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While the benefits of early antiretroviral therapy (ART) initiation in perinatally infected infants are well documented, early initiation is not always possible in postnatal pediatric HIV infections. The timing of ART initiation is likely to affect the size of the latent viral reservoir established, as well as the development of adaptive immune responses, such as the generation of neutralizing antibody responses against the virus. How these parameters impact the ability of infants to control viremia and the time to viral rebound after ART interruption is unclear and has never been modeled in infants. To investigate this question we used an infant nonhuman primate Simian/Human Immunodeficiency Virus (SHIV) infection model. Infant Rhesus macaques (RMs) were orally challenged with SHIV.C.CH505 375H dCT and either given ART at 4-7 days post-infection (early ART condition), at 2 weeks post-infection (intermediate ART condition), or at 8 weeks post-infection (late ART condition). These infants were then monitored for up to 60 months post-infection with serial viral load and immune measurements. To gain insight into early after analytic treatment interruption (ATI), we constructed mathematical models to investigate the effect of time of ART initiation in delaying viral rebound when treatment is interrupted, focusing on the relative contributions of latent reservoir size and autologous virus neutralizing antibody responses. We developed a stochastic mathematical model to investigate the joint effect of latent reservoir size, the autologous neutralizing antibody potency, and CD4+ T cell levels on the time to viral rebound for RMs rebounding up to 60 days post-ATI. We find that the latent reservoir size is an important determinant in explaining time to viral rebound in infant macaques by affecting the growth rate of the virus. The presence of neutralizing antibodies can also delay rebound, but we find this effect for high potency antibody responses only. Finally, we discuss the therapeutic implications of our findings.

Abstract An effective HIV-1 vaccine remains a critical unmet need for ending the AIDS epidemic. Vaccine trials conducted to date have suggested the need to increase the durability and functionality of vaccine-elicited antibodies to improve efficacy. We hypothesized that a conjugate vaccine based on the learned response to immunization with hepatitis B virus could be utilized to expand T cell help and improve antibody production against HIV-1. To test this, we developed an innovative conjugate vaccine regimen that used a modified vaccinia virus Ankara (MVA) co-expressing HIV-1 envelope (Env) and the hepatitis B virus surface antigen (HBsAg) as a prime, followed by two Env–HBsAg conjugate protein boosts. We compared the immunogenicity of this conjugate regimen to matched HIV-1 Env-only vaccines in two groups of 5 juvenile rhesus macaques previously immunized with hepatitis B vaccines in infancy. We found expansion of both HIV-1 and HBsAg-specific circulating T follicular helper cells and elevated serum levels of CXCL13, a marker for germinal center activity, after boosting with HBsAg–Env conjugate antigens in comparison to Env alone. The conjugate vaccine elicited higher levels of antibodies binding to select HIV Env antigens, but we did not observe significant improvement in antibody functionality, durability, maturation, or B cell clonal expansion. These data suggests that conjugate vaccination can engage both HIV-1 Env and HBsAg specific T cell help and modify antibody responses at early time points, but more research is needed to understand how to leverage this strategy to improve the durability and efficacy of next-generation HIV vaccines.

Traditional sparkling wines are produced in a two-step sequence of alcoholic fermentations, followed by extended aging which is an influential factor for the final aroma profile. Traditionally, the second fermentation and aging are conducted in bottles over a minimum of 18 months, resulting in an aroma profile which is shaped by oxidative secondary metabolites like aldehydes, acids and fatty acid esters. In this study, a total of 29 traditional commercial sparkling wines from the categories Champagne, Cava, California Champagne, and others (Prosecco and Cremant) were analyzed. The objective was to determine the impact of microbial activity on the stylistic characteristics of traditional sparkling wines and allow winemakers to reproduce the specific fermentation conditions. The results indicate that malolactic fermentation plays an important role in Champagne and some Cavas, but not in the other sparkling wine categories. The metabolic activity of lactic acid bacteria results in an altered acid profile, amino acid utilization, and aroma production. While primary fermentation esters like phenylethyl acetate and isoamyl acetate are significantly reduced in Champagne and Cava, aroma compounds from secondary microbial activity like ethyl lactate and 2-acetyl-1-pyrroline are increased. This underlines the importance of diverse microbial activity of the characteristic style of traditional sparkling wines.

Pregnancy is associated with a 5–26 times increased risk of invasive Haemophilus influenzae infection and subsequent adverse pregnancy outcomes. Incidence rate and outcome are published in some regions, but the characterisation of bacterial isolates is limited. We performed comparative genomic analyses of isolates from 12 pregnancy-associated cases, cultured from maternal bacteraemia in pregnancy (nine), postpartum bacteraemia (one), neonatal bacteraemia (one), and placental tissue (one). In two bacteraemia cases, identical isolates were also cultured from cervical swabs. Eight cases occurred early in pregnancy (gestational week 7–26), and seven of them resulted in miscarriage or neonatal death. All bacterial genomes were devoid of capsule loci, and they were evenly distributed in the major phylogenetic group I of the species. The conspicuous tropism of H. influenzae for pregnancy and placental tissue is associated with the species rather than specific clonal subtypes.

Abstract Objective Neuroimaging studies of obsessive‐compulsive disorder (OCD) patients have highlighted the important role of deep gray matter structures. Less work has however focused on subcortical shape in OCD patients. Methods Here we pooled brain MRI scans from 412 OCD patients and 368 controls to perform a meta‐analysis utilizing the ENIGMA‐Shape protocol. In addition, we investigated modulating effects of medication status, comorbid anxiety or depression, and disease duration on subcortical shape. Results There was no significant difference in shape thickness or surface area between OCD patients and healthy controls. For the subgroup analyses, OCD patients with comorbid depression or anxiety had lower thickness of the hippocampus and caudate nucleus and higher thickness of the putamen and pallidum compared to controls. OCD patients with comorbid depression had lower shape surface area in the thalamus, caudate nucleus, putamen, hippocampus, and nucleus accumbens and higher shape surface area in the pallidum. OCD patients with comorbid anxiety had lower shape surface area in the putamen and the left caudate nucleus and higher shape surface area in the pallidum and the right caudate nucleus. Further, OCD patients on medication had lower shape thickness of the putamen, thalamus, and hippocampus and higher thickness of the pallidum and caudate nucleus, as well as lower shape surface area in the hippocampus and amygdala and higher surface area in the putamen, pallidum, and caudate nucleus compared to controls. There were no significant differences between OCD patients without co‐morbid anxiety and/or depression and healthy controls on shape measures. In addition, there were also no significant differences between OCD patients not using medication and healthy controls. Conclusions The findings here are partly consistent with prior work on brain volumes in OCD, insofar as they emphasize that alterations in subcortical brain morphology are associated with comorbidity and medication status. Further work is needed to understand the biological processes contributing to subcortical shape.

Human cytomegalovirus (HCMV) is the most common congenital infection and a leading cause of stillbirth, neurodevelopmental impairment, and pediatric hearing loss worldwide. Development of a maternal vaccine or therapeutic to prevent congenital HCMV has been hindered by limited knowledge of the immune responses that protect against HCMV transmission in utero. To identify protective antibody responses, we measured HCMV-specific IgG binding and antiviral functions in paired maternal and cord blood sera from HCMV-seropositive transmitting (n = 41) and non-transmitting (n = 40) mother-infant dyads identified via a large, US-based, public cord blood bank. We found that high-avidity IgG binding to HCMV and antibody-dependent cellular phagocytosis (ADCP) were associated with reduced risk of congenital HCMV infection. We also determined that HCMV-specific IgG activation of FcγRI and FcγRII was enhanced in non-transmitting dyads and that increased ADCP responses were mediated through both FcγRI and FcγRIIA expressed on human monocytes. These findings suggest that engagement of FcγRI/FcγRIIA and Fc effector functions including ADCP may protect against congenital HCMV infection. Taken together, these data can guide future prospective studies on immune correlates against congenital HCMV transmission and inform HCMV vaccine and immunotherapeutic development.

Abstract Background Population segmentation and risk stratification are important strategies for allocating resources in public health, health care and social care. Social exclusion, which is defined as the cumulation of disadvantages in social, economic, cultural and political domains, is associated with an increased risk of health problems, low agency, and as a consequence, a higher need for health and social care. The aim of this study is to test social exclusion against traditional social stratifiers to identify high-risk/high-need population segments. Methods We used data from 33,285 adults from the 2016 Public Health Monitor of four major cities in the Netherlands. To identify at-risk populations for cardiovascular risk, cancer, low self-rated health, anxiety and depression symptoms, and low personal control, we compared relative risks (RR) and population attributable fractions (PAF) for social exclusion, which was measured with the Social Exclusion Index for Health Surveys (SEI-HS), and four traditional social stratifiers, namely, education, income, labour market position and migration background. Results The analyses showed significant associations of social exclusion with all the health indicators and personal control. Particular strong RRs were found for anxiety and depression symptoms (7.95) and low personal control (6.36), with corresponding PAFs of 42 and 35%, respectively. Social exclusion was significantly better at identifying population segments with high anxiety and depression symptoms and low personal control than were the four traditional stratifiers, while the two approaches were similar at identifying other health problems. The combination of social exclusion with a low labour market position (19.5% of the adult population) captured 67% of the prevalence of anxiety and depression symptoms and 60% of the prevalence of low personal control, as well as substantial proportions of the other health indicators. Conclusions This study shows that the SEI-HS is a powerful tool for identifying high-risk/high-need population segments in which not only ill health is concentrated, as is the case with traditional social stratifiers, but also a high prevalence of anxiety and depression symptoms and low personal control are present, in addition to an accumulation of social problems. These findings have implications for health care practice, public health and social interventions in large cities.

Early initiation of antiretroviral therapy (ART) significantly improves clinical outcomes and reduces mortality of infants/children living with HIV. However, the ability of infected cells to establish latent viral reservoirs shortly after infection and to persist during long-term ART remains a major barrier to cure. In addition, while early ART treatment of infants living with HIV can limit the size of the virus reservoir, it can also blunt HIV-specific immune responses and does not mediate clearance of latently infected viral reservoirs. Thus, adjunctive immune-based therapies that are geared towards limiting the establishment of the virus reservoir and/or mediating the clearance of persistent reservoirs are of interest for their potential to achieve viral remission in the setting of pediatric HIV. Because of the differences between the early life and adult immune systems, these interventions may need to be tailored to the pediatric settings. Understanding the attributes and specificities of the early life immune milieu that are likely to impact the virus reservoir is important to guide the development of pediatric-specific immune-based interventions towards viral remission and cure. In this review, we compare the immune profiles of pediatric and adult HIV elite controllers, discuss the characteristics of cellular and anatomic HIV reservoirs in pediatric populations, and highlight the potential values of current cure strategies using immune-based therapies for long-term viral remission in the absence of ART in children living with HIV.

Pregnancy significantly elevates the risk of developing severe viral diseases, which can have a detrimental effect on fetal development and increases maternal mortality. In addition, certain viruses can be transmitted vertically from mother to babies, either in utero, during delivery, or postnatally during breastfeeding, resulting in congenital or neonatal diseases and associated sequelae. While neonates are highly susceptible to viral infections and severe disease outcomes, due to the immaturity of their developing immune system, virus-specific maternal antibodies transferred either trans-placentally or via breast milk provide protection to infants against intestinal, respiratory, or systemic infections, during the first months of life. Thus, maternal prenatal immunization is important not only to protect pregnant women from viral diseases, but also to prevent infection and/or improve disease outcomes for the fetuses and neonates via passively transferred antibodies. In this review, we discuss the protective role of maternal antibodies against three categories of viruses: (i) viruses that cause severe maternal disease outcomes with mainly indirect consequences to the fetus (e.g. SARS-CoV-2, influenza, DENV, filovirus), (ii) those that are vertically transmitted from mother to their infants and cause congenital diseases (e.g. HIV, ZIKV and CMV), and (iii) those that cause elevated disease severity among neonates and infants postnatally (e.g. RSV, Rotavirus, Norovirus, HSV and HBV). Furthermore, we review relevant pre-clinical animal models that can be employed to develop novel immunization strategies against these viruses to enhance protection of pregnant women and their babies.

ABSTRACT Improved access to antiretroviral therapy (ART) and antenatal care has significantly reduced in utero and peripartum mother-to-child human immunodeficiency virus (HIV) transmission. However, as breast milk transmission of HIV still occurs at an unacceptable rate, there remains a need to develop an effective vaccine for the pediatric population. Previously, we compared different HIV vaccine strategies, intervals, and adjuvants in infant rhesus macaques to optimize the induction of HIV envelope (Env)-specific antibodies with Fc-mediated effector function. In this study, we tested the efficacy of an optimized vaccine regimen against oral simian-human immunodeficiency virus (SHIV) acquisition in infant macaques. Twelve animals were immunized with 1086.c gp120 protein adjuvanted with 3M-052 in stable emulsion and modified vaccinia Ankara (MVA) virus expressing 1086.c HIV Env. Twelve control animals were immunized with empty MVA. The vaccine prime was given within 10 days of birth, with booster doses being administered at weeks 6 and 12. The vaccine regimen induced Env-specific plasma IgG antibodies capable of antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis (ADCP). Beginning at week 15, infants were exposed orally to escalating doses of heterologous SHIV-1157(QNE)Y173H once a week until infected. Despite the induction of strong Fc-mediated antibody responses, the vaccine regimen did not reduce the risk of infection or time to acquisition compared to controls. However, among vaccinated animals, ADCC postvaccination and postinfection was associated with reduced peak viremia. Thus, nonneutralizing Env-specific antibodies with Fc effector function elicited by this vaccine regimen were insufficient for protection against heterologous oral SHIV infection shortly after the final immunization but may have contributed to control of viremia. IMPORTANCE Women of childbearing age are three times more likely to contract HIV infection than their male counterparts. Poor HIV testing rates coupled with low adherence to antiretroviral therapy (ART) result in a high risk of mother-to-infant HIV transmission, especially during the breastfeeding period. A preventative vaccine could curb pediatric HIV infections, reduce potential health sequalae, and prevent the need for lifelong ART in this population. The results of the current study imply that the HIV Env-specific IgG antibodies elicited by this candidate vaccine regimen, despite a high magnitude of Fc-mediated effector function but a lack of neutralizing antibodies and polyfunctional T cell responses, were insufficient to protect infant rhesus macaques against oral virus acquisition.

Background: Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive neuromodulation technique to treat psychiatric disorders, such as obsessive-compulsive disorder (OCD). However, the rTMS response varies across subjects. Objective/hypothesis: We hypothesize that baseline network properties of the rTMS target may help understand this variation and predict response. Methods: Excitatory rTMS to the dorsolateral prefrontal cortex (dlPFC) was applied in 19 unmedicated OCD patients, while inhibitory dlPFC-rTMS was applied in 17 healthy controls. The vertex was used as an active control target (19 patients, 18 controls). The rTMS response was operationalized as the individual change in state distress rating during an emotion regulation task. At baseline, subjects underwent resting-state functional MRI. The brain network was constructed by calculating wavelet coherence between regional activity of regions in the Brainnetome atlas. Local and integrative static connectivity and the dynamic network role of the target were calculated. Baseline target region network features were non-parametrically correlated to rTMS response. Results: In the dlPFC-stimulated patients, greater local connectivity (Kendall’s Tau = −0.415, p = 0.013) and less promiscuous role of the target (Kendall’s Tau = 0.389, p = 0.025) at baseline were related to greater distress reduction after excitatory rTMS. There were no significant associations in healthy subjects nor in the active control stimulated patients. Conclusions: Pre-treatment network topological indices predict rTMS-induced emotional response changes in OCD, such that greater baseline resting-state local connectivity and less temporal integration of the target region imply greater stimulation effects. These results may lead the way towards personalized neuromodulation in OCD.

Soft tissue sarcomas (STS) are rare malignant tumors often associated with poor outcomes and high local recurrence rates. Current tools for intraoperative and definitive margin assessment include intraoperative frozen section and permanent pathology, respectively. Indocyanine green dye (ICG) is a historically safe fluorophore dye that has demonstrated efficacy for intraoperative margin assessment in the surgical management of both breