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Histamine plays pivotal role in normal physiology and dysregulated production of histamine or signaling through histamine receptors (HRH) can promote pathology. Previously, we showed that Bordetella pertussis or pertussis toxin can induce histamine sensitization in laboratory inbred mice and is genetically controlled by Hrh1/HRH1. HRH1 allotypes differ at three amino acid residues with P263-V313-L331 and L263-M313-S331, imparting sensitization and resistance respectively. Unexpectedly, we found several wild-derived inbred strains that carry the resistant HRH1 allotype (L263-M313-S331) but exhibit histamine sensitization. This suggests the existence of a locus modifying pertussis-dependent histamine sensitization. Congenic mapping identified the location of this modifier locus on mouse chromosome 6 within a functional linkage disequilibrium domain encoding multiple loci controlling sensitization to histamine. We utilized interval-specific single-nucleotide polymorphism (SNP) based association testing across laboratory and wild-derived inbred mouse strains and functional prioritization analyses to identify candidate genes for this modifier locus. Atg7, Plxnd1, Tmcc1, Mkrn2, Il17re, Pparg, Lhfpl4, Vgll4, Rho and Syn2 are candidate genes within this modifier locus, which we named Bphse, enhancer of Bordetella pertussis induced histamine sensitization. Taken together, these results identify, using the evolutionarily significant diversity of wild-derived inbred mice, additional genetic mechanisms controlling histamine sensitization.

Pleasant sensation is an underexplored avenue for modulation of chronic pain. Deeper pressure is perceived as pleasant and calming, and can improve sleep. Although pressure can reduce acute pain, its effect on chronic pain is poorly characterized. The current remote, double-blind, randomized controlled trial tested the hypothesis that wearing a heavy weighted blanket – providing widespread pressure to the body – relative to a light weighted blanket would reduce ratings of chronic pain, mediated by improvements in anxiety and sleep. Ninety-four adults with chronic pain were randomized to wear a 15-lb. (heavy) or 5-lb. (light) weighted blanket during a brief trial and overnight for one week. Measures of anxiety and chronic pain were collected pre- and post-intervention, and ratings of pain intensity, anxiety, and sleep were collected daily. After controlling for expectations and trait anxiety, the heavy weighted blanket produced significantly greater reductions in broad perceptions of chronic pain than the light weighted blanket (Cohen's f = .19, CI [-1.97, -.91]). This effect was stronger in individuals with high trait anxiety (P = .02). However, weighted blankets did not alter pain intensity ratings. Pain reductions were not mediated by anxiety or sleep. Given that the heavy weighted blanket was associated with greater modulation of affective versus sensory aspects of chronic pain, we propose that the observed reductions are due to interoceptive and social/affective effects of deeper pressure. Overall, we demonstrate that widespread pressure from a weighted blanket can reduce the severity of chronic pain, offering an accessible, home-based tool for chronic pain. The study purpose, targeted condition, study design, and primary and secondary outcomes were pre-registered in ClinicalTrials.gov (NCT04447885: “Weighted Blankets and Chronic Pain”). Perspective: This randomized-controlled trial showed that a 15-lb weighted blanket produced significantly greater reductions in broad perceptions of chronic pain relative to a 5-lb weighted blanket, particularly in highly anxious individuals. These findings are relevant to patients and providers seeking home-based, nondrug therapies for chronic pain relief.

Gentle stroking of the skin is a common social touch behavior with positive affective consequences. A preference for slow versus fast stroking of hairy skin has been closely linked to the firing of unmyelinated C-tactile (CT) somatosensory afferents. Because the firing of CT afferents strongly correlates with touch pleasantness, the CT pathway has been considered a social-affective sensory pathway. Recently, ablation of the spinothalamic pathway-thought to convey all C-fiber sensations-in patients with cancer pain impaired pain, temperature, and itch, butnotratings of pleasant touch. This suggested integration of A and CT fiber input in the spinal cord, or A-fiber contributions to computations of touch pleasantness in the brain. However, the causal contribution of A-fibers to touch pleasantness- in humanswithoutpain-remains unknown. In the current, single-blinded study we performed two types of peripheral nerve blocks in healthy adults to temporarily eliminate the contribution of A-fibers to touch perception. Our findings show that when A-fiber function is greatly diminished, the perceived intensityandpleasantness of both gentle stroking and deep pressure are nearly abolished. These findings demonstrate that explicit perception of the pleasantness of CT-targeted brushing and pressure both critically depend on A-fibers.

Neuroscientific research on pleasant touch has focused on the C-tactile pathway for gentle stroking and has successfully explained how these sensory fibers transmit information about affective social touch to the brain and induce sensations of pleasantness. The C-tactile social/affective touch hypothesis even proposes that C-tactile fibers form a privileged pathway underlying social touch. However, deep pressure is a type of touch commonly considered pleasant and calming, occurring in hugs, cuddling, and massage. In this paper we introduce a paradigm for studying pleasant deep pressure and propose that it constitutes another important form of social touch. We describe development of the oscillating compression sleeve (OCS) as one approach to administering deep pressure and demonstrate that this touch is perceived as pleasant and calming. Further, we show that deep pressure can be imaged with functional magnetic resonance imaging (MRI) using the air-pressure-driven OCS and that deep pressure activates brain regions highly similar to those that respond to C-tactile stroking, as well as regions not activated by stroking. We propose that deep pressure constitutes another social touch pathway of evolutionary importance signaling the close proximity of conspecifics.

