Surgical management of unilateral restrictive strabismus in an 8-month-old dog.

CASE HISTORY: An 8-month-old male, entire, mixed-breed dog was presented with a 1-month history of left exophthalmos and green mucopurulent ocular discharge. Subsequently, exophthalmos resolved but esotropia (medial strabismus) developed in the left eye, prompting referral to an ophthalmologist. CLINICAL FINDINGS: At the initial referral consultation, enophthalmos and esotropia of the left eye were identified. The patient showed mild improvement after a 3-week tapering course of oral prednisolone and doxycycline. MRI was performed and showed left medial rectus muscle atrophy with increased contrast enhancement which was consistent with chronic extraocular muscle myositis (EOM). A forced duction test was performed to confirm the diagnosis of fibrosing esotropia, which is likely a sequela of chronic EOM. DIAGNOSIS: Fibrosing esotropia presumably caused by untreated EOM. TREATMENT AND OUTCOME: One month later, esotropia progressed to a marked ventro-medial strabismus resulting in visual deprivation. Surgical release of the ventral oblique, medial and ventral recti muscles was performed, resulting in immediate resolution of the enophthalmos. Despite a tapering post-operative course of oral prednisolone, mild esotropia was present 4 weeks later. In an effort to stabilise the globe position, the low dose of prednisolone was increased to a higher anti-inflammatory dose before slowly tapering over 2 months. The vision in the left eye was improved after surgery and has been maintained since without further treatment. CLINICAL RELEVANCE: This is the first documented case of fibrosing esotropia in a young dog with prior signs of acute exophthalmos. Fibrosing esotropia has been documented in certain breeds or as a sequela to chronic EOM. In this patient, it was presumably caused by EOM, which was strongly supported by the case history, progression and MRI findings. Most historical reports of EOM described it as a bilateral condition that resolves with systemic corticosteroids at an anti-inflammatory dose. EOM has been shown to also present unilaterally and it can progress to strabismus if not promptly recognised and treated with systemic steroids. Surgical management can restore vision when severe strabismus results in visual deprivation.

Ischemic alopecia as a complication from therapeutic embolization of the middle meningeal artery.

Selective endovascular embolization using microspheres is a widely used, relatively low-risk procedure to control intracranial bleeding. Side effects such as cranial nerve palsies and stroke have been reported in the literature. Skin necrosis and alopecia are exceedingly rare complications of endovascular embolization with a reported incidence of less than 1%. We report a case of a 55-year-old female who developed alopecia following a therapeutic embolization of the middle meningeal artery using microspheres. The clinical-histopathologic diagnosis and relevant literature are reviewed.

College Students' Knowledge, Attitudes, and Beliefs about the 2017-2018 H3N2 Influenza Virus and Vaccination.

OBJECTIVES: To observe the state of knowledge, attitudes, and beliefs regarding the effectiveness of the 2017-2018 H3N2 influenza virus vaccine in a representative sample of college students and determine how many students experienced flu-like symptoms, whether vaccinated or unvaccinated. METHODS: In March 2018, a 19-item survey related to the 2017-2018 flu virus vaccine was e-mailed to a random sample of 4961 rural southeastern university undergraduate and graduate students. A total of 634 students participated. RESULTS: Among 634 respondents, 37.5% received a flu vaccination. Knowledge about the flu was significantly associated with the decision to be vaccinated (χ2 = 18.68, P < 0.001). Of those who received the vaccine, 25.2% reported that they knew "a lot" about the flu. Approximately 28.8% of respondents believed the vaccine to be "very effective" (n = 145). CONCLUSION: Increased knowledge about the flu indicates an association with a higher rate of flu vaccinations among college students.

Hooking-Up, Religiosity, and Sexting Among College Students.

The purpose of this study was to evaluate the mediation effect of sexting, and taking sexually suggestive photos on religiosity and hooking-up with three separate sexual outcomes. A web-based survey examined the relationship between religiosity and the three hooking-up outcomes among students reporting sexting or taking a sexually suggestive photo in the last 30 days (n = 231). Sexting, as well as taking sexually suggestive photos mediated the relationship between religiosity and hooking-up among females. Sexting may be initiated by females as a way to engage in a nonphysical sexual interaction, which ultimately predisposes them to a physical sexual outcome.

