals the endogenous and neoplastic responses to immunotherapies in cutaneous T cell lymphoma.

Cutaneous T cell lymphomas (CTCLs) are skin cancers with poor survival rates and limited treatments. While immunotherapies have shown some efficacy, the immunological consequences of administering immune-activating agents to CTCL patients have not been systematically characterized. We apply a suite of high-dimensional technologies to investigate the local, cellular, and systemic responses in CTCL patients receiving either mono- or combination anti-PD-1 plus interferon-gamma (IFN-γ) therapy. Neoplastic T cells display no evidence of activation after immunotherapy. IFN-γ induces muted endogenous immunological responses, while anti-PD-1 elicits broader changes, including increased abundance of CLA+CD39+ T cells. We develop an unbiased multi-omic profiling approach enabling discovery of immune modules stratifying patients. We identify an enrichment of activated regulatory CLA+CD39+ T cells in non-responders and activated cytotoxic CLA+CD39+ T cells in leukemic patients. Our results provide insights into the effects of immunotherapy in CTCL patients and a generalizable framework for multi-omic analysis of clinical trials.

Sexual abuse and disclosure concerns of youth in foster care.

BACKGROUND: Youth in foster care have higher lifetime rates of sexual abuse victimization than their peers who are not in foster care. This sexual abuse occurs before, during, and after their placement. Yet there is a dearth of qualitative research focused on the characteristics of the abuse and the disclosure experiences of youth in foster care. OBJECTIVE: We aimed to understand potential barriers to disclosure for youth who were abused while in foster care. PARTICIPANTS & SETTING: Our study used anonymous, archival data of 143 one-on-one chat sessions on the US based National Sexual Assault Online Hotline (NSAOH) with youth currently living in foster care who sought help for sexual abuse. METHODS: Hotline staff summarized youth's disclosure experiences and barriers using an assessment that included open-ended responses. We used thematic analysis to code text segments. RESULTS: Youth in foster care most often discussed that the abuse was being perpetrated by a foster family member (66 %). Disclosure barriers included concerns for physical safety, not wanting to move placements, not trusting the system to keep them safe, and not wanting to disclose again after previously receiving a negative reaction to their disclosure. CONCLUSIONS: Youth in foster care who seek help for sexual abuse while in the foster care system have unique barriers to disclosure. This study underscores the need for more qualitative research with youth in foster care and includes safety recommendations and implications for training and education of those who work with youth in foster care.

Profiles of Adoptee Adjustment in Young Adulthood.

The developmental stage of young adulthood, the period from one's late twenties through thirties, has grown in attention and research focus among general populations. However, little is known about the adjustment of adopted individuals during this phase. The present study sought to expand our understanding of the various patterns of adoptee adjustment in young adulthood. Latent profile analysis was used to identify profiles across eight domains of functioning spanning physical and mental health to relationships, achievement, and engagement. Three profiles were identified, demonstrating varying levels of adult functioning. Adoption related and non-adoption related variables were explored using a series of multinomial logistic regressions to determine which factors differentiated between profiles. It appears that, although some adoption related variables remain significant in young adulthood, non-adoption related variables are more strongly linked to adoptee adjustment at this developmental stage. Implications and future directions for clinical care and research are discussed.

Resilience and alcohol use in adulthood in the United States: A scoping review.

High levels of alcohol use and the development of alcohol use disorder (AUD) are associated with various adverse consequences. Resilience has been proposed as a protective factor against increased alcohol use, though the existing research is limited by inconsistencies in the conceptualization and measurement of resilience. As such, the current scoping review examined 14 studies on individual, trait-level resilience as a protective factor against alcohol use and related consequences in adults over the age of 21 in the United States. Findings from the included studies generally suggest resilience as a protective factor against various outcomes, though methodological limitations should be considered. Although future research in this area should improve upon methodological limitations, the present review suggests clinical implications of resilience as beneficial in prevention and intervention programming for alcohol use outcomes.

Why does thionating a carbonyl molecule make it a better electron acceptor?