Background Beverage and food taxes have become a popular ‘best buy’ public health intervention in the global battle to tackle noncommunicable diseases. Though many countries have introduced taxes, mainly targeting products containing sugar, there is great heterogeneity in tax design. For taxes levied as import tariffs, there is limited evidence of effectiveness in changing the price and sale of taxed products, while the evidence base is stronger for excise taxes levied as a fixed amount per quantity of product. This paper examines the effect of the Bermuda Discretionary Foods Tax, which was based on import tariff changes, on retail prices and sales of sugar-sweetened beverages (SSBs), and on selected fruits and vegetables that benefited from a tariff reduction. Methods We used weekly electronic point-of-sale data from a major food retailer in Bermuda. We assessed historical weekly sales and price data using an interrupted time series design on 2,703 unique products between the dates of January 2018 through January 2020, covering 103 weeks. Results By January 2020, the average price per ounce of SSBs increased by 26.0%, while the price of untaxed beverages (including waters and non-added sugar drinks) remained constant. The increasing price of SSBs was the sole observable structural driver of SSB market share, responsible for a decrease in the market share by nearly eight percentage points by the end of the study period. The subsidy on fruits and vegetables was ineffective in changing prices and sales, due to the relatively small 5% import tax decrease. Conclusions The tax was largely passed through to consumers. However, several factors mitigated the impact of the tax on the prices paid for SSBs by consumers, including the specific design of the tax, price promotions and consumer responses. The experience of Bermuda provides important lessons for the planning of similar taxes in the future.

OBJECTIVE Expectations contribute to cognitive pain modulation through opioidergically mediated descending inhibition. Mindfulness meditation reduces pain independent of endogenous opioids, engaging unique corticothalamocortical mechanisms. However, it remains unknown whether expectations for pain relief predict mindfulness-induced analgesia and if these expectations are modified by endogenous opioids. METHODS In this secondary analysis of previously published work, 78 pain-free participants (mean age, 27 ± 7 years; 50% women) were randomized to a four-session mindfulness meditation or book listening regimen. Expectations for intervention-induced pain relief were assessed before and after each intervention. Pain ratings were examined after meditation or rest (control group) during noxious heat (49°C) and intravenous administration of saline placebo or the opioid antagonist naloxone (0.15 mg/kg bolus + 0.1 mg kg-1 h-1 infusion. RESULTS Mindfulness significantly lowered pain during saline and naloxone infusion. Higher expected pain relief from mindfulness predicted lower pain intensity (r(40) = -0.41, p = .009). The relationship between meditation-related expectations and pain intensity reductions was exhibited during naloxone (r(20) = -0.76, p < .001) but not saline (r(20) = -0.22, p = .36). Expectations for book listening-based analgesia did not significantly predict pain changes during saline (r(20) = -0.37, p = .11) or naloxone (r(18) = 0.26, p = .30) in the control group. CONCLUSIONS These novel findings demonstrate a significant role for expectations in mindfulness-based pain relief. However, this role was minimal during saline and stronger during opioid blockade, despite similar pain reductions. This supports growing evidence that mindfulness engages multiple mechanisms to reduce pain, suggesting that mindfulness might be an effective pain-reducing technique even for individuals with low expectations for pain relief.

BackgroundTaxes on discretionary foods and sugar-sweetened beverages have emerged as a strategy for health promotion. Between 2018-2019, the Bermuda government introduced a phased sugar tax on imported sugar-sweetened beverages, confectionery, products containing cocoa and pure sugar. The aim of this study was to conduct a qualitative evaluation of perceptions of the tax among the general population and key stakeholders.MethodsWe conducted a survey of the general population (N = 400), and semi-structured interviews with key informants (N = 14) from the government, food and beverage, and health sectors to understand awareness, acceptability, and perceived impact of the tax after implementation. Summary statistics and thematic analysis were conducted for the general population survey data, and thematic analysis using the framework method was conducted for key informant interviews.ResultsGeneral population respondents had high awareness of the sugar tax (94%) but lower awareness of the healthy food subsidy (32%). Most respondents (67%) felt the tax was not an appropriate way to motivate healthier consumption behaviour largely due to perceptions the tax would not be effective (44%), and due to the high price of healthy food (20%). However, nearly half (48%) of respondents reported consuming fewer taxed products, primarily for health reasons but also motivated by price increases. Key informants indicated there was high awareness, but limited understanding of the tax policy. Most informants expressed support for taxation as a health promotion strategy, conditional on policy implementation. The tax was not believed to have had an impact on consumption. Factors include the lack of clear price differentiation and the absence of accompanying health education or health promotion. No informants were aware of use of tax revenues for health purposes and tax revenue was reportedly re-directed after implementation.ConclusionsThere was high awareness, but limited acceptability of the tax as implemented. Clarity in the tax policy, appropriateness of the tax mechanism, and use of revenue in alignment with the tax aim are critical components for acceptance. The absence of complementary education and health promotion further affected acceptance and may limit potential health impacts. The lessons learned in Bermuda can inform similar policies in other settings.

Background Taxes on discretionary foods and sugar-sweetened beverages have emerged as a strategy for health promotion. Between 2018–2019, the Bermuda government introduced a phased tax on imported sugar-sweetened beverages, confectionery, products containing cocoa and pure sugar, and eliminated import duties on select healthy food items. The aim of this study was to conduct an mixed methods evaluation of perceptions of the tax among the general population and key stakeholders. Methods We conducted a survey of the general population (N = 400), and semi-structured interviews with key informants (N = 14) from the government, food and beverage, and health sectors to understand awareness, acceptability, and perceived impact of the tax after implementation. Survey data was analysed using thematic analysis, summary statistics, and Chi-squared tests. Key informant interviews were analysed using the framework method. Results General population respondents had high awareness of the sugar tax (94%) but low awareness of the healthy food subsidy (32%). Most respondents (67%) felt the tax was not an appropriate way to motivate healthier consumption due to beliefs the tax would not be effective (44%), and because of the high price of healthy food (20%). However, nearly half (48%) reported consuming fewer taxed products, primarily for health reasons but also motivated by price increases. Key informants indicated there was high awareness but limited understanding of the tax policy. Informants expressed support for taxation as a health promotion strategy, conditional on policy implementation. The lack of clear price differentiation between taxed and un-taxed products and the absence of accompanying health education were key factors believed to affect the impact of the tax. No informants were aware of use of tax revenues for health purposes and tax revenue was reportedly re-directed to other priorities after implementation. Conclusions There was high awareness, but limited acceptability of the Bermuda sugar tax as implemented. Clarity in the tax policy, appropriateness of the tax mechanism, and use of revenue in alignment with the tax aim are critical components for acceptance. The absence of complementary education and health promotion affected acceptance and may limit potential health impacts. The lessons learned in Bermuda can inform similar policies in other settings.

