Circulating CD4+ T cells in people with HIV and history of pulmonary tuberculosis have more intact HIV DNA.

Background: The primary barrier to curing HIV infection is the pool of intact HIV proviruses integrated into host cell DNA throughout the bodies of people living with HIV (PLHIV), called the HIV reservoir. Reservoir size is impacted by the duration of HIV infection, delay in starting antiretroviral therapy (ART), and breakthrough viremia during ART. The leading infectious cause of death worldwide for PLHIV is TB, but we don't know how TB impacts the HIV reservoir. Methods: We designed a case-control study to compare HIV provirus-containing CD4 in PLHIV with vs. without a history of active TB disease. Study participants in the pilot and confirmatory cohort were enrolled at GHESKIO Centers in Port au Prince, Haiti. Intact and non-intact proviral DNA were quantified using droplet digital PCR of PBMC-derived CD4 cells. For a subset, Th1 and Th2 cytokines were assayed in plasma. Kruskal-Wallis tests were used to compare medians with tobit regression for censoring. Results: In the pilot cohort, we found that PLHIV with history of active pulmonary TB (n=20) had higher intact provirus than PLHIV without history of active TB (n=47) (794 vs 117 copies per million CD4, respectively; p<0.0001). In the confirmatory cohort, the quantity of intact provirus was higher in the TB group (n=13) compared with the non-TB group (n=18) (median 102 vs. 0 intact provirus per million CD4, respectively p=0.03). Additionally, we found that the frequencies of CD4+ T cells with any detectable proviral fragment was directly proportional to the levels of IL1B (p= 0.0025) and IL2 (p=0.0002). Conclusions: This is the first assessment of HIV provirus using IPDA in a clinical cohort from a resource limited setting, and the finding of larger reservoir in PLHIV with history of TB has significant implications for our understanding of TB-HIV coinfection and HIV cure efforts in TB-endemic settings.

The Effectiveness of Unguided Internet-Based Cognitive Behavioral Therapy for Tinnitus for Patients with Tinnitus Alone or Combined with Hyperacusis and/or Misophonia: A Preliminary Analysis.

BACKGROUND: In the UK, audiologist-delivered cognitive behavioral therapy (CBT) is a key intervention to alleviate the distress caused by tinnitus and its comorbid hyperacusis. However, the availability of face-to-face CBT is limited, and such therapy involves significant costs. CBT provided via the internet provides a potential solution to improve access to CBT for tinnitus. PURPOSE: The aim was to perform a preliminary assessment of the effect of a specific program of non-guided internet-based CBT for tinnitus, denoted iCBT(T), in alleviating the problems caused by tinnitus alone or tinnitus combined with hyperacusis. RESEARCH DESIGN: This was a retrospective cross-sectional study. STUDY SAMPLE: The data for 28 people with tinnitus who completed the iCBT(T) program and answered a series of questions about their tinnitus and hearing status were included in the study. Twelve patients reported also having hyperacusis (including five also with misophonia). DATA COLLECTION AND ANALYSIS: The iCBT(T) program has seven self-help modules. Anonymous data were collected retrospectively from patients' answers to the questions in the iCBT(T) initial and final assessment modules. Questionnaires administered within the iCBT(T) program were: 4C Tinnitus Management Questionnaire (4C), Screening for Anxiety and Depression in Tinnitus (SAD-T), and the CBT Effectiveness Questionnaire (CBT-EQ). RESULTS: Responses to the 4C showed a significant improvement from pre- to post-treatment, with a medium effect size. The mean improvement was similar for those with and without hyperacusis. Responses to the SAD-T questionnaire also showed a significant improvement from pre- to post-treatment with a medium effect size. The improvement was significantly greater for participants with tinnitus alone than for participants who also had hyperacusis. For both the 4C and the SAD-T, the improvements were not significantly related to age or gender. Participants' views of the effectiveness of the iCBT(T) program were assessed using the CBT-EQ. The mean score was 50 out of a maximum of 80, indicating moderately high effectiveness. CBT-EQ scores did not differ for those with and without hyperacusis. CONCLUSIONS: Based on this preliminary analysis, the iCBT(T) program showed promising result in improving the ability to manage tinnitus and decreasing symptoms of anxiety and depression. Future studies with larger samples and control group(s) are required to further assess various aspects of this program.

A comparison of interaural asymmetry, audiogram slope, and psychometric measures of tinnitus, hyperacusis, anxiety and depression for patients with unilateral and bilateral tinnitus.

