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.

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.

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.

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.

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.

Evidence for contrasting roles of dimethylsulfoniopropionate production in Emiliania huxleyi and Thalassiosira oceanica.

Dimethylsulfoniopropionate (DMSP) is a globally abundant marine metabolite and a significant source of organic carbon and sulfur for marine microbial ecosystems with the potential to influence climate regulation. However, the physiological function of DMSP has remained enigmatic for >30 yr. Recent insight suggests that there are different physiological roles for DMSP based on the cellular DMSP concentrations in producers. Differential production of DMSP was tested with multiple physiological experiments that altered nitrate availability, salinity and temperature to create stressed growth and target different metabolic conditions in Emiliania huxleyi, a high DMSP producer and Thalassiosira oceanica, a low DMSP producer. Emiliania huxleyi intracellular DMSP did not respond to metabolically imbalanced conditions, while Thalassiosira oceanica intracellular DMSP was significantly correlated to stressed growth rate across all conditions tested and exhibited a plastic response on a timescale of hours in nonsteady-state. The previous assumption that proposed DMSP mechanism(s) can be universally applied to all producers is shown to be unlikely. Rather, two distinct ecological roles for DMSP likely exist that differ by producer type, where: (1) the primary role of DMSP in high producers is a constitutive compatible solute; and (2) DMSP production in low producers is a finely tuned stress response.

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.

Patterns of Spiritual Connectedness during Adolescence: Links to Coping and Adjustment in Low-Income Urban Youth.

Religiosity and spirituality are influential experiences that buffer adverse effects of stressors. Spirituality typically declines during adolescence, although not universally. Using Latent Class Growth Analysis, we examined changes in spiritual connectedness among 188 early (52% female; M age = 10.77, SD = 0.65 years) and 167 middle (56% female; M age = 13.68, SD = 0.82 years) predominantly African American adolescents participating in a 4-year longitudinal study. Three distinct profiles of spiritual connectedness emerged: low and steady, moderate with declines over the study period, and high and steady. Profile distributions varied across developmental level: there were more early adolescents in the high and steady profile and more middle adolescents in the decliner profile. Youth in the high and steady profile evidenced more goal-directedness and life satisfaction and more effective emotion management and coping strategies than youth in other profiles. Contributions to the positive development literature are discussed.

Do Parent-Adolescent Discrepancies Predict Deviant Peer Affiliation and Subsequent Substance Use?

Recent evidence suggests parent-adolescent discrepancies regarding adolescent disclosure can provide insight into parent-child relations and adolescent adjustment. However, pathways linking discrepancies to adjustment are not well known. We tested a model linking parent-adolescent discrepancies in disclosure to adolescent substance use through affiliation with deviant peers. Using three annual waves of data from a community-based study (N = 357; 91% African American; 53% female; Mage = 13.13 years, SD = 1.62 years at baseline), findings revealed that adolescent-reported secrecy and deviant peer affiliation were positively associated with substance use one and two years later, respectively, but there was no evidence of mediation. The results highlight associations of adolescent secrecy and adjustment, and the role peers play in adolescent substance use behaviors.

Systematic Review: Exposure to Community Violence and Physical Health Outcomes in Youth.

Objective: To systematically review the evidence for associations between exposure to community violence and physical health outcomes in children and adolescents. Methods: A thorough search of multiple online databases and careful consideration of inclusion and exclusion criteria yielded a final 28 studies for detailed review. In addition to review of findings, studies were rated on overall quality based on study design. Results: Seven categories of physical health outcomes emerged, including asthma/respiratory health, cardiovascular health, immune functioning, hypothalamic-pituitary-adrenal axis functioning, sleep problems, weight, and a general health category. There were mixed findings across these categories. Evidence for a positive association between community violence exposure and health problems was strongest in the cardiovascular health and sleep categories. Conclusion: There is reason to believe that community violence exposure has an effect on some areas of physical health. Additional well-designed research that focuses on mechanisms as well as outcomes is warranted.

Differential Binding of Rimantadine Enantiomers to Influenza A M2 Proton Channel.