Introduction The Case Surveillance and Vital Registration (CSAVR) model within Spectrum estimates HIV incidence trends from surveillance data on numbers of new HIV diagnoses and HIV‐related deaths. This article describes developments of the CSAVR tool to more flexibly model diagnosis rates over time, estimate incidence patterns by sex and age group and by key population group. Methods We modelled HIV diagnosis rate trends as a mixture of three factors, including temporal and opportunistic infection components. The tool was expanded to estimate incidence rate ratios by sex and age for countries with disaggregated reporting of new HIV diagnoses and AIDS deaths, and to account for information on key populations such as men who have sex with men (MSM), males who inject drugs (MWID), female sex workers (FSW) and females who inject drugs (FWID). We used a Bayesian framework to calibrate the tool in 71 high‐income or low‐HIV burden countries. Results Across countries, an estimated median 89% (interquartile range [IQR]: 78%–96%) of HIV‐positive adults knew their status in 2019. Mean CD4 counts at diagnosis were stable over time, with a median of 456 cells/μl (IQR: 391–508) across countries in 2019. In European countries reporting new HIV diagnoses among key populations, median estimated proportions of males that are MSM and MWID was 1.3% (IQR: 0.9%–2.0%) and 0.56% (IQR: 0.51%–0.64%), respectively. The median estimated proportions of females that are FSW and FWID were 0.36% (IQR: 0.27%–0.45%) and 0.14 (IQR: 0.13%–0.15%), respectively. HIV incidence per 100 person‐years increased among MSM, with median estimates reaching 0.43 (IQR: 0.29–1.73) in 2019, but remained stable in MWID, FSW and FWID, at around 0.12 (IQR: 0.04–1.9), 0.09 (IQR: 0.06–0.69) and 0.13% (IQR: 0.08%–0.91%) in 2019, respectively. Knowledge of HIV status among HIV‐positive adults gradually increased since the early 1990s to exceed 75% in more than 75% of countries in 2019 among each key population. Conclusions CSAVR offers an approach to using routine surveillance and vital registration data to estimate and project trends in both HIV incidence and knowledge of HIV status.

Histamine is a bioactive amine associated with a plethora of normal and pathophysiological processes, with the latter being dependent on both genetic and environmental factors including infectious agents. Previously, we showed in mice that susceptibility to Bordetella pertussis and pertussis toxin (PTX) induced histamine sensitization (Bphs) is controlled by histamine receptor H1 (Hrh1/HRH1) alleles. Bphs susceptible and resistant alleles (Bphss/Bphsr) encode for two-conserved protein haplotypes. Given the importance of HRH1 signaling in health and disease, we sequenced Hrh1 across an extended panel of laboratory and wild-derived inbred strains and phenotyped them for Bphs. Unexpectedly, eight strains homozygous for the Bphsr allele phenotyped as Bphss, suggesting the existence of a modifying locus segregating among the strains capable of complementing Bphsr. Genetic analyses mapped this modifier locus to mouse chromosome 6; designated Bphs-enhancer (Bphse), within a functional linkage disequilibrium domain encoding multiple loci controlling responsiveness to histamine (Bphs/Hrh1 and Histh1-4). Interval-specific single-nucleotide polymorphism (SNP) based association testing across 50 laboratory and wild-derived inbred mouse strains and functional prioritization analyses resulted in the identification of candidate genes for Bphse within a ∼5.5 Mb interval (Chr6:111.0-116.4 Mb), including Atg7, Plxnd1, Tmcc1, Mkrn2, Il17re, Pparg, Lhfpl4, Vgll4, Rho and Syn2. Taken together, these results demonstrate the power of combining network-based computational methods with the evolutionarily significant diversity of wild-derived inbred mice to identify novel genetic mechanisms controlling susceptibility and resistance to histamine shock.

International audience; UNAIDS and other partners provide support to countries to develop estimates of HIV and related indicators on an annual basis. These estimates are used to monitor epidemic trends, guide program planning and resource allocation, and inform policy decision-making. The collection of articles in this AIDS supplement provide the headline results for the 2019 UNAIDS estimates and describe the new developments in the methods used to produce these estimates.

Genetic mapping is a primary tool of genetics in model organisms; however, many quantitative trait loci (QTL) contain tens or hundreds of positional candidate genes. Prioritizing these genes for validation is often ad hoc and biased by previous findings. Here we present a technique for computationally prioritizing positional candidates based on computationally inferred gene function. Our method uses machine learning with functional genomic networks, whose links encode functional associations among genes, to identify network-based signatures of functional association to a trait of interest. We demonstrate the method by functionally ranking positional candidates in a large locus on mouse Chr 6 (45.9 Mb to 127.8 Mb) associated with histamine hypersensitivity (Hhs). Hhs is characterized by systemic vascular leakage and edema in response to histamine challenge, which can lead to multiple organ failure and death. Although Hhs risk is strongly influenced by genetics, little is known about its underlying molecular or genetic causes, due to genetic and physiological complexity of the trait. To dissect this complexity, we ranked genes in the Hhs locus by predicting functional association with multiple Hhs-related processes. We integrated these predictions with new single nucleotide polymorphism (SNP) association data derived from a survey of 23 inbred mouse strains and congenic mapping data. The top-ranked genes included Cxcl12, Ret, Cacna1c, and Cntn3, all of which had strong functional associations and were proximal to SNPs segregating with Hhs. These results demonstrate the power of network-based computational methods to nominate highly plausible quantitative trait genes even in highly challenging cases involving large QTLs and extreme trait complexity.