OBJECTIVE: To evaluate differences in tinnitus impact, hyperacusis and hearing threshold level (HTL) between patients with unilateral and bilateral tinnitus. For patients with unilateral tinnitus, to compare audiological variables for the tinnitus ear and the non-tinnitus ear. To assess whether the presence of unilateral tinnitus increases the likelihood of interaural hearing asymmetry (relative to bilateral tinnitus) that warrants referral for an MRI scan. DESIGN: Retrospective cross-sectional. STUDY SAMPLE: Data regarding HTLs and responses to self-report questionnaires were collected from the records of 311 patients attending a tinnitus clinic. RESULTS: 38.5% had unilateral tinnitus and the ears with tinnitus had higher HTLs and greater HTL slopes than the ears without tinnitus. There was no significant difference in tinnitus impact and hyperacusis between patients with unilateral and bilateral tinnitus. 40% of patients with unilateral tinnitus and 13% of patients with bilateral tinnitus had a between-ear difference in HTL ≥15 dB at two adjacent frequencies (2AF15 asymmetry). Unilateral tinnitus increased the risk of 2AF15 asymmetry by a factor of 4.4. CONCLUSIONS: Unilateral tinnitus increases the risk of having interaural asymmetry in HTLs that warrants referral for an MRI scan.

SARS CoV-2 mRNA vaccination exposes latent HIV to Nef-specific CD8+ T-cells.

Efforts to cure HIV have focused on reactivating latent proviruses to enable elimination by CD8+ cytotoxic T-cells. Clinical studies of latency reversing agents (LRA) in antiretroviral therapy (ART)-treated individuals have shown increases in HIV transcription, but without reductions in virologic measures, or evidence that HIV-specific CD8+ T-cells were productively engaged. Here, we show that the SARS-CoV-2 mRNA vaccine BNT162b2 activates the RIG-I/TLR - TNF - NFκb axis, resulting in transcription of HIV proviruses with minimal perturbations of T-cell activation and host transcription. T-cells specific for the early gene-product HIV-Nef uniquely increased in frequency and acquired effector function (granzyme-B) in ART-treated individuals following SARS-CoV-2 mRNA vaccination. These parameters of CD8+ T-cell induction correlated with significant decreases in cell-associated HIV mRNA, suggesting killing or suppression of cells transcribing HIV. Thus, we report the observation of an intervention-induced reduction in a measure of HIV persistence, accompanied by precise immune correlates, in ART-suppressed individuals. However, we did not observe significant depletions of intact proviruses, underscoring challenges to achieving (or measuring) HIV reservoir reductions. Overall, our results support prioritizing the measurement of granzyme-B-producing Nef-specific responses in latency reversal studies and add impetus to developing HIV-targeted mRNA therapeutic vaccines that leverage built-in LRA activity.

Audiological and Other Factors Predicting the Presence of Misophonia Symptoms Among a Clinical Population Seeking Help for Tinnitus and/or Hyperacusis.

This paper evaluates the proportion and the audiological and other characteristics of patients with symptoms of misophonia among a population seeking help for tinnitus and/or hyperacusis at an audiology clinic (n = 257). To assess such symptoms, patients were asked "over the last 2 weeks, how often have you been bothered by any of the following problems? Feeling angry or anxious when hearing certain sounds related to eating noises, lip-smacking, sniffling, breathing, clicking sounds, tapping?". The results of routine audiological tests and self-report questionnaires were gathered retrospectively from the records of the patients. Measures included: pure tone audiometry, uncomfortable loudness levels (ULLs), and responses to the tinnitus impact questionnaire (TIQ), the hyperacusis impact questionnaire (HIQ), and the screening for anxiety and depression in tinnitus (SAD-T) questionnaire. The mean age of the patients was 53 years (SD = 16) (age range 17 to 97 years). Fifty four percent were female. Twenty-three percent of patients were classified as having misophonia. The presence and frequency of reporting misophonia symptoms were not related to audiometric thresholds, except that a steeply sloping audiogram reduced the likelihood of frequent misophonia symptoms. Those with more frequent misophonia symptoms had lower values of ULLmin (the across-frequency average of ULLs for the ear with lower average ULLs) than those with less frequent or no reported symptoms. The reported frequency of experiencing misophonia symptoms increased with increasing impact of tinnitus (TIQ score ≥9), increasing impact of hyperacusis (HIQ score >11), and symptoms of anxiety and depression (SAD-T score ≥4). It is concluded that, when assessing individuals with tinnitus and hyperacusis, it is important to screen for misophonia, particularly when ULLmin is abnormally low or the TIQ, HIQ or SAD-T score is high. This will help clinicians to distinguish patients with misophonia, guiding the choice of therapeutic strategies.