The past decade has witnessed a surge of biomedical and materials applications of thiocarbonyl molecules (R2CS), such as in photodynamic therapy, organic field-effect transistors, and rechargeable batteries. The success of these applications originates from thiocarbonyl's small optical gap in the visible region and the enhanced electron affinity compared to the carbonyl analogues (R2CO). Although these observations seem to be contrary to the implication based on a simple electronegativity consideration (2.58 for sulfur and 3.44 for oxygen), a natural bond orbital (NBO) analysis gives a straightforward explanation for the LUMO-lowering effect of CO → CS substitution. In comparison to the valence (2p)C/(2p)O interactions in CO, the higher 3p orbital of sulfur and its weaker overlap with the 2p level of carbon result in a weaker antibonding interaction in NBO, a prominent contributor to the LUMO. Such an analysis also provides a semi-quantitative understanding of the electronic effect of substituents on or in π-conjugation with a (thio)carbonyl functionality. The intuitive concepts uncovered here offer a simple rule to predict the electronic properties of π-conjugated molecules that incorporate heavy heteroelements and would facilitate materials development.

Video speeding can be efficient and speeding-induced preference cost can be lessened by selective speeding.

Over the past decade, screen-captured instructional videos have become popular tools for learning. Viewers wanting to learn efficiently can play these videos at faster-than-normal speeds, a feature offered by hosting services such as YouTube. Although previous research suggests that moderate speeding may not lessen learning, little research has tested this form of media for speeding-induced learning impairments. Further, even if learning is not impaired by speeding, the degree to which users find speed increases taxing and/or unpleasant is unknown. We therefore created a set of screen-captured instructional videos and tested whether speeding them by up to 250% affected learning, perceived workload, and preferences. Speed increases of up to 200% minimally affected learning, but even modest 150% speed increases substantially increased perceived workload and reduced viewer preferences. However, we were able to create videos that were more selectively speeded by concentrating speeding on pauses and relatively unimportant and slow speech. These videos were just as time efficient as the 150% speeded videos, but viewers preferred them. Our findings demonstrate that speeded instructional videos have the potential to facilitate efficient learning, and they suggest techniques such as selective speeding that may be used to support efficiency while lessening viewer preference costs. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Emulating Membrane Protein Environments─How Much Lipid Is Required for a Native Structure: Influenza S31N M2.

This report investigates the homotetrameric membrane protein structure of the S31N M2 protein from Influenza A virus in the presence of a high molar ratio of lipid. The structured regions of this protein include a single transmembrane helix and an amphipathic helix. Two structures of the S31N M2 conductance domain from Influenza A virus have been deposited in the Protein Data Bank (PDB). These structures present different symmetries about the channel main axis. We present new magic angle spinning and oriented sample solid-state NMR spectroscopic data for S31N M2 in liquid crystalline lipid bilayers using protein tetramer:lipid molar ratios ranging from 1:120 to 1:240. The data is consistent with an essentially 4-fold-symmetric structure very similar to the M2 WT structure that also has a single conformation for the four monomers, except at the His37 and Trp41 functional sites when characterized in samples with a high molar ratio of lipid. While detergent solubilization is well recognized today as a nonideal environment for small membrane proteins, here we discuss the influence of a high lipid to protein ratio for samples of the S31N M2 protein to stabilize an essentially 4-fold-symmetric conformation of the M2 membrane protein. While it is generally accepted that the chemical and physical properties of the native environment of membrane proteins needs to be reproduced judiciously to achieve the native protein structure, here we show that not only the character of the emulated membrane environment is important but also the abundance of the environment is important for achieving the native structure. This is a critical finding as a membrane protein spectroscopist's goal is always to generate a sample with the highest possible protein sensitivity while obtaining spectra of the native-like structure.

European Mistletoe (Viscum album) Extract Is Cytotoxic to Canine High-Grade Astrocytoma Cells In Vitro and Has Additive Effects with Mebendazole.

