Canalith-Repositioning Maneuvers and Balance Interventions on a Patient with Multiple-Canal BPPV: A Case Study

The purpose of this case report is to demonstrate using canalith-repositioning maneuvers and balance training as interventions to reduce vertigo and improve balance and gait in a patient with multiple-canal BPPV.https://soar.usa.edu/flsasummer2018/1006/thumbnail.jp

Feasibility study of the Home-based Exercises for Responsible Sex (HERS) intervention to promote correct and consistent condom use among young women.

Background Male condoms are effective in preventing common sexually transmitted infections (STIs) and unintended pregnancy, if used correctly and consistently. However, condom use errors and problems are common and young people report negative experiences, such as reduced pleasure. The Kinsey Institute Home-Based Exercises for Responsible Sex (KIHERS) is a novel condom promotion intervention for young women, which aims to reduce condom errors and problems, increase self-efficacy and improve attitudes towards condoms, using a pleasure-focussed approach. The study objective was to test the operability, viability and acceptability of an adapted version of the KIHERS intervention with young women aged 16–25 years in the United Kingdom (UK) (Home-Based Exercises for Responsible Sex-UK (HERS-UK). Methods A repeated-measures single-arm design was used, with a baseline (T1) and two follow-up assessments (T2 and T3), conducted 4 weeks and 8 weeks post intervention over a 3-month period. Participants were provided a condom kit containing different condoms and lubricants and were asked to experiment with condoms alone using a dildo and/or with a sexual partner. Ten process evaluation interviews were conducted post intervention. Results Fifty-five young women received the intervention; 36 (65%) completed T2 and 33 (60%) completed T3. Condom use errors and problems decreased, self-efficacy increased and attitudes towards condoms improved significantly. The proportion of participants who reported using a condom for intercourse in the past 4 weeks increased from T1 (20; 47%) to T2 (27; 87%) and T3 (23; 77%) and using lubricant with a condom for intercourse increased from T1 (6; 30%) to T2 (13; 48%)) and T3 (16; 70%). However, motivation to use condoms did not change. Cronbach’s alpha scores indicated good internal consistency of measures used. Qualitative data provided strong evidence for the acceptability of the intervention. Conclusions HERS-UK was implemented as intended and the recruitment strategy was successful within a college/university setting. This feasibility study provided an early indication of the potential effectiveness and acceptability of the intervention, and the benefits of using a pleasure-focussed approach with young women. Measures used captured change in outcome variables and were deemed fit for purpose. Future research should explore cost-effectiveness of this intervention, in a large-scale controlled trial using a diverse sample and targeting young women most at risk of STIs

A novel HLA-B18 restricted CD8+ T cell epitope is efficiently cross-presented by dendritic cells from soluble tumor antigen

NY-ESO-1 has been a major target of many immunotherapy trials because it is expressed by various cancers and is highly immunogenic. In this study, we have identified a novel HLA-B*1801-restricted CD8<sup>+</sup>T cell epitope, NY-ESO-1<sub>88–96</sub> (LEFYLAMPF) and compared its direct- and cross-presentation to that of the reported NY-ESO-1<sub>157–165</sub> epitope restricted to HLA-A*0201. Although both epitopes were readily cross-presented by DCs exposed to various forms of full-length NY-ESO-1 antigen, remarkably NY-ESO-1<sub>88–96</sub> is much more efficiently cross-presented from the soluble form, than NY-ESO-1<sub>157–165</sub>. On the other hand, NY-ESO-1<sub>157–165</sub> is efficiently presented by NY-ESO-1-expressing tumor cells and its presentation was not enhanced by IFN-γ treatment, which induced immunoproteasome as demonstrated by Western blots and functionally a decreased presentation of Melan A<sub>26–35</sub>; whereas NY-ESO-1<sub>88–96</sub> was very inefficiently presented by the same tumor cell lines, except for one that expressed high level of immunoproteasome. It was only presented when the tumor cells were first IFN-γ treated, followed by infection with recombinant vaccinia virus encoding NY-ESO-1, which dramatically increased NY-ESO-1 expression. These data indicate that the presentation of NY-ESO-1<sub>88–96</sub> is immunoproteasome dependent. Furthermore, a survey was conducted on multiple samples collected from HLA-B18+ melanoma patients. Surprisingly, all the detectable responses to NY-ESO-1<sub>88–96</sub> from patients, including those who received NY-ESO-1 ISCOMATRIX™ vaccine were induced spontaneously. Taken together, these results imply that some epitopes can be inefficiently presented by tumor cells although the corresponding CD8<sup>+</sup>T cell responses are efficiently primed in vivo by DCs cross-presenting these epitopes. The potential implications for cancer vaccine strategies are further discussed

A map of transcriptional heterogeneity and regulatory variation in human microglia.

Microglia, the tissue-resident macrophages of the central nervous system (CNS), play critical roles in immune defense, development and homeostasis. However, isolating microglia from humans in large numbers is challenging. Here, we profiled gene expression variation in primary human microglia isolated from 141 patients undergoing neurosurgery. Using single-cell and bulk RNA sequencing, we identify how age, sex and clinical pathology influence microglia gene expression and which genetic variants have microglia-specific functions using expression quantitative trait loci (eQTL) mapping. We follow up one of our findings using a human induced pluripotent stem cell-based macrophage model to fine-map a candidate causal variant for Alzheimer's disease at the BIN1 locus. Our study provides a population-scale transcriptional map of a critically important cell for human CNS development and disease

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

NY-ESO-1_88–96 is cross-presented efficiently by DCs from soluble antigen.

<p>In A, MoDCs expressing both HLA-A2 and HLA-B18 were cultured for 7 days, and then incubated overnight under the indicated conditions before being co-cultured with the indicated T_CD8+ lines for 5 hrs in the presence of BFA. NY-ESO-1 specific T_CD8+ activation was assessed by tetramer and ICS. IFN-γ producing cells out of total antigen-specific (tetramer positive) T_CD8+ were converted to percentages of maximum activation induced by the respective minimum peptide (peptide activation of NY-ESO-1_157–174 T_CD8+ line and NY-ESO-1_79–96 T_CD8+ line were both 30% to 45% for all three experiments conducted, data not shown) and plotted as “% Maximum activation”. After data conversion, mean values and standard deviations were calculated from data obtained from three similar experiments. In B, one of the control experiments was shown for APCs that were either pulsed with the corresponding peptide or soluble NY-ESO-1 for one hour followed with BFA addition to demonstrate the nature of intracellular cross-presentation for both T_CD8+ epitopes without affecting extracellular peptide presentation. Similar results were obtained twice.</p

NY-ESO-1_88–96-specific T cells are vaccine boosted and utilize polyclonal T cell receptors.

<p>PBMCs from patient 8 collected before (day 0) and after (day 70) vaccination with NY-ESO-1 ISCOMATRIX™ vaccine were expanded with 18 mer NY-ESO-1_79–96 and the T cells were assessed by ICS (A). A similar T cell line expanded from day 70 PBMC sample from patient 8 was first stimulated with NY-ESO-1_88–96 peptide, then split into multiple wells and stained with anti-CD8 and a panel of antibodies specific to various TCR Vβ families separately, followed with ICS for IFN-γ (B). Graph indicates the percentage of NY-ESO-1_88–96-specific (IFN-γ-producing) T cells expressing the indicated TCR Vβ families.</p

NY-ESO-1_88–96 is not naturally presented by melanoma cells.

<p><i>A</i>, NY-ESO-1_157–165– and NY-ESO-1_88–96–specific T_CD8+ lines were expanded from PBMCs collected from the previously reported patient 7 <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0044707#pone.0044707-Davis1" target="_blank">[6]</a> and patient 8 with 18 mer peptides NY-ESO-1_157–174 and NY-ESO-1_79–96 respectively. These T cells were then co-incubated with tumor line (SK-MEL-8) with or without a 48 hr IFN-γ induction (see <b><a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0044707#s4" target="_blank">Materials and Methods</a></b> for details). The untreated SK-MEL-8 cells were also pulsed with both peptides followed by washing out excessive peptides to serve as a maximum antigen presentation control. Antigen-specific T cell activation was then revealed by tetramer and IFN-γ double staining. Percentage represents antigen-specific, IFN-γ-producing cells amongst total tetramer positive cells (note, the double negative cell population was not included in the percentage calculation). <i>B</i>, the same T_CD8+ lines used in A were also assessed for their affinity by peptide titration. Percentage represents Ag-specific T cells among total CD8⁺ T cells. Similar data were obtained from three similar experiments.</p

NY-ESO-1_88–96 is directly presented by tumor cells expressing high level of immunoproteasome.

<p>Five melanoma lines, including SK-MEL-8, were left untreated or treated with either IFN-γ for 48 hrs or were further infected with rVV.NY-ESO-1 for 5 hrs. The tumor cells were then co-cultured with T cell lines specific for NY-ESO-1_157–174, NY-ESO-1_88–96 and Melan A26–35 as described in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0044707#pone-0044707-g003" target="_blank">Figure 3</a>. The purity of the T_CD8+ lines were 42%, 88% and 68% respectively (data not shown). The antigen presentation results are shown in A and the western blot results for LMP2, LMP7 and the loading control GAPDH for the corresponding tumor lines and the treatment conditions are shown in B. The FACS analysis results of the cell surface HLA molecules as Mean Channel Fluorescence intensity (MCF) are shown in C. The MCF values for HLA-A2 and B18 were about 100 for the FITC-conjugated secondary antibody alone; and those values for the All Class I group for the PE-conjugated secondary antibody alone were about 300. Similar data were obtained from three similar experiments.</p

T_CD8+ response to HLA-B18/NY-ESO-1_88–96.

<p>Melanoma patients from three clinical trials (see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0044707#s4" target="_blank">Materials and Methods</a>) with detectable anti-NY-ESO-1 antibody responses and HLA-B18 expression were selected for the screen. T cells from PBMC samples post vaccination (or placebo controls that did not receive the NY-ESO-1 ISCOMATRIX™ vaccine but received diluents) were expanded with 18 mer NY-ESO-1_79–96 peptide for 12∼15 days and assessed with NY-ESO-1_88–96 in an ICS assay (only ICS results <0.1% are shown as negative “–” indicated by ‘*’). For patients who showed positive T_CD8+ response to this epitope (>0.1%, data not shown) in their post vaccination samples, pre- and post-vaccination PBMC samples were then expanded the same way side-by-side in a second screen intended to determine whether the response was a result of the vaccination. The peptide-specific T_CD8+ in the second screen were assessed with the specific HLA-B18/NY-ESO-1_88–96 tetramer. Tetramer results >0.1% of total CD8⁺ T cells with a discrete staining pattern are shown; and those results <0.1% are shown as “-”. Pre – pre-existed response; Boosted – vaccine-boosted response; ND – not determined, Pre-vac, prior to vaccination; Post-vac, after vaccination.</p