Progression of anal intraepithelial neoplasia in HIV-positive individuals: predisposing factors.

BACKGROUND: The aim of the present study was to evaluate patient factors that affect the progression of anal dysplasia in human immunodeficiency virus (HIV)-positive individuals. METHODS: A retrospective cohort study of HIV-positive adults with human papilloma virus related anal lesions was performed from 2012 to 2017. All patients underwent surgical excision or biopsy and fulguration of lesions in the operating room without using high resolution anoscopy. Patients with initial presentation of squamous cell carcinoma were excluded. The study was designed to investigate progression between the first available histology and either the follow up histology or a negative examination. Patient files were reviewed and data was collected. A bivariate analysis of continuous and categorical variables was performed. RESULTS: One hundred and sixty-one patients met the inclusion criteria. Ninety-seven percent were male. Mean age was 41 years. Thirty-five percent were African American and 47% were Caucasian. After a median follow-up interval of 331 days (IQR 120-615 days) 14 (9%) of patients had progression of disease. Visible lesions on initial presentation, as opposed to lesions found  in patients undergoing examination under anesthesia because of HSIL on anal pap smear, was associated with progression (p = 0.0.2). A lower initial CD4 count (p = 0.01) and initial surgical pathology of anal condylomata (p = 0.01) were also associated with progression. High-risk serotype was associated with no change or regression (p = 0.01). CONCLUSIONS: In our large cohort of HIV-positive patients treated without high resolution anoscopy the rate of progression was low.  Most notably, visible lesions at initial presentation and CD4 count when lower were associated with progression. Initial surgical pathology of anal condylomata was associated with progression, while high-risk serotypes correlated with regression or stability. Identification of risk factors has important implications concerning postoperative surveillance and counseling of HIV-positive patients with anal condylomata/ anal dysplasia.

Correction to: Progression of anal intraepithelial neoplasia in HIV-positive individuals: predisposing factors.

Unfortunately, the "Informed consent" statement was incorrectly published in the original version. The complete correct reference should read as follows.

Selective CD28 Blockade Results in Superior Inhibition of Donor-Specific T Follicular Helper Cell and Antibody Responses Relative to CTLA4-Ig.

Donor-specific antibodies (DSAs) are a barrier to improved long-term outcomes after kidney transplantation. Costimulation blockade with CTLA4-Ig has shown promise as a potential therapeutic strategy to control DSAs. T follicular helper (Tfh) cells, a subset of CD4+ T cells required for optimal antibody production, are reliant on the CD28 costimulatory pathway. We have previously shown that selective CD28 blockade leads to superior allograft survival through improved control of CD8+ T cells relative to CTLA4-Ig, but the impact of CD28-specific blockade on CD4+ Tfh cells is unknown. Thus, we identified and characterized donor-reactive Tfh cells in a murine skin transplant model and then used this model to evaluate the impact of selective CD28 blockade with an anti-CD28 domain antibody (dAb) on the donor-specific Tfh cell-mediated immune response. We observed that the anti-CD28 dAb led to superior inhibition of donor-reactive CXCR5+ PD-1high Tfh cells, CD95+ GL7+ germinal center B cells and DSA formation compared with CTLA4-Ig. Interestingly, donor-reactive Tfh cells differentially upregulated CTLA4 expression, suggesting an important role for CTLA4 in mediating the superior inhibition observed with the anti-CD28 dAb. Therefore, selective CD28 blockade as a novel approach to control Tfh cell responses and prevent DSA after kidney transplantation warrants further study.

Evaluation of a hepatitis C clinical care coordination programme's effect on treatment initiation and cure: A surveillance-based propensity score matching approach.

Hepatitis C (HCV) is a viral infection that if left untreated can severely damage the liver. Project INSPIRE was a 3 year HCV care coordination programme in New York City (NYC) that aimed to address barriers to treatment initiation and cure by providing patients with supportive services and health promotion. We examined whether enrolment in Project INSPIRE was associated with differences in HCV treatment and cure compared with a demographically similar group not enrolled in the programme. INSPIRE participants in 2015 were matched with a cohort of HCV-infected persons identified in the NYC surveillance registry, using full optimal matching on propensity scores and stratified by INSPIRE enrolment status. Conditional logistic regression was used to assess group differences in the two treatment outcomes. Two follow-up sensitivity analyses using individual pair-matched sets and the full unadjusted cohort were also conducted. Treatment was initiated by 72% (790/1130) of INSPIRE participants and 36% (11 960/32 819) of study-eligible controls. Among initiators, 65% (514/790) of INSPIRE participants compared with 47% (5641/11 960) of controls achieved cure. In the matched analysis, enrolment in INSPIRE increased the odds of treatment initiation (OR: 5.25, 95% CI: 4.47-6.17) and cure (OR: 2.52, 95% CI: 2.00-3.16). Results from the sensitivity analyses showed agreement with the results from the full optimal match. Participation in the HCV care coordination programme significantly increased the probability of treatment initiation and cure, demonstrating that care coordination for HCV-infected individuals improves treatment outcomes.

Effects of Social Support Network Size on Mortality Risk: Considerations by Diabetes Status.

OBJECTIVE: Previous work demonstrates that social support is inversely associated with mortality risk. Less research, however, has examined the effects of the size of the social support network on mortality risk among those with and without diabetes, which was the purpose of this study. METHODS: Data from the 1999-2008 National Health and Nutrition Examination Survey were used, with participants followed through 2011. This study included 1,412 older adults (≥60 years of age) with diabetes and 5,872 older adults without diabetes. The size of the social support network was assessed via self-report and reported as the number of participants' close friends. RESULTS: Among those without diabetes, various levels of social support network size were inversely associated with mortality risk. However, among those with diabetes, only those with a high social support network size (i.e., at least six close friends) had a reduced risk of all-cause mortality. That is, compared to those with zero close friends, those with diabetes who had six or more close friends had a 49% reduced risk of all-cause mortality (hazard ratio 0.51, 95% CI 0.27-0.94). CONCLUSION: To mitigate mortality risk, a greater social support network size may be needed for those with diabetes.

Increased Pretransplant Frequency of CD28+ CD4+ TEM Predicts Belatacept-Resistant Rejection in Human Renal Transplant Recipients.

While most human T cells express the CD28 costimulatory molecule constitutively, it is well known that age, inflammation, and viral infection can drive the generation of CD28null T cells. In vitro studies have demonstrated that CD28null cell effector function is not impacted by the presence of the CD28 costimulation blocker belatacept. As such, a prevailing hypothesis suggests that CD28null cells may precipitate costimulation blockade-resistant rejection. However, CD28+ cells possess more proliferative and multifunctional capacity, factors that may increase their ability to successfully mediate rejection. Here, we performed a retrospective immunophenotypic analysis of adult renal transplant recipients who experienced acute rejection on belatacept treatment as compared to those who did not. Intriguingly, our findings suggest that patients possessing higher frequency of CD28+ CD4+ TEM prior to transplant were more likely to experience acute rejection following treatment with a belatacept-based immunosuppressive regimen. Mechanistically, CD28+ CD4+ TEM contained significantly more IL-2 producers. In contrast, CD28null CD4+ TEM isolated from stable belatacept-treated patients exhibited higher expression of the 2B4 coinhibitory molecule as compared to those isolated from patients who rejected. These data raise the possibility that pretransplant frequencies of CD28+ CD4+ TEM could be used as a biomarker to predict risk of rejection following treatment with belatacept.

Belatacept-Resistant Rejection Is Associated With CD28+ Memory CD8 T Cells.

Recently, newer therapies have been designed to more specifically target rejection in an effort to improve efficacy and limit unwanted toxicity. Belatacept, a CD28-CD80/86 specific reagent, is associated with superior patient survival and graft function compared with traditional therapy, but its adoption as a mainstay immunosuppressive therapy has been tempered by increased rejection rates. It is essential that the underlying mechanisms associated with this rejection be elucidated before belatacept is more widely used. To that end, we designed a study in a nonhuman primate kidney transplant model where animals were treated with either a belatacept- or a tacrolimus-based immunosuppressive regimen. Interestingly, we found that elevated pretransplant frequencies of CD28+ CD8+ TEMRA cells are associated with rejection on belatacept but not tacrolimus treatment. Further analysis showed that the CD28+ CD8+ TEMRA cells rapidly lose CD28 expression after transplant in those animals that go on to reject with the allograft infiltrate being predominantly CD28- . These data suggest that CD28+ memory T cells may be resistant to belatacept, capable of further differentiation including loss of CD28 expression while maintaining effector function. The unique signaling requirements of CD28+ memory T cells provide opportunities for the development of targeted therapies, which may synergize with belatacept to prevent costimulation-independent rejection.

Fc-Silent Anti-CD154 Domain Antibody Effectively Prevents Nonhuman Primate Renal Allograft Rejection.

The advent of costimulation blockade provides the prospect for targeted therapy with improved graft survival in transplant patients. Perhaps the most effective costimulation blockade in experimental models is the use of reagents to block the CD40/CD154 pathway. Unfortunately, successful clinical translation of anti-CD154 therapy has not been achieved. In an attempt to develop an agent that is as effective as previous CD154 blocking antibodies but lacks the risk of thromboembolism, we evaluated the efficacy and safety of a novel anti-human CD154 domain antibody (dAb, BMS-986004). The anti-CD154 dAb effectively blocked CD40-CD154 interactions but lacked crystallizable fragment (Fc) binding activity and resultant platelet activation. In a nonhuman primate kidney transplant model, anti-CD154 dAb was safe and efficacious, significantly prolonging allograft survival without evidence of thromboembolism (Median survival time 103 days). The combination of anti-CD154 dAb and conventional immunosuppression synergized to effectively control allograft rejection (Median survival time 397 days). Furthermore, anti-CD154 dAb treatment increased the frequency of CD4+ CD25+ Foxp3+ regulatory T cells. This study demonstrates that the use of a novel anti-CD154 dAb that lacks Fc binding activity is safe without evidence of thromboembolism and is equally as potent as previous anti-CD154 agents at prolonging renal allograft survival in a nonhuman primate preclinical model.

Perceptions of the Exercise Is Medicine Initiative in a Geographically Defined Deep South Population.

OBJECTIVES: To examine the population's perceptions of the Exercise Is Medicine (EiM) initiative, as well as factors that influence the accurate perception of the EiM. METHODS: Participants (N = 179; 24 primary care advanced-level practitioners, 79 exercise science students, and 76 people from the general population) residing in Oxford, Mississippi, were surveyed for this study. RESULTS: Only 34.7% of advanced-care practitioners, 20.2% of students, and 19.4% of the general population defined the term medicine as having treatment and preventive aspects. Awareness of the EiM was reported as follows: advanced-care practitioners, 25.0%; students, 20.2%; and the general population, 14.2%. In total, 45.0% of advanced-care practitioners, 34.7% of students, and 32.9% of the general population defined the EiM as having treatment and preventive aspects; 10.0%, 10.1%, and 31.4% of advanced-care practitioners, students, and general population, respectively, viewed the EiM as being preventive only. Women had a 56% reduced odds of having an accurate perception of the EiM (odds ratio 0.44, P = 0.05). When compared with those perceiving their health as excellent/very good, those perceiving their health as good or worse had a sixfold increased odds of having an accurate perception of the EiM (odds ratio 6.08, P = 0.003). CONCLUSIONS: On average, all of the subpopulations were unaware of the initiative and had misguided perceptions of the EiM. Sex and health status were associated with accurate perceptions of the initiative. Clinical implications of these findings are discussed herein.

Rapamycin ameliorates the CTLA4-Ig-mediated defect in CD8(+) T cell immunity during gammaherpesvirus infection.

Latent viral infections are a major concern among immunosuppressed transplant patients. During clinical trials with belatacept, a CTLA4-Ig fusion protein, patients showed an increased risk of Epstein-Barr virus-associated posttransplant lymphoproliferative disorder, thought to be due to a deficient primary CD8(+) T cell response to the virus. Using a murine model of latent viral infection, we observed that rapamycin treatment alone led to a significant increase in virus-specific CD8(+) T cells, as well as increased functionality of these cells, including the ability to make multiple cytokines, while CTLA4-Ig treatment alone significantly dampened the response and inhibited the generation of polyfunctional antigen-specific CD8(+) T cells. However, the addition of rapamycin to the CTLA4-Ig regimen was able to quantitatively and qualitatively restore the antigen-specific CD8(+) T cell response to the virus. This improvement was physiologically relevant, in that CTLA4-Ig treated animals exhibited a greater viral burden following infection that was reduced to levels observed in untreated immunocompetent animals by the addition of rapamycin. These results reveal that modulation of T cell differentiation though inhibition of mTOR signaling can restore virus-specific immune competence even in the absence of CD28 costimulation, and have implications for improving protective immunity in transplant recipients.

Pathogen Stimulation History Impacts Donor-Specific CD8(+) T Cell Susceptibility to Costimulation/Integrin Blockade-Based Therapy.

Recent studies have shown that the quantity of donor-reactive memory T cells is an important factor in determining the relative heterologous immunity barrier posed during transplantation. Here, we hypothesized that the quality of T cell memory also potently influences the response to costimulation blockade-based immunosuppression. Using a murine skin graft model of CD8(+) memory T cell-mediated costimulation blockade resistance, we elicited donor-reactive memory T cells using three distinct types of pathogen infections. Strikingly, we observed differential efficacy of a costimulation and integrin blockade regimen based on the type of pathogen used to elicit the donor-reactive memory T cell response. Intriguingly, the most immunosuppression-sensitive memory T cell populations were composed primarily of central memory cells that possessed greater recall potential, exhibited a less differentiated phenotype, and contained more multi-cytokine producers. These data, therefore, demonstrate that the memory T cell barrier is dependent on the specific type of pathogen infection via which the donor-reactive memory T cells are elicited, and suggest that the immune stimulation history of a given transplant patient may profoundly influence the relative barrier posed by heterologous immunity during transplantation.

Resonant Charge Transfer of Hydrogen Rydberg Atoms Incident on a Cu(100) Projected Band-Gap Surface.

The charge transfer (ionization) of hydrogen Rydberg atoms (n=25-34) incident on a Cu(100) surface is investigated. Unlike fully metallic surfaces, where the Rydberg electron energy is degenerate with the conduction band of the metal, the Cu(100) surface has a projected band gap at these energies, and only discrete image states are available through which charge transfer can take place. Resonant enhancement of charge transfer is observed for Rydberg states whose energy matches one of the image states, and the integrated surface ionization signals (signal versus applied field) show clear periodicity as a function of n as the energies come in and out of resonance with the image states. The surface ionization dynamics show a velocity dependence; decreased velocity of the incident H atom leads to a greater mean distance of ionization and a lower field required to extract the ion. The surface ionization profiles for "on resonance" n values show a changing shape as the velocity is changed, reflecting the finite field range over which resonance occurs.

Phase transitions and optical properties of the semiconducting and metallic phases of single-layer MoS2.

We report density functional theory calculations for single layer MoS2 in its 2H, semiconducting and 1T metallic phases in order to understand the relative stability of these two phases and transition between them in the presence of adsorbed lithium atoms and under compressive strain. We have determined the diffusion barriers between the two phases and demonstrate how the presence of Li adatoms or strain can significantly reduce these barriers. We show that the 2H and 1T structures have the same energy under 15% biaxial, compressive strain. This is the same strain value posited by Lin et al (2014 Nat. Nanotechnology 9 391-396) for their intermediate α phase. Calculations of the 1T and 2H permittivity and electron energy loss spectrum are also performed and characterized.

Braking bad: novel mechanisms of CTLA-4 inhibition of T cell responses.

The coinhibitory receptor cytotoxic T-lymphocyte antigen 4 (CTLA-4) is a master regulator of T cell responses and its function is critical in models of transplant tolerance. The CD28/CTLA-4 pathway is also an important therapeutic target, as the costimulation blocker belatacept was recently approved for use following renal transplantation. While the traditional model of CTLA-4 coinhibition focuses on its ability to directly counteract CD28 costimulation, recently this paradigm has significantly broadened. Recent work has uncovered the ability of CTLA-4 to act as a cell-extrinsic coinhibitory molecule on CD4(+) T cell effectors. While it has been appreciated that CTLA-4 is required for FoxP3(+) regulatory T cell (Treg) suppression, current studies have elucidated important differences in the function of CTLA-4 on Tregs compared to effectors. CTLA-4 expression patterns also differ by T cell subset, with Th17 cells expressing significantly higher levels of CTLA-4. Thus, in contrast to the traditional model of CTLA-4 as a negative receptor to counter CD28 costimulation, recent work has begun to define CTLA-4 as a global regulator of T cell responses with subset-specific functions. Future studies must continue to uncover the molecular mechanisms that govern CTLA-4 function. These novel findings have implications for novel strategies to maximize the regulatory potential of CTLA-4 during allogeneic T cell responses.

High CTLA-4 expression on Th17 cells results in increased sensitivity to CTLA-4 coinhibition and resistance to belatacept.

The CD28/cytotoxic T-lymphocyte antigen 4 (CTLA-4)blocker belatacept selectively inhibits alloreactive T cell responses but is associated with a high incidence of acute rejection following renal transplantation,which led us to investigate the etiology of belatacept­resistant graft rejection. T cells can differentiate into functionally distinct subsets of memory T cellsthat collectively enable protection against diverse classes of pathogens and can cross-react with allogeneicantigen and mediate graft rejection. T helper 17(Th17) cells are a pro-inflammatory CD4+ lineage that provides immunity to pathogens and are pathogenic in autoimmune disease. We found that T helper 1 (Th1)and Th17 memory compartments contained a similar frequency of divided cells following allogeneic stimulation.Compared to Th1 cells, Th17 memory cells expressed significantly higher levels of the coinhibitory molecule CTLA-4. Stimulation in the presence of belatacept inhibited Th1 responses but augmented Th17 cells due to greater sensitivity to coinhibition by CTLA-4. Th17 cells from renal transplant recipients were resistant to ex vivo CD28/CTLA-4 blockade with belatacept, and an elevated frequency of Th17 memory cells was associated with acute rejection during belatacept therapy. These data highlight important differences in costimulatory and coinhibitory requirements of CD4+ memory subsets, and demonstrate that the heterogeneity of pathogen-derived memory has implications for immunomodulation strategies.

Grounding evidence-based approaches to cancer prevention in the community: a case study of mammography barriers in underserved African American women.

When community health planners select an evidence-based intervention that has been developed and tested in one situation and adapt it for use in a different situation or community, best practice suggests needs assessment and formative research in the new setting. Cancer prevention planners who are interested in adopting and adapting evidence-based approaches need to base their choices on a sound understanding of the health or behavioral risk problem in which they mean to intervene. This requires a balancing act of weighing community information against a broader perspective from the scientific literature and using the combination to identify and adapt an evidence-based intervention program that is likely to be effective in the new setting. This report is a case study of a community and organizational assessment conducted as a foundation for selecting and recommending adaptation of an evidence-based intervention for improving mammography appointment attendance. We used an inductive sequential exploratory mixed-methods design to inform this process. The process provides a model for formative research grounding evidence-based practice for cancer control planners. Future studies that incorporate findings from needs assessment into the adaptation of the selected intervention program may promote the effective dissemination of evidence-based programs.