Psychometric Evaluation of a Patient Experience Questionnaire (PEQ) for Outpatient Appointments: Analysis Using Data from a U.K. National Health Service Audiology Department.

BACKGROUND: The Audiology Department at the Royal Surrey NHS Foundation Trust (RSFT), United Kingdom, developed a patient experience questionnaire (PEQ) to assess and compare patients' experiences of attending a wide range of appointments (e.g., hearing assessment, hearing aid fitting, hearing aid review, tinnitus therapy, balance assessment, and balance rehabilitation). PURPOSE: The aim of this study was to assess the psychometric properties of the PEQ. The PEQ is a unidimensional instrument with four items that assess a patient's experience of an outpatient appointment. RESEARCH DESIGN: Retrospective cross-sectional study. STUDY SAMPLE: Patients attending appointments for audiology services at RSFT between January and March 2020. DATA COLLECTION AND ANALYSIS: All patients (n = 656) attending appointments for audiology services at RSFT during randomly selected days between January and March 2020 were given the questionnaire to complete themselves (PEQ-self) or to complete on their child's behalf (PEQ-parent). The factor structures for the PEQ-self and PEQ-parent were assessed separately, using confirmatory factor analysis. A multiple-causes, multiple-indicators (MIMIC) model was fitted to explore potential bias due to gender and age. Internal consistency was assessed using Cronbach's α. The bivariate correlations between PEQ scores and other variables were evaluated using the nonparametric Spearman correlation coefficient. Floor and ceiling effects were assessed using the distribution of total scores. RESULTS: Confirmatory factor analysis revealed that a one-factor model gave a close fit to the data for both the self and parent versions. Cronbach's α for the total score was 0.77 for the PEQ-self and 0.86 for the PEQ-parent. The MIMIC model showed no significant direct effects of age or gender for either version. CONCLUSIONS: Both the PEQ-self and PEQ-parent questionnaire can be reliably used to measure patients' experiences of outpatient audiology appointments. Future studies should aim to assess the psychometric properties of the PEQ-self and PEQ-parent for a range of outpatient appointments other than audiology.

Psychometric Evaluation of the Hyperacusis Impact Questionnaire (HIQ) and Sound Sensitivity Symptoms Questionnaire (SSSQ) Using a Clinical Population of Adult Patients with Tinnitus Alone or Combined with Hyperacusis.

BACKGROUND: Hyperacusis can be defined as an intolerance of certain everyday sounds, which are perceived as too loud or uncomfortable and which cause significant distress and impairment in the individual's day-to-day activities. It is important to assess symptoms of sound intolerance and their impact on the patient's life, so as to evaluate the need for treatment and to assess the effectiveness of treatments. PURPOSE: The aim was to evaluate the psychometric properties of the Hyperacusis Impact Questionnaire (HIQ), and the Sound Sensitivity Symptoms Questionnaire (SSSQ). The 8-item HIQ focuses on assessing the impact of hyperacusis on the patient, while the 5-item SSSQ is designed to assess the type and severity of sound intolerance symptoms. RESEARCH DESIGN: This was a retrospective cross-sectional study. STUDY SAMPLE: In total, 266 consecutive patients who attended a Tinnitus and Hyperacusis Therapy Clinic in the United Kingdom within a 6-month period. Fifty-five percent were female. The average age was 54 years (standard deviation = 16 years). DATA COLLECTION AND ANALYSIS: Data were collected retrospectively from the records of patients held at the audiology department. Audiological measures were pure-tone audiometry and Uncomfortable Loudness Levels (ULLs). Questionnaires administered in addition to the HIQ and SSSQ were: Tinnitus Handicap Inventory, Hyperacusis Questionnaire (HQ), and Screening for Anxiety and Depression in Tinnitus. RESULTS: Exploratory factor analysis suggested one-factor solutions for both the HIQ and SSSQ. Multiple-causes multiple-indicators (MIMIC) models showed some small influences of gender but negligible effects of age for both the HIQ and SSSQ. Receiver Operating Characteristic (ROC) analysis showed no significant effects of covariates on the ROC curves. Cronbach's α was 0.93 for the HIQ, and 0.87 for the SSSQ, indicating high internal consistency. Convergent validity was supported by moderate correlations between HQ and HIQ scores and between SSSQ scores and ULLs. CONCLUSION: The HIQ and SSSQ are internally consistent questionnaires that can be used in clinical and research settings.

Hyperacusis in Autism Spectrum Disorders.

Hyperacusis is highly prevalent in the autism spectrum disorder (ASD) population. This auditory hypersensitivity can trigger pragmatically atypical reactions that may impact social and academic domains. Objective: The aim of this report is to describe the relationship between decreased sound tolerance disorders and the ASD population. Topics covered: The main topics discussed include (1) assessment and prevalence of hyperacusis in ASD; (2) etiology of hyperacusis in ASD; (3) treatment of hyperacusis in ASD. Conclusions: Knowledge of the assessment and treatment of decreased sound tolerance disorders within the ASD population is growing and changing.

A participant-derived xenograft model of HIV enables long-term evaluation of autologous immunotherapies.

HIV-specific CD8+ T cells partially control viral replication and delay disease progression, but they rarely provide lasting protection, largely due to immune escape. Here, we show that engrafting mice with memory CD4+ T cells from HIV+ donors uniquely allows for the in vivo evaluation of autologous T cell responses while avoiding graft-versus-host disease and the need for human fetal tissues that limit other models. Treating HIV-infected mice with clinically relevant HIV-specific T cell products resulted in substantial reductions in viremia. In vivo activity was significantly enhanced when T cells were engineered with surface-conjugated nanogels carrying an IL-15 superagonist, but it was ultimately limited by the pervasive selection of a diverse array of escape mutations, recapitulating patterns seen in humans. By applying mathematical modeling, we show that the kinetics of the CD8+ T cell response have a profound impact on the emergence and persistence of escape mutations. This "participant-derived xenograft" model of HIV provides a powerful tool for studying HIV-specific immunological responses and facilitating the development of effective cell-based therapies.

HIV-specific T cell responses reflect substantive in vivo interactions with antigen despite long-term therapy.

Antiretroviral therapies (ARTs) abrogate HIV replication; however, infection persists as long-lived reservoirs of infected cells with integrated proviruses, which reseed replication if ART is interrupted. A central tenet of our current understanding of this persistence is that infected cells are shielded from immune recognition and elimination through a lack of antigen expression from proviruses. Efforts to cure HIV infection have therefore focused on reactivating latent proviruses to enable immune-mediated clearance, but these have yet to succeed in reducing viral reservoirs. Here, we revisited the question of whether HIV reservoirs are predominately immunologically silent from a new angle: by querying the dynamics of HIV-specific T cell responses over long-term ART for evidence of ongoing recognition of HIV-infected cells. In longitudinal assessments, we show that the rates of change in persisting HIV Nef-specific responses, but not responses to other HIV gene products, were associated with residual frequencies of infected cells. These Nef-specific responses were highly stable over time and disproportionately exhibited a cytotoxic, effector functional profile, indicative of recent in vivo recognition of HIV antigens. These results indicate substantial visibility of the HIV-infected cells to T cells on stable ART, presenting both opportunities and challenges for the development of therapeutic approaches to curing infection.

Self-Reported Tinnitus Severity Prior to and During the COVID-19 Lockdown in the United Kingdom.

BACKGROUND AND PURPOSE: The aim of this study was to assess whether the severity of tinnitus, as measured using ratings of tinnitus loudness, annoyance, and effect on life, was influenced by the lockdown related to the coronavirus disease 2019 (COVID-19) pandemic. RESEARCH DESIGN: This was a retrospective study. STUDY SAMPLE: The data for 105 consecutive patients who were seen at a tinnitus clinic in an audiology department in the United Kingdom during the COVID-19 lockdown between April and June 2020 and 123 patients seen in the same period of the previous year, prior to the COVID-19 pandemic were included. DATA COLLECTION: Demographic data for the patients, results of their pure-tone audiometry, and their score on visual analog scale (VAS) of tinnitus loudness, annoyance, and effect on life were imported from their records held at the audiology department. This was a retrospective survey comparing ratings on the VAS of tinnitus loudness, annoyance, and effect on life for consecutive patients seen during the COVID-19 lockdown and consecutive patients seen in the same period of the previous year, prior to the COVID-19 pandemic. Patients seen prior to lockdown used a pen and paper version of the VAS, while the patients who were assessed during the COVID-19 lockdown used an adapted version of the VAS, via telephone. All patients were seeking help for their tinnitus for the first time. RESULTS: The mean scores for tinnitus loudness, annoyance, and effect on life did not differ significantly for the groups seen prior to and during lockdown. CONCLUSION: Any changes in psychological well-being or stress produced by the lockdown did not significantly affect ratings of the severity of tinnitus.

Internal Consistency and Convergent Validity of the Inventory of Hyperacusis Symptoms.

OBJECTIVES: The aim was to assess the internal consistency and convergent and discriminant validity of a new questionnaire for hyperacusis, the Inventory of Hyperacusis Symptoms (IHS; Greenberg & Carlos 2018), using a clinical population. DESIGN: This was a retrospective study. Data were gathered from the records of 100 consecutive patients who sought help for tinnitus and/or hyperacusis from an audiology clinic in the United Kingdom. The average age of the patients was 55 years (SD = 13 years). Audiological measures were the pure-tone average threshold (PTA) and uncomfortable loudness levels (ULL). Questionnaires administered were: IHS, Tinnitus Handicap Inventory (THI), Hyperacusis Questionnaire (HQ), Insomnia Severity Index, Generalized Anxiety Disorder, and Patient Health Questionnaire-9. RESULTS: Cronbach's alpha for the 25-item IHS questionnaire was 0.96. Neither the total IHS score nor scores for any of its five subscales were correlated with the PTA of the better or worse ear. This supports the discriminant validity of the IHS, as hyperacusis is thought to be independent of the PTA. There were moderately strong correlations between IHS total scores and scores for the HQ, Tinnitus Handicap Inventory, Generalized Anxiety Disorder, and Patient Health Questionnaire-9, with r = 0.58, 0.58, 0.61, 0.54, respectively. Thus, although IHS scores may reflect hyperacusis itself, they may also reflect the coexistence of tinnitus, anxiety, and depression. The total score on the IHS was significantly different between patients with and without hyperacusis (as diagnosed based on ULLs or HQ scores). Using the HQ score as a reference, the area under the receiver operating characteristic for the IHS was 0.80 (95% confidence interval = 0.71 to 0.89) and the cutoff point of the IHS with highest overall accuracy was 56/100. The corresponding sensitivity and specificity were 74% and 82%. CONCLUSIONS: The IHS has good internal consistency and reasonably high convergent validity, as indicated by the relationship of IHS scores to HQ scores and ULLs, but IHS scores may also partly reflect the co-occurrence of tinnitus, anxiety, and depression. We propose an IHS cutoff score of 56 instead of 69 for diagnosing hyperacusis.

Roles of fragment crystallizable-mediated effector functions in broadly neutralizing antibody activity against HIV.

PURPOSE OF REVIEW: 'Broadly neutralizing antibodies' (bNAbs), are rare HIV-specific antibodies which exhibit the atypical ability to potently neutralize diverse viral isolates. While efforts to elicit bNAbs through vaccination have yet to succeed, recent years have seen remarkable preclinical and clinical advancements of passive immunization approaches targeting both HIV prevention and cure. We focus here on the potential to build upon this success by moving beyond neutralization to additionally harness the diverse effector functionalities available to antibodies via fragment crystallizable-effector (Fc) functions. RECENT FINDINGS: Recent studies have leveraged the ability to engineer bNAb Fc domains to either enhance or abrogate particular effector functions to demonstrate that activities such as antibody-dependent cell-mediated cytotoxicity contribute substantially to in-vivo antiviral activity. Intriguingly, recent studies in both nonhuman primates and in humans have suggested that passive bNAb infusion can lead to durable immunity by enhancing virus-specific T-cell responses through a 'vaccinal effect'. SUMMARY: The combination of antibody engineering strategies designed to enhance effector functions, with the broad and potent antigen recognition profile of bNAbs, has the potential to give rise to powerful new therapeutics for HIV. We aim to provide a timely review of recent advances to catalyze this development.

Seminal Plasma-Derived Extracellular-Vesicle Fractions from HIV-Infected Men Exhibit Unique MicroRNA Signatures and Induce a Proinflammatory Response in Cells Isolated from the Female Reproductive Tract.