Rimantadine hydrochloride (α-methyl-1-adamantane-methalamine hydrochloride) is a chiral compound which exerts antiviral activity against the influenza A virus by inhibiting proton conductance of the M2 ion channel. In complex with M2, rimantadine has always been characterized as a racemic mixture. Here, we report the novel enantioselective synthesis of deuterium-labeled (R)- and (S)-rimantadine and the characterization of their protein-ligand interactions using solid-state NMR. Isotropic chemical shift changes strongly support differential binding of the enantiomers to the proton channel. Position restrained simulations satisfying distance restraints from (13)C-(2)H rotational-echo double-resonance NMR show marked differences in the hydrogen-bonding pattern of the two enantiomers at the binding site. Together these results suggest a complex set of interactions between (R)-rimantadine and the M2 proton channel, leading to a higher stability for this enantiomer of the drug in the channel pore.

Sampling and Recruiting Community-Based Programs Using Community-Partnered Participation Research.

The inclusion of community partners in participatory leadership roles around statistical design issues like sampling and randomization has raised concerns about scientific integrity. This article presents a case study of a community-partnered, participatory research (CPPR) cluster-randomized, comparative effectiveness trial to examine implications for study validity and community relevance. Using study administrative data, we describe a CPPR-based design and implementation process for agency/program sampling, recruitment, and randomization for depression interventions. We calculated participation rates and used cross-tabulation to examine balance by intervention status on service sector, location, and program size and assessed differences in potential populations served. We achieved 51.5% agency and 89.6% program participation rates. Programs in different intervention arms were not significantly different on service sector, location, or program size. Participating programs were not significantly different from eligible, nonparticipating programs on community characteristics. We reject claims that including community members in research design decisions compromises scientific integrity. This case study suggests that a CPPR process can improve implementation of a community-grounded, rigorous randomized comparative effectiveness trial.

What effect do different 200 µm laser fibres have on deflection and irrigation flow rates in a flexible ureterorenoscope?

The objective of the study is to evaluate the reduction in flow and scope deflection of four leading 200-µm marketed laser fibres (Boston Scientific Flexiva™ 200, Boston Scientific Flexiva™ Trac Tip 200, Lumenis SlimLine™ EZ200 and Optical Integrity ScopeSafe™) via a flexible ureterorenoscope. A laboratory-based bench test was performed using a Flex X2™ flexible ureterorenoscope. Mean upward/downward deflection angles and flow rates (ml/min) for each fibre were calculated and compared to a control. The Optical Integrity ScopeSafe™ fibre has the least loss of deflection, losing only 8 % upward and 6 % downward deflection. Deflection loss was significantly less with this fibre compared to all other fibres (p < 0.0001). Mean flow rates were significantly greater with the Optical Integrity ScopeSafe™ laser fibre at 23 ml/min (p < 0.0001). Despite all fibres marketed as 200 µm, the deflection and flow properties show marked variations. The Optical Integrity ScopeSafe™ 200-µm laser fibre offers the best overall performance with significantly improved flow rates and the least loss of scope deflection.

Correlates of perceived risk of developing cancer among African-Americans in South Los Angeles.

There are differences in cancer-risk perception among racial/ethnic groups that may affect health risk behaviors. Using a community partnered-participatory research approach, we conducted a survey on cancer screening, risk behaviors, and related knowledge/attitudes within 11 churches in South Los Angeles with predominantly African-American parishioners. This analysis examines correlates of perceived risk of developing cancer among 755 African American adults. Almost 15 % of participants indicated higher perceived risk for cancer compared to the average man/woman of the same age, 38 % indicated same risk, whereas 48 % perceived lower risk. Sixty-nine individuals (9 %) reported a cancer history and 63 % reported at least one blood relative with cancer. Controlling for demographic characteristics and healthcare access, participants who reported higher risk of cancer had higher level of cancer-related knowledge; were current and ex-smokers; had poorer health status; had a blood relative with cancer; had a cancer history; and had discussed their risk of cancer with their doctor. The bivariate association between high perceived cancer risk and lack of exercise and obesity disappeared after adjusting for demographic characteristics and perceived health status. Our data suggest that a substantial proportion of African Americans in South Los Angeles may underestimate their cancer risk. Additionally, lack of exercise and obesity are not recognized as independent cancer risk factors as much as smoking and personal and family history of cancer. Next steps will be to inform participating churches about our findings and explore their interest in taking steps to reduce health risk behaviors among their parishioners.

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.

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.

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.

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.