Malignant gliomas are associated with extremely poor clinical outcomes in both humans and dogs, and novel therapies are needed. Glioma-bearing canine patients may serve as promising preclinical models for human therapies, including complementary medicine. The objective of this study was to evaluate the effects of mistletoe extract (Viscum album) alone and in combination with mebendazole in an in vitro model of canine high-grade astrocytoma using the cell line SDT-3G. SDT-3G cells were exposed to a range of concentrations of mistletoe extract alone to obtain an IC50. In separate experiments, cells were exposed to mebendazole at a previously determined IC50 (0.03 µM) alone or in conjunction with varying concentrations of mistletoe extract to determine the additive effects. The IC50 for mistletoe alone was 5.644 ± 0.09 SD µg/mL. The addition of mistletoe at 5 µg/mL to mebendazole at 0.03 µM led to increased cell death compared to what would be expected for each drug separately. The cytotoxicity of mistletoe in vitro and its additive effect with mebendazole support future expanded in vitro and in vivo studies in dogs and supply early evidence that this may be a useful adjunct therapeutic agent for use in glioma-bearing dogs. To the authors' knowledge, this is the first published report of Viscum album extract in canine glioma.

Effect of CD4+ T cell count on treatment-emergent adverse events among patients with and without HIV receiving immunotherapy for advanced cancer.

BACKGROUND: The Food and Drug Administration recommends that people living with HIV (PWH) with a CD4+ T cell count (CD4) ≥350 cells/µL may be eligible for any cancer clinical trial, but there is reluctance to enter patients with lower CD4 counts into cancer studies, including immune checkpoint inhibitor (ICI) studies. Patients with relapsed or refractory cancers may have low CD4 due to prior cancer therapies, irrespective of HIV status. It is unclear how baseline CD4 prior to ICI impacts the proportion of treatment-emergent adverse events (TEAE) and whether it differs by HIV status in ICI treated patients. METHODS: We conducted a pilot retrospective cohort study of participants eligible for ICI for advanced cancers from three phase 1/2 trials in the USA and Spain. We determined whether baseline CD4 counts differed by HIV status and whether the effect of CD4 counts on incidence of TEAE was modified by HIV status using a multivariable logistic regression model. RESULTS: Of 122 participants, 66 (54%) were PWH who received either pembrolizumab or durvalumab and 56 (46%) were HIV-negative who received bintrafusp alfa. Median CD4 at baseline was 320 cells/µL (IQR 210-495) among PWH and 356 cells/µL (IQR 260-470) among HIV-negative participants (p=0.5). Grade 3 or worse TEAE were recorded among 7/66 (11%) PWH compared with 7/56 (13%) among HIV-negative participants. When adjusted for prior therapies, age, sex, and race, the effect of baseline CD4 on incidence of TEAE was not modified by HIV status for any TEAE (interaction term p=0.7), or any grade ≥3 TEAE (interaction term p=0.1). CONCLUSIONS: There was no significant difference in baseline CD4 or the proportions of any TEAE and grade ≥3 TEAE by HIV status. CD4 count thresholds for cancer clinical trials should be carefully reviewed to avoid unnecessarily excluding patients with HIV and cancer.

The Incomplete Tyranny of Dynamic Stimuli: Gaze Similarity Predicts Response Similarity in Screen-Captured Instructional Videos.

Although eye tracking has been used extensively to assess cognitions for static stimuli, recent research suggests that the link between gaze and cognition may be more tenuous for dynamic stimuli such as videos. Part of the difficulty in convincingly linking gaze with cognition is that in dynamic stimuli, gaze position is strongly influenced by exogenous cues such as object motion. However, tests of the gaze-cognition link in dynamic stimuli have been done on only a limited range of stimuli often characterized by highly organized motion. Also, analyses of cognitive contrasts between participants have been mostly been limited to categorical contrasts among small numbers of participants that may have limited the power to observe more subtle influences. We, therefore, tested for cognitive influences on gaze for screen-captured instructional videos, the contents of which participants were tested on. Between-participant scanpath similarity predicted between-participant similarity in responses on test questions, but with imperfect consistency across videos. We also observed that basic gaze parameters and measures of attention to centers of interest only inconsistently predicted learning, and that correlations between gaze and centers of interest defined by other-participant gaze and cursor movement did not predict learning. It, therefore, appears that the search for eye movement indices of cognition during dynamic naturalistic stimuli may be fruitful, but we also agree that the tyranny of dynamic stimuli is real, and that links between eye movements and cognition are highly dependent on task and stimulus properties.

Enrolling a rural community pharmacy as a Vaccines for Children provider to increase HPV vaccination: a feasibility study.