This review examines recent (2016 onwards) neuroscientific findings on the mechanisms supporting mindfulness-associated pain relief. To date, its clear that mindfulness lowers pain by engaging brain processes that are distinct from placebo and vary across meditative training level. Due to rapid developments in the field of contemplative neuroscience, an update review on the neuroimaging studies focused on mindfulness, and pain is merited. Mindfulness-based therapies produce reliably reductions in a spectrum of chronic pain conditions through psychological, physiological, and neural mechanisms supporting the modulation of evaluation and appraisal of innocuous and noxious sensory events. Neuroimaging and randomized control studies confirm that mindfulness meditation reliably reduces experimentally induced and clinical pain by engaging multiple, unique, non-opioidergic mechanisms that are distinct from placebo and which vary across meditative training level. These promising findings underscore the potential of mindfulness-based approaches to produce long-lasting improvements in pain-related symptomology.

Background In line with the Joint United Nations Programme on HIV/AIDS (UNAIDS) 90-90-90 target, Norway aims for at least 90% of people living with HIV (PLHIV) to know their HIV-status. We produced current estimates of the number of PLHIV and undiagnosed population in Norway, overall and for six key subpopulations: Norwegian-born men who have sex with men (MSM), migrant MSM, Norwegian-born heterosexuals, migrant Sub-Saharan Africa (SSA)-born heterosexuals, migrant non-SSA-born heterosexuals and people who inject drugs. Methods We used the European Centre for Disease Prevention and Control (ECDC) HIV Modelling Tool on Norwegian HIV surveillance data through 2018 to estimate incidence, time from infection to diagnosis, PLHIV, and the number and proportion undiagnosed. As surveillance data on CD4 count at diagnosis were not collected in Norway, we ran two models; using default model CD4 assumptions, or a proxy for CD4 distribution based on Danish national surveillance data. We also generated alternative overall PLHIV estimates using the Spectrum AIDS Impact Model, to compare with those obtained from the ECDC tool. Results Estimates of the overall number of PLHIV in 2018 using different modelling approaches aligned at approximately 5000. In both ECDC models, the overall number undiagnosed decreased continuously from 2008. The proportion undiagnosed in 2018 was lower using default model CD4 assumptions (7.1% [95%CI: 5.3–8.9%]), than the Danish CD4 proxy (10.2% [8.3–12.1%]). This difference was driven by results for heterosexual migrants. Estimates for Norwegian-born MSM, migrant MSM and Norwegian-born heterosexuals were similar in both models. In these three subpopulations, incidence in 2018 was Conclusions Results allow cautious confidence in concluding that Norway has achieved the first UNAIDS 90–90-90 target, and clearly highlight the success of prevention strategies among MSM. Estimates for subpopulations strongly influenced by migration remain less clear, and future modelling should appropriately account for all-cause mortality and out-migration, and adjust for time of in-migration.

Research suggests that the discriminative and affective aspects of touch are processed differently in the brain. Primary somatosensory cortex is strongly implicated in touch discrimination, whereas insular and prefronal regions have been associated with pleasantness aspects of touch. However, the role of secondary somatosensory cortex (S2) is less clear. In the current study we used inhibitory repetitive transcranial magnetic stimulation (rTMS) to temporarily deactivate S2 and probe its role in touch perception. Nineteen healthy adults received two sessions of 1-Hz rTMS on separate days, one targeting right S2 and the other targeting the vertex (control). Before and after rTMS, subjects rated the intensity and pleasantness of slow and fast gentle brushing of the hand and performed a 2-point tactile discrimination task, followed by fMRI during additional brushing. rTMS to S2 (but not vertex) decreased intensity ratings of fast brushing, without altering touch pleasantness or spatial discrimination. MRI showed a reduced response to brushing in S2 (but not in S1 or insula) after S2 rTMS. Together, our results show that reducing touch-evoked activity in S2 decreases perceived touch intensity, suggesting a causal role of S2 in touch intensity perception.

Month-season of birth (M-SOB) is a risk factor in multiple chronic diseases, including multiple sclerosis (MS), where the lowest and greatest risk of developing MS coincide with the lowest and highest birth rates, respectively. To determine whether M-SOB effects in such chronic diseases as MS can be experimentally modeled, we examined the effect of M-SOB on susceptibility of C57BL/6J mice to experimental autoimmune encephalomyelitis (EAE). As in MS, mice that were born during the M-SOB with the lowest birth rate were less susceptible to EAE than mice born during the M-SOB with the highest birth rate. We also show that the M-SOB effect on EAE susceptibility is associated with differential production of multiple cytokines/chemokines by neuroantigen-specific T cells that are known to play a role in EAE pathogenesis. Taken together, these results support the existence of an M-SOB effect that may reflect seasonally dependent developmental differences in adaptive immune responses to self-antigens independent of external stimuli, including exposure to sunlight and vitamin D. Moreover, our documentation of an M-SOB effect on EAE susceptibility in mice allows for modeling and detailed analysis of mechanisms that underlie the M-SOB effect in not only MS but in numerous other diseases in which M-SOB impacts susceptibility.-Reynolds, J. D., Case, L. K., Krementsov, D. N., Raza, A., Bartiss, R., Teuscher, C. Modeling month-season of birth as a risk factor in mouse models of chronic disease: from multiple sclerosis to autoimmune encephalomyelitis.

Males of many species, ranging from humans to insects, are more susceptible than females to parasitic, fungal, bacterial, and viral infections. One mechanism that has been proposed to account for this difference is the immunocompetence handicap model, which posits that the greater infectious disease burden in males is due to testosterone, which drives the development of secondary male sex characteristics at the expense of suppressing immunity. However, emerging data suggest that cell-intrinsic (chromosome X and Y) sex-specific factors also may contribute to the sex differences in infectious disease burden. Using a murine model of influenza A virus (IAV) infection and a panel of chromosome Y (ChrY) consomic strains on the C57BL/6J background, we present data showing that genetic variation in ChrY influences IAV pathogenesis in males. Specific ChrY variants increase susceptibility to IAV in males and augment pathogenic immune responses in the lung, including activation of proinflammatory IL-17-producing γδ T cells, without affecting viral replication. In addition, susceptibility to IAV segregates independent of copy number variation in multicopy ChrY gene families that influence susceptibility to other immunopathological phenotypes, including survival after infection with coxsackievirus B3. These results demonstrate a critical role for genetic variation in ChrY in regulating susceptibility to infectious disease.

This chapter provides a review of the main clinical alterations of body representation in neurological and psychiatric diseases. First, we describe instances of altered body representations in neurological conditions, either constrained to a specific body part (e.g., personal neglect, somatoparaphenia, phantom limbs) or impacting the whole body (autoscopic phenomena, feeling of a presence). In the second part of this chapter, we present body representation disorders associated with chronic pain and psychiatric conditions including anorexia nervosa, schizophrenia, and gender dysphoria. Beyond their clinical relevance, these conditions provide valuable insights into understanding the way our body is normally represented, and the way it is consciously experienced.

We characterize a small minority of individuals who self-report frequent, involuntary alternation in their gender identity (Alternating Gender; AG) in an attempt to glean insight into gender identity from a cognitive neuroscience perspective. We conducted an online survey of 73 AG individuals (44 male natal sex), with follow-up phone interviews and psychological assessment of 20 participants. Our results suggest that AG may be a previously uncharacterized gender phenomenon not explained by existing psychological diagnoses or commonly recognized gender identities. Further research on AG may yield novel insight into the neural and psychological correlates of gender identity by allowing the study of gender variation within individuals over time.

Regulation of gene expression in immune cells is known to be under genetic control, and likely contributes to susceptibility to autoimmune diseases such as multiple sclerosis (MS). How this occurs in concert across multiple immune cell types is poorly understood. Using a mouse model that harnesses the genetic diversity of wild-derived mice, more accurately reflecting genetically diverse human populations, we provide an extensive characterization of the genetic regulation of gene expression in five different naive immune cell types relevant to MS. The immune cell transcriptome is shown to be under profound genetic control, exhibiting diverse patterns: global, cell-specific and sex-specific. Bioinformatic analysis of the genetically controlled transcript networks reveals reduced cell type specificity and inflammatory activity in wild-derived PWD/PhJ mice, compared with the conventional laboratory strain C57BL/6J. Additionally, candidate MS-GWAS (genome-wide association study candidate genes for MS susceptibility) genes were significantly enriched among transcripts overrepresented in C57BL/6J cells compared with PWD. These expression level differences correlate with robust differences in susceptibility to experimental autoimmune encephalomyelitis, the principal model of MS, and skewing of the encephalitogenic T-cell responses. Taken together, our results provide functional insights into the genetic regulation of the immune transcriptome, and shed light on how this in turn contributes to susceptibility to autoimmune disease.

Growing interest in affective touch has delineated a neural network that bypasses primary somatosensory cortex (S1). Several recent studies, however, have cast doubt on the segregation of touch discrimination and affect, suggesting that S1 also encodes affective qualities. We used functional magnetic resonance imaging (fMRI) and repetitive transcranial magnetic stimulation (rTMS) to examine the role of S1 in processing touch intensity and pleasantness. Twenty-six healthy human adults rated brushing on the hand during fMRI. Intensity ratings significantly predicted activation in S1, whereas pleasantness ratings predicted activation only in the anterior cingulate cortex. Nineteen subjects also received inhibitory rTMS over right hemisphere S1 and the vertex (control). After S1 rTMS, but not after vertex rTMS, sensory discrimination was reduced and subjects with reduced sensory discrimination rated touch as more intense. In contrast, rTMS did not alter ratings of touch pleasantness. Our findings support divergent neural processing of touch intensity and pleasantness, with affective touch encoded outside of S1.SIGNIFICANCE STATEMENTGrowing interest in affective touch has identified a neural network that bypasses primary somatosensory cortex (S1). Several recent studies, however, cast doubt on the separation of touch discrimination and affect. We used functional magnetic resonance imaging and repetitive transcranial magnetic stimulation to demonstrate the representation of touch discrimination and intensity in S1, but the representation of pleasantness in the anterior cingulate cortex, not S1. Our findings support divergent neural processing of touch intensity and pleasantness, with affective touch encoded outside of S1. Our study contributes to growing delineation of the affective touch system, a crucial step in understanding its dysregulation in numerous clinical conditions such as autism, eating disorders, depression, and chronic pain.

The sensation of pressure allows us to feel sustained compression and body strain. While our understanding of cutaneous touch has grown significantly in recent years, how deep tissue sensations are detected remains less clear. Here, we use quantitative sensory evaluations of patients with rare sensory disorders, as well as nerve blocks in typical individuals, to probe the neural and genetic mechanisms for detecting non-painful pressure. We show that the ability to perceive innocuous pressures is lost when myelinated fiber function is experimentally blocked in healthy volunteers and that two patients lacking Aβ fibers are strikingly unable to feel innocuous pressures at all. We find that seven individuals with inherited mutations in the mechanoreceptor PIEZO2 gene, who have major deficits in touch and proprioception, are nearly as good at sensing pressure as healthy control subjects. Together, these data support a role for Aβ afferents in pressure sensation and suggest the existence of an unknown molecular pathway for its detection., The mechanisms underlying deep pressure sensing are not fully understood. Here the authors demonstrate that while two individuals lacking Aβ fibers demonstrate impaired deep pressure sensing, seven individuals with PIEZO2 loss of function mutations display normal deep pressure responses.

Tissue injury and inflammation markedly alter touch perception, making normally innocuous sensations become intensely painful. Although this sensory distortion, known as tactile allodynia, is one of the most common types of pain, the mechanism by which gentle mechanical stimulation becomes unpleasant remains enigmatic. The stretch-gated ion channel PIEZO2 has been shown to mediate light touch, vibration detection, and proprioception. However, the role of this ion channel in nociception and pain has not been resolved. Here, we examined the importance of Piezo2 in the cellular representation of mechanosensation using in vivo imaging in mice. Piezo2-knockout neurons were completely insensitive to gentle dynamic touch but still responded robustly to noxious pinch. During inflammation and after injury, Piezo2 remained essential for detection of gentle mechanical stimuli. We hypothesized that loss of PIEZO2 might eliminate tactile allodynia in humans. Our results show that individuals with loss-of-function mutations in PIEZO2 completely failed to develop sensitization and painful reactions to touch after skin inflammation. These findings provide insight into the basis for tactile allodynia, identify the PIEZO2 mechanoreceptor as an essential mediator of touch under inflammatory conditions, and suggest that this ion channel might be targeted for treating tactile allodynia.

We explored the ongoing question of whether placebo analgesia alters afferent nociceptive processing in a novel paradigm designed to minimize the role of response bias in placebo measurement. First, healthy adult participants received a standard heat placebo induction and conditioning procedure using a topical “analgesic” cream applied to one arm. During a subsequent placebo testing procedure, participants rated stimuli on the placebo-treated arm and untreated arm, using a task that minimized subjects’ ability to guess the expected response, thus reducing experimenter demand. Retrospectively participants reported moderate analgesia effectiveness (mean = 5.3/10), but for individual temperature ratings, only 2 subjects exhibited a perceptual placebo response >5 points. Next, these subjects completed a novel, exploratory task designed to measure changes in inter-arm in discriminative accuracy that would be expected from changes in afferent nociception. Both placebo responders (but no non-responders) showed reduced discriminative ability when the hotter stimulus occurred on the placebo arm, an effect consistent with alterations in nociceptive afferent flow and unlikely to be caused by response bias. Keywords: Placebo, Analgesia, Sensory discrimination, Pain, Intensity

Both light skin stroking (engaging the C-tactile afferent sensory pathway) and deep pressure touch (as in deep tissue massage) are commonly perceived as pleasant and relaxing. Opioid blockade has been found to increase receipt of grooming in monkeys, suggesting possible opioid modulation of touch pleasantness. Recently, human data [1] suggested that blocking opioid receptors might decrease the perceived intensity of gentle brushing but increase its pleasantness. The current study examined the role of endogenous opioids in the perceived intensity and pleasantness of pleasant touch. Using a double-blind cross-over design, 24 healthy adult participants received intravenous naloxone or saline (control) on separate days. Blocks of gentle brushing and deep pressure compression were administered on the lower left calf. Participants rated the intensity and pleasantness of each stimulus, as well as current mood and anxiety. Naloxone significantly reduced perceived intensity of gentle brushing (p = 0.039), but did not affect brushing pleasantness (p = 0.44) or intensity or pleasantness of deep pressure (p = 0.97; p = 0.85). The naloxone-induced reduction in gentle touch intensity replicates results previously seen in chronic pain patients [1]. The lack of effect on pleasantness in this study versus [1] could relate to differences in the location of touch (arm or leg), sex of the experimenters, or whether the touch followed pain tasks. However, in the current study, naloxone was marginally anxiolytic (p = 0.07), and naloxone-induced changes in touch pleasantness were significantly more correlated with subsequent mood and anxiety ratings than were changes during saline (mood p = 0.04; anxiety p

Much evidence from pain patients and animal models shows that chronic pain does not exist in a vacuum, but has varied co-morbidities and far-reaching consequences. Patients with long-term pain often develop anxiety and depression and can manifest changes in cognitive functioning, particularly with working memory. Longitudinal studies in rodent models also show the development of anxiety-like behavior and cognitive changes weeks to months after an injury causing long-term pain. Brain imaging studies in pain patients and rodent models find that chronic pain is associated with anatomical and functional alterations in the brain. Nevertheless, studies in humans reveal that life-style choices, such as the practice of meditation or yoga, can reduce pain perception and have the opposite effect on the brain as does chronic pain. In rodent models, studies show that physical activity and a socially enriched environment reduce pain behavior and normalize brain function. Together, these studies suggest that the burden of chronic pain can be reduced by non-pharmacological interventions.

Multiple sclerosis is a disabling and progressive neurological disease that has significant negative effects on health-related quality of life. This exploratory efficacy study examined the effects of Healing Light Guided Imagery (HLGI), a novel variant of guided imagery, compared with a wait-list control in patients with relapsing-remitting multiple sclerosis. Changes in the Beck Depression Inventory, Fatigue Severity Scale, and Multiple Sclerosis Quality of Life instrument (physical and mental components) were compared between groups. Patients who completed HLGI (N = 9) showed significant reductions in depressed mood ( P < .05) and fatigue ( P < .01) and showed significant gains in physical ( P = .01) and mental ( P < .01) quality of life compared with journaling (N = 8). Our results suggest that HLGI can improve self-reported physical and mental well-being in patients with relapsing-remitting multiple sclerosis. Further research is needed to study the effectiveness of this therapy, as well as its mind-body mechanisms of action.

Global health organizations frequently set disease-specific targets with the goal of eliciting adoption at the national-level; consideration of the influence of target setting on national policies, programme and health budgets is of benefit to those setting targets and those intended to respond. In 2014, the Joint United Nations Programme on HIV/AIDS set ‘ambitious’ treatment targets for country adoption: 90% of HIV-positive persons should know their status; 90% of those on treatment; 90% of those achieving viral suppression. Using case studies from Ghana and Uganda, we explore how the target and its associated policy content have been adopted at the national level. That is whether adoption is in rhetoric only or supported by programme, policy or budgetary changes. We review 23 (14 from Ghana, 9 from Uganda) national policy, operational and strategic documents for the HIV response and assess commitments to ‘90–90–90’. In-person semi-structured interviews were conducted with purposively sampled key informants (17 in Ghana, 20 in Uganda) involved in programme-planning and resource allocation within HIV to gain insight into factors facilitating adoption of 90–90–90. Interviews were transcribed and analysed thematically, inductively and deductively, guided by pre-existing policy theories, including Dolowitz and Marsh’s policy transfer framework to describe features of the transfer and the Global Health Advocacy and Policy Project framework to explain observations. Regardless of notable resource constraints, transfer of the 90–90–90 targets was evident beyond rhetoric with substantial shifts in policy and programme activities. In both countries, there was evidence of attempts to minimize resource constraints by seeking programme efficiencies, prioritization of programme activities and devising domestic financing mechanisms; however, significant resource gaps persist. An effective health network, comprised of global and local actors, mediated the adoption and adaptation, facilitating a shift in the HIV programme from ‘business as usual’ to approaches targeting geographies and populations.

Select humans and animals control persistent viral infections via adaptive immune responses that include production of neutralizing antibodies. The precise genetic basis for the control remains enigmatic. Here, we report positional cloning of the gene responsible for production of retrovirus-neutralizing antibodies in mice of the I/LnJ strain. It encodes the beta subunit of the non-classical Major Histocompatibility Complex class II (MHC-II)-like molecule H2-O, a negative regulator of antigen presentation. The recessive and functionally null I/LnJ H2-Ob allele supported the production of virus-neutralizing antibodies independently of the classical MHC haplotype. Subsequent bioinformatics and functional analyses of the human H2-Ob homologue, HLA-DOB revealed both loss- and gain-of-function alleles, which could affect the ability of their carriers to control infections with Human Hepatitis B (HBV) and C (HCV) viruses. Thus, understanding of the previously unappreciated role of H2-O (HLA-DO) in immunity to infections may suggest new approaches in achieving neutralizing immunity to viruses.

The Joint United Nations Programme on HIV/AIDS (UNAIDS) publishes estimates of the HIV epidemic every year [1]. For 2016, estimates are available for 160 countries representing 98% of the global population. These estimates are produced by countries with guidance from UNAIDS. The methods used in this process continue to evolve over time under the stewardship of the UNAIDS Reference Group on Estimates, Modelling and Projections [2]. In 2014, the WHO convened the Guidelines for Accurate and Transparent Health Estimates Reporting (GATHER) Working Group with the aim to define and promote good practice in reporting global health estimates [3]. The GATHER Statement is the outcome produced by this group. It defines a list of reporting requirements to allow for the accurate interpretation, and facilitate the appropriate use, of global health estimates [4]. UNAIDS fully endorses and supports the GATHER Statement. The current special supplement, which details the methods used to produce the 2016 UNAIDS estimates, further supports the routine publication of data sources and methods used as part of an open and transparent process. It provides updates of the evolving understanding of the data on which the estimates are based, the methods used to derive the estimates, justification of changes in these methods, and the sources of new data available to inform these modifications. It follows a series of such collections [5–10] which have documented and described the evolving methods used to produce the UNAIDS Global AIDS estimates since 2004.

Background: Joint United Nations Programme on HIV/AIDS (UNAIDS) and Murray et al. have both produced sets of estimates for worldwide HIV incidence, prevalence and mortality. Understanding differences in these estimates can strengthen the interpretation of each. Methods: We describe differences in the two sets of estimates. Where possible, we have drawn on additional published data to which estimates can be compared. Findings: UNAIDS estimates that there were 6 million more people living with HIV (PLHIV) in 2013 (35 million) compared with the Murray et al. estimates (29 million). Murray et al. estimate that new infections and AIDS deaths have declined more gradually than does UNAIDS. Just under one third of the difference in PLHIV is in Africa, where Murray et al. have relied more on estimates of adult mortality trends than on data on survival times. Another third of the difference is in North America, Europe, Central Asia and Australasia. Here Murray et al. estimates of new infections are substantially lower than the number of new HIV/AIDS diagnoses reported by countries, whereas published UNAIDS estimate tend to be greater. The remaining differences are in Latin America and Asia where the data upon which the UNAIDS methods currently rely are more sparse, whereas the mortality data leveraged by Murray et al. may be stronger. In this region, however, anomalies appear to exist between the both sets of estimates and other data. Interpretation: Both estimates indicate that approximately 30 million PLHIV and that antiretroviral therapy has driven large reductions in mortality. Both estimates are useful but show instructive discrepancies with additional data sources. We find little evidence to suggest that either set of estimates can be considered systematically more accurate. Further work should seek to build estimates on as wide a base of data as possible.

Every year, the Joint United Nations Programme on HIV/AIDS (UNAIDS) produces estimates that chart the magnitude of the worldwide HIV epidemic, its impact and the progress taken to curb its spread and reduce its impact. The UNAIDS Reference Group on Estimates, Modelling and Projections [1] exists to review and develop the methods supported by UNAIDS to generate national estimates of HIV and related indicators. UNAIDS and its Reference Group routinely produce special editions of scientific journals to document the methods used to produce the UNAIDS estimates and to provide updates on the directions the methods are expected to take in the future [2–6]. The work of the Reference Group is two-fold – to continually calibrate, update and validate the methods, while simultaneously extending the methods to take advantage of new data sources, and to adapt approaches so as to maximise their usefulness to country programme planning and in evaluation. The articles in this supplement fall into both of these categories. Two articles document recent improvements to the estimation and projection models that are used, and another compares the UNAIDS estimates with other sets of published estimates and data. Several other articles show how the methods have expanded to accommodate the need to better understand data requirements for young children and older people; how estimates of key indicators are produced at finer spatial scales; and finally, how methods can and will synthesise newly available data into estimates. We address each of these topics in turn below. Together, these updates, modifications and new methods aim to provide more accurate knowledge and better understanding of HIV epidemics which should inform and assist programme planners and decision makers, as well as scientists, researchers and the wider public.

The estrogens are female sex hormones that are involved in a variety of physiological processes, including reproductive development and function, wound healing, and bone growth. They are mainly known for their roles in reproductive tissues—specifically, 17β-estradiol (E2), the primary estrogen, which is secreted by the ovaries and induces cellular proliferation and growth of the uterus and mammary glands. In addition to the role of estrogens in promoting tissue growth and development during normal physiological states, they have a well-established role in determining susceptibility to disease, particularly cancer, in reproductive tissues. The responsiveness of various tissues to estrogen is genetically controlled, with marked quantitative variation observed across multiple species, including humans. This variation presents both researchers and clinicians with a veritable physiological puzzle, the pieces of which—many of them unknown—are complex and difficult to fit together. Although genetics is known to play a major role in determining sensitivity to estrogens, there are other factors, including parent of origin and the maternal environment, that are intimately linked to heritable phenotypes but do not represent genotype, per se. The objectives of this review article were to summarize the current knowledge of the role of genotype, and uterine and neonatal environments, in phenotypic variation in the response to estrogens; to discuss recent findings and the potential mechanisms involved; and to highlight exciting research opportunities for the future.—Wall, E. H., Hewitt, S. C., Case, L. K, Lin, C.-Y., Korach, K. S., Teuscher, C. The role of genetics in estrogen responses: a critical piece of an intricate puzzle.

Mirror neurons allow us to covertly simulate the sensation and movement of others. If mirror neurons are sensory and motor neurons, why do we not actually feel this simulation- like "mirror-touch synesthetes"? Might afferent sensation normally inhibit mirror representations from reaching consciousness? We and others have reported heightened sensory referral to phantom limbs and temporarily anesthetized arms. These patients, however, had experienced illness or injury of the deafferented limb. In the current study we observe heightened sensory and motor referral to the face after unilateral nerve block for routine dental procedures. We also obtain double-blind, quantitative evidence of heightened sensory referral in healthy participants completing a mirror-touch confusion task after topical anesthetic cream is applied. We suggest that sensory and motor feedback exist in dynamic equilibrium with mirror representations; as feedback is reduced, the brain draws more upon visual information to determine- perhaps in a Bayesian manner- what to feel.

Histamine (HA) is a key regulator of experimental allergic encephalomyelitis (EAE), the autoimmune model of multiple sclerosis. HA exerts its effects through four known G-protein–coupled receptors: H1, H2, H3, and H4 (histamine receptors; H1–4R). Using HR-deficient mice, our laboratory has demonstrated that H1R, H2R, H3R, and H4R play important roles in EAE pathogenesis, by regulating encephalitogenic T cell responses, cytokine production by APCs, blood–brain barrier permeability, and T regulatory cell activity, respectively. Histidine decarboxylase–deficient mice (HDCKO), which lack systemic HA, exhibit more severe EAE and increased Th1 effector cytokine production by splenocytes in response to myelin oligodendrocyte gp35–55. In an inverse approach, we tested the effect of depleting systemic canonical HA signaling on susceptibility to EAE by generating mice lacking all four known G-protein–coupled-HRs (H1–4RKO mice). In this article, we report that in contrast to HDCKO mice, H1–4RKO mice develop less severe EAE compared with wild-type animals. Furthermore, splenocytes from immunized H1–4RKO mice, compared with wild-type mice, produce a lower amount of Th1/Th17 effector cytokines. The opposing results seen between HDCKO and H1–4RKO mice suggest that HA may signal independently of H1–4R and support the existence of an alternative HAergic pathway in regulating EAE resistance. Understanding and exploiting this pathway has the potential to lead to new disease-modifying therapies in multiple sclerosis and other autoimmune and allergic diseases.

Multiple sclerosis (MS), a demyelinating immune-mediated central nervous system disease characterized by increasing female penetrance, is the leading cause of disability in young adults in the developed world. Epidemiological data strongly implicate an environmental factor, acting at the population level during gestation, in the increasing incidence of female MS observed over the last 50 years, yet the identity of this factor remains unknown. Gestational exposure to bisphenol A (BPA), an endocrine disruptor used in the manufacture of polycarbonate plastics since the 1950s, has been reported to alter a variety of physiological processes in adulthood. BPA has estrogenic activity, and we hypothesized that increased gestational exposure to environmental BPA may therefore contribute to the increasing female MS risk. To test this hypothesis, we utilized two different mouse models of MS, experimental autoimmune encephalomyelitis (EAE) in C57BL/6J mice (chronic progressive) and in SJL/J mice (relapsing-remitting). Dams were exposed to physiologically relevant levels of BPA in drinking water starting 2 weeks prior to mating and continuing until weaning of offspring. EAE was induced in adult offspring. No significant changes in EAE incidence, progression, or severity were observed with BPA exposure, despite changes in cytokine production by autoreactive T cells. However, endocrine disruption was evidenced by changes in testes development, and transcriptomic profiling revealed that BPA exposure altered the expression of several genes important for testes development, including Pdgfa, which was downregulated. Overall, our results do not support gestational BPA exposure as a significant contributor to the increasing female MS risk.

The uterotropic response of the uterus to 17β-estradiol (E2) is genetically controlled, with marked variation observed depending on the mouse strain studied. Previous genetic studies from our laboratory using inbred mice that are high [C57BL/6J (B6)] or low [C3H/HeJ (C3H)] responders to E2 led to the identification of quantitative trait (QT) loci associated with phenotypic variation in uterine growth and leukocyte infiltration. The mechanisms underlying differential responsiveness to E2, and the genes involved, are unknown. Therefore, we used a microarray approach to show association of distinct E2-regulated transcriptional signatures with genetically controlled high and low responses to E2 and their segregation in (C57BL/6J×C3H/HeJ) F1 hybrids. Among the 6664 E2-regulated transcripts, analysis of cellular functions of those that were strain specific indicated C3H-selective enrichment of apoptosis, consistent with a 7-fold increase in the apoptosis indicator CASP3, and a 2.4-fold decrease in the apoptosis inhibitor Naip1 (Birc1a) in C3H vs. B6 following treatment with E2. In addition, several differentially expressed transcripts reside within our previously identified QT loci, including the ERα-tethering factor Runx1, demonstrated to enhance E2-mediated transcript regulation. The level of RUNX1 in uterine epithelial cells was shown to be 3.5-fold greater in B6 compared to C3H. Our novel insights into the mechanisms underlying the genetic control of tissue sensitivity to estrogen have great potential to advance understanding of individualized effects in physiological and disease states.—Wall, E. H., Hewitt, S. C., Liu, L., del Rio, R., Case, L. K., Lin, C.-Y., Korach, K. S., Teuscher, C. Genetic control of estrogen-regulated transcriptional and cellular responses in mouse uterus.