The continuing spread of HIV/AIDS is predominantly fueled by sexual exposure to HIV-contaminated semen. Seminal plasma (SP), the liquid portion of semen, harbors a variety of factors that may favor HIV transmission by facilitating viral entry into host cells, eliciting the production of proinflammatory cytokines, and enhancing the translocation of HIV across the genital epithelium. One important and abundant class of factors in SP is extracellular vesicles (EVs), which, in general, are important intercellular signal transducers. Although numerous studies have characterized blood plasma-derived EVs from both uninfected and HIV-infected individuals, little is known about the properties of EVs from the semen of HIV-infected individuals. We report here that fractionated SP enriched for EVs from HIV-infected men induces potent transcriptional responses in epithelial and stromal cells that interface with the luminal contents of the female reproductive tract. Semen EV fractions from acutely infected individuals induced a more proinflammatory signature than those from uninfected individuals. This was not associated with any observable differences in the surface phenotypes of the vesicles. However, microRNA (miRNA) expression profiling analysis revealed that EV fractions from infected individuals exhibit a broader and more diverse profile than those from uninfected individuals. Taken together, our data suggest that SP EVs from HIV-infected individuals exhibit unique miRNA signatures and exert potent proinflammatory transcriptional changes in cells of the female reproductive tract, which may facilitate HIV transmission.IMPORTANCE Seminal plasma (SP), the major vehicle for HIV, can modulate HIV transmission risk through a variety of mechanisms. Extracellular vesicles (EVs) are extremely abundant in semen, and because they play a key role in intercellular communication pathways and immune regulation, they may impact the likelihood of HIV transmission. However, little is known about the properties and signaling effects of SP-derived EVs in the context of HIV transmission. Here, we conduct a phenotypic, transcriptomic, and functional characterization of SP and SP-derived EVs from uninfected and HIV-infected men. We find that both SP and its associated EVs elicit potent proinflammatory transcriptional responses in cells that line the genital tract. EVs from HIV-infected men exhibit a more diverse repertoire of miRNAs than EVs from uninfected men. Our findings suggest that EVs from the semen of HIV-infected men may significantly impact the likelihood of HIV transmission through multiple mechanisms.

Integrated Assessment of Viral Transcription, Antigen Presentation, and CD8+ T Cell Function Reveals Multiple Limitations of Class I-Selective Histone Deacetylase Inhibitors during HIV-1 Latency Reversal.

Clinical trials investigating histone deacetylase inhibitors (HDACi) to reverse HIV-1 latency aim to expose reservoirs in antiretroviral (ARV)-treated individuals to clearance by immune effectors, yet have not driven measurable reductions in the frequencies of infected cells. We therefore investigated the effects of the class I-selective HDACi nanatinostat and romidepsin on various blocks to latency reversal and elimination, including viral splicing, antigen presentation, and CD8+ T cell function. In ex vivo CD4+ T cells from ARV-suppressed individuals, both HDACi significantly induced viral transcription, but not splicing nor supernatant HIV-1 RNA. In an HIV-1 latency model using autologous CD8+ T cell clones as biosensors of antigen presentation, neither HDACi-treated CD4+ T cell condition induced clone degranulation. Both HDACi also impaired the function of primary CD8+ T cells in viral inhibition assays, with nanatinostat causing less impairment. These findings suggest that spliced or cell-free HIV-1 RNAs are more indicative of antigen expression than unspliced HIV-RNAs and may help to explain the limited abilities of HDACi to generate CD8+ T cell targets in vivoIMPORTANCE Antiretroviral (ARV) drug regimens suppress HIV-1 replication but are unable to cure infection. This leaves people living with HIV-1 burdened by a lifelong commitment to expensive daily medication. Furthermore, it has become clear that ARV therapy does not fully restore health, leaving individuals at elevated risk for cardiovascular disease, certain types of cancers, and neurocognitive disorders, as well as leaving them exposed to stigma. Efforts are therefore under way to develop therapies capable of curing infection. A key focus of these efforts has been on a class of drugs called histone deacetylase inhibitors (HDACi), which have the potential of exposing hidden reservoirs of HIV-1 to elimination by the immune system. Unfortunately, clinical trial results with HDACi have thus far been disappointing. In the current study, we integrate a number of experimental approaches to build a model that provides insights into the limited activity of HDACi in clinical trials and offers direction for future approaches.

Cognitive Behavioral Therapy For Alleviating The Distress Caused By Tinnitus, Hyperacusis And Misophonia: Current Perspectives.

This article reviews the evidence related to the efficacy of Cognitive Behavioral Therapy (CBT) for alleviating the distress caused by tinnitus, hyperacusis and misophonia. Where available, the review was focused on meta-analyses of randomized controlled trials (RCTs) using either passive control groups (typically waiting list or education only) or active control groups (receiving some other form of treatment). Where data from RCTs were not available, case studies and retrospective studies were reviewed. Analyses were conducted separately for studies of patients with tinnitus, hyperacusis and misophonia. RCTs show that CBT is effective in alleviating the distress caused by tinnitus in comparison to passive control groups and sometimes active control groups. CBT for tinnitus can be effective both in individual and in group settings, whether delivered by psychiatrists, clinical psychologists, or specially trained audiologists. CBT for tinnitus can also be effective when delivered via the internet, when combined with help from audiologists. Usually, CBT does not reduce the loudness of tinnitus but it can improve quality of life. Case studies and some limited RCTs suggest that CBT can also be effective in alleviating the distress caused by hyperacusis and misophonia. However, RCTs with active control groups are currently lacking. There is strong evidence supporting the effectiveness of CBT in alleviating the distress caused by tinnitus. However, it is not yet clear whether CBT is more effective than some other forms of treatment. RCTs with active control groups are needed to establish more clearly the extent to which CBT is effective in alleviating the distress caused by hyperacusis and misophonia.

Parental Mental Illness in Childhood as a Risk Factor for Suicidal and Self-Harm Ideations in Adults Seeking Help for Tinnitus and/or Hyperacusis.

Purpose The aim of this study was to explore the relationship between parental mental illness in childhood with suicidal and self-harm ideations in adults seeking help for their tinnitus and/or hyperacusis. Method This was a retrospective, cross-sectional study. The data for 292 consecutive patients who attended a Tinnitus and Hyperacusis Therapy Specialist Clinic in the United Kingdom were included. Results Forty-six of 292 patients, or 15.75% of the patients, expressed that they have been bothered by suicidal and self-harm ideations within the last 2 weeks. Furthermore, 38.7% of the patients (113/292) reported that, while they were growing up during the first 18 years of life, their parent(s) were suffering from a mental illness. Logistic regression analysis showed a significant relationship between suicidal and self-harm ideations and the history of parental mental illness after adjusting the model for (a) tinnitus disability as measured via the Tinnitus Handicap Inventory (Newman, Jacobson, & Spitzer, 1996), (b) hyperacusis as measured via the Hyperacusis Questionnaire (Khalfa et al., 2002), (c) anxiety as measured via the Generalized Anxiety Disorder Questionnaire (Spitzer, Kroenke, Williams, & Löwe, 2006), (d) depression as measured via the Patient Health Questionnaire (Kroenke, Spitzer, & Williams, 2001), and (e) age and gender. Adjusted odds ratio was 2.5 (95% CI [1.14, 5.6], p = .022). The only other variable that was significantly related to the risk of suicidal and self-harm ideations was depression; adjusted odds ratio was 7.7 (95% CI [2.6, 26.3], p = .001). Conclusions Clinicians who offer tinnitus and hyperacusis rehabilitation should screen for suicidal and self-harm ideations among patients, especially for those with symptoms of depression and a childhood history of parental mental illness. Patients with suicidal and self-harm ideations should be referred to mental health services for further diagnosis and treatment.

Influence of blood storage age on immune and coagulation parameters in critically ill transfused patients.

BACKGROUND: Several retrospective studies have suggested that transfusion with red blood cells (RBCs) stored for longer periods is associated with increased mortality. The Age of Blood Evaluation (ABLE) study randomized subjects to receive fresh vs. standard issue RBC units and showed no difference in the primary or secondary endpoints of mortality or change in multi-organ dysfunction syndrome (MODS) score. METHODS: In this study a subset of 100 ABLE subjects were enrolled to measure coagulation and immune parameters. Samples were collected pre-transfusion and on days 2, 6, 28, and 180 post-transfusion. Levels of 16 coagulation parameters, regulatory and functional T cells, 25 cytokines, and 16 markers of extracellular vesicles (EVs) were determined. RESULTS: Changes from baseline in levels of protein C, factor V, and EVs expressing phosphatidyl serine and CTLA-4 (CD152) differed between recipients of fresh and standard storage age RBC units, with the vast majority of coagulation and EV markers and all cytokines tested showing no difference between study arms. Although most analytes showed no difference between subjects in the fresh and standard arms of the study, 6 coagulation parameters, 15 cytokines, and 7 EV parameters changed significantly in the period post-transfusion. DISCUSSION: Transfusion of fresh vs. standard issue RBC units does not result in substantial changes in coagulation or immune parameters, up to day 35 of RBC storage. Furthermore, significant changes in multiple coagulation and immune parameters are detectable post-transfusion, though causality cannot be determined based on the current study.

Effects of blood storage age on immune, coagulation, and nitric oxide parameters in transfused patients undergoing cardiac surgery.

BACKGROUND: Retrospective studies suggested that storage age of RBCs is associated with inflammation and thromboembolism. The Red Cell Storage Duration Study (RECESS) trial randomized subjects undergoing complex cardiac surgery to receive RBCs stored for shorter versus longer periods, and no difference was seen in the primary outcome of change in multiple organ dysfunction score. STUDY DESIGN AND METHODS: In the current study, 90 subjects from the RECESS trial were studied intensively using a range of hemostasis, immunologic, and nitric oxide parameters. Samples were collected before transfusion and on Days 2, 6, 28, and 180 after transfusion. RESULTS: Of 71 parameters tested, only 4 showed a significant difference after transfusion between study arms: CD8+ T-cell interferon-γ secretion and the concentration of extracellular vesicles bearing the B-cell marker CD19 were higher, and plasma endothelial growth factor levels were lower in recipients of fresh versus aged RBCs. Plasma interleukin-6 was higher at Day 2 and lower at Days 6 and 28 in recipients of fresh versus aged RBCs. Multiple parameters showed significant modulation after surgery and transfusion. Most analytes that changed after surgery did not differ based on transfusion status. Several extracellular vesicle markers, including two associated with platelets (CD41a and CD62P), decreased in transfused patients more than in those who underwent surgery without transfusion. CONCLUSIONS: Transfusion of fresh versus aged RBCs does not result in substantial changes in hemostasis, immune, or nitric oxide parameters. It is possible that transfusion modulates the level of platelet-derived extracellular vesicles, which will require study of patients randomly assigned to receipt of transfusion to define.

Parental Mental Health in Childhood as a Risk Factor for Anxiety and Depression among People Seeking Help for Tinnitus and Hyperacusis.

BACKGROUND: Parental mental illness is a risk factor for mental health disorders in the offspring. However, the relationship between parental illness in childhood and mental health disorders in adulthood among patients with tinnitus and/or hyperacusis is not known. PURPOSE: The aim was to explore the relationship between parental mental health in childhood and anxiety and depression for patients experiencing tinnitus and/or hyperacusis. RESEARCH DESIGN: This was a retrospective cross-sectional study with a correlational design. STUDY SAMPLE: Two hundred eighty-seven consecutive patients who attended a Tinnitus and Hyperacusis Therapy Specialist Clinic in the United Kingdom were included. Their average age was 52.5 years. DATA COLLECTION AND ANALYSIS: The association was explored between anxiety and depression measured via the Generalized Anxiety Disorder questionnaire (GAD-7) and the Patient Health questionnaire (PHQ-9) and responses to the question "While you were growing up during the first 18 years of life did your parent(s) have depression or mental illness?" RESULTS: Thirty-nine percent of patients (111/287) responded "yes" to the question about their parents' mental health, which is about double the incidence in the general population. Regression analysis showed that parental mental illness significantly increased the risk of anxiety and depression, with unadjusted odds ratios (ORs) of 2.7 (95% confidence interval [CI]: 1.5-4.9, p = 0.001) for the PHQ-9 and 2.6 (95% CI: 1.4-4.8, p = 0.002) for the GAD-7. However, when the models were adjusted for the effects of age, gender, tinnitus handicap as measured via the Tinnitus Handicap Inventory, hyperacusis handicap as measured via the Hyperacusis questionnaire, uncomfortable loudness levels, GAD-7 scores (for the depression model only), and PHQ-9 scores (for the anxiety model only), parental mental health was only significantly associated with depression, with an OR of 2.7 (95% CI: 1.08-6.7, p = 0.033). CONCLUSIONS: Audiologists offering tinnitus and hyperacusis rehabilitation should screen patients for parental mental illness in childhood, especially for those with comorbid depression, and make onward referral to appropriate mental health services when needed. Future research should analyze the breadth and type of adverse childhood experiences among patients with tinnitus and hyperacusis and their relationship with mental problems and treatment efficacy.