BACKGROUND: Human papillomavirus (HPV) is the most common sexually transmitted infection in the U.S. with over 80 million infected individuals. High-risk strains are associated with 6 different cancers. Although infection is preventable, U.S. vaccination rates remain suboptimal and there are noted disparities between urban and rural communities due to economic barriers, lack of access, and low awareness and education. METHODS: The current pilot study sought to overcome these barriers through an interprofessional collaborative enrolling a community pharmacy in a rural, medically underserved Alabama county as a Vaccines for Children (VFC) provider to provide free vaccines to eligible adolescents. Program evaluation was conducted to determine the intervention's feasibility. Potential efficacy was assessed by analyzing county-level HPV vaccination uptake and completion rates using state immunization registry data. RESULTS: Over the 8-month study, 166 total vaccines were administered to 89 adolescents ages 10-18, including 55 doses of HPV vaccine, 53 doses of Tdap vaccine, 45 doses of meningococcal vaccine, and 13 doses of influenza vaccine. Among these adolescents, mean age was 12.6 years old, and 64 (71.9%) were VFC patients. The pharmacy recorded an increase in total vaccine administration of 158.8%, an increase in prescription revenue of 34.8%, and an increase in total revenue by 24.4% during the course of the study, compared to the previous year. CONCLUSIONS: Findings from the current work demonstrate the potential of this strategy and can serve as a blueprint for statewide and national dissemination and implementation to ultimately increase access to vaccination services, increase vaccination rates, and reduce urban-rural vaccine disparities.

The Scoliosis Research Society adult spinal deformity standard outcome set.

PURPOSE: Symptomatic adult spinal deformity (ASD) with an extremely variable presentation with pain, with and without neurogenic leg pain, and/or disturbed sagittal and coronal balance, causes a significant societal burden of disease. It is an important consequence of the aging adult population, generating a plethora of spine-related interventions with variable treatment efficacy and consistently high costs. Recent years have witnessed more than a threefold increase in the prevalence and treatment of ASD, and further increases over the coming decades are expected with the growing elderly population worldwide. The ability to monitor and assess clinical outcomes has not kept pace with these developments. This paper addresses the pressing need to provide a set of common outcome metrics for this growing group of patients with back pain and other disabilities due to an adult spinal deformity. METHODS: The standard outcome set was created by a panel with global representation, using a thorough modified Delphi procedure. The three-tiered outcome hierarchy (Porter) was used as a framework to capture full cycle of care. The standardized language of the International Classification of Functioning, Disability and Health (WHO-ICF) was used. RESULTS: Consensus was reached on a core set of 25 WHO-ICF outcome domains ('What to measure'); on the accompanying globally available clinician and patient reported measurement instruments and definitions ('How to measure'), and on the timing of the measurements ('When to measure'). The current work has brought to light domains not routinely reported in the spinal literature (such as pulmonary function, return to work, social participation), and domains for which no adequate instruments have yet been identified (such as how to clinically quantify in routine practice lumbar spinal stenosis, neurogenic claudication, radicular pain, and loss of lower extremity motor function). CONCLUSION: A standard outcome set was developed for patients undergoing treatment for adult spinal deformity using globally available outcome metrics. The current framework can be considered a reference for further work, and may provide a starting point for routine methodical and systematic monitoring of outcomes. Post-COVID e-health may accelerate the routine capture of these types of data.

Is there bias in the treatment of degenerative spine disease? Analysis of anonymous voting via a multidisciplinary conference.

Many institutions have developed shared decision-making conferences as a mechanism for reducing treatment costs and improving patient outcomes. Little is known about the process of shared decision-making that takes place in these conferences, and there is the possibility of bias among surgeons and nonsurgeons for treatment within their respective specialties. This study was conducted to determine who is contributing to the decision-making process in a multidisciplinary spine conference and to what extent treatment biases exist among the surgical and nonsurgical members of this conference. Voting data were collected during weekly multidisciplinary spine conferences. Descriptive statistics were calculated on the cases presented and the number and type of physicians voting for each case. The likelihood of a particular vote in the surgeon and nonsurgeon cohorts was evaluated using relative risk calculation and multinomial logistic regression. A total of 262 consecutive cases were analyzed. No significant differences in treatment recommendation were observed between surgery and nonsurgical management (relative risk, 1.1; 95% CI, 0.97-1.25) when comparing votes from the surgeon and nonsurgeon cohorts. Multinomial logistic regression showed the odds of nonsurgeons recommending nonsurgical management over surgery was 20% greater than receiving that recommendation from their surgeon colleagues. Individual surgeon and nonsurgeon voters were evenly distributed above and below the mean for treatment recommendation. Individual and group biases exist among surgeons and nonsurgeons treating degenerative spine diseases. Multidisciplinary conferences may or may not level these biases, depending on how they are conducted.

Developmental trajectories of infants born at less than 30 weeks' gestation on the Bayley-III Scales.

OBJECTIVE: To describe the cognitive, language and motor developmental trajectories of children born very preterm and to identify perinatal factors that predict the trajectories. DESIGN: Data from a cohort of 1142 infants born at <30 weeks' gestation who were prospectively assessed on the Bayley Scales of Infant and Toddler Development, third edition (Bayley-III) at 3, 6, 12 and 24 months corrected age, were analysed using the Super Imposition by Translation and Rotation (SITAR) growth curve analysis model. MAIN OUTCOME MEASURES: Developmental trajectory SITAR models for Bayley-III cognitive, language (receptive and expressive communication subscales) and motor (fine and gross motor subscales) scores. RESULTS: The successfully fitted SITAR models explained 62% of variance in cognitive development, 68% in receptive communication, 53% in fine motor and 68% in the gross motor development. There was too much variation in the expressive communication subscale to fit a SITAR model. The rate of development (gradient of the curve) best explains the variation in trajectories of development in all domains. Lower gestational age, lower birth weight and male sex significantly predicted a slower rate of development. CONCLUSION: The rate of development, rather than single time point developmental assessment, best predicts the very preterm infant's developmental trajectory and should be the focus for monitoring and early intervention.

Team Approach: Safety and Value in the Practice of Complex Adult Spinal Surgery.

Surgical management of complex adult spinal deformities is of high risk, with a substantial risk of operative mortality. Current evidence shows that potential risk and morbidity resulting from surgery for complex spinal deformity may be minimized through risk-factor optimization. The multidisciplinary team care model includes neurosurgeons, orthopaedic surgeons, physiatrists, anesthesiologists, hospitalists, psychologists, physical therapists, specialized physician assistants, and nurses. The multidisciplinary care model mimics previously described integrated care pathways designed to offer a structured means of providing a comprehensive preoperative medical evaluation and evidence-based multimodal perioperative care. The role of each team member is illustrated in the case of a 66-year-old male patient with previous incomplete spinal cord injury, now presenting with Charcot spinal arthropathy and progressive vertebral-body destruction resulting in lumbar kyphosis.

Maternal and Family Correlates of Intrinsic Religiosity Profiles Among Low-Income Urban African American Adolescents.

National trends show that African American adolescents, relative to most other demographic groups, are more religious, and show fewer declines in religiosity, despite drastic decreases in religiosity among youth over the past 25 years. These broad findings are limiting because they fail to acknowledge religious heterogeneity among African American teens. Further, there are few empirical investigations of the transmission of religiosity within African American families. Building on a recent study that identified three distinctive profiles of intrinsic religiosity in a sample of low-income African American adolescents who were followed over four years (N = 326; Youth Mage = 12.1, SD = 1.6 years; 54% female), the present study examined contributions of maternal religiosity and family emotional climate in distinguishing these profiles. Univariate analyses revealed that maternal religious attendance and commitment, adolescents' felt acceptance from mothers and the emotional climate in the home differentiated youth who retained high levels of intrinsic religiosity (41%) from youth who declined in religiosity (37%) or who had low levels of religiosity (22%). Multivariate analyses showed that after accounting for demographic covariates, felt acceptance from mothers differentiated adolescents with high versus low levels of religiosity; both maternal religious attendance and felt acceptance from mothers distinguished adolescents who retained high levels of religiosity from youth who declined in religiosity. Implications for family dynamics in African American adolescent religious development and well-being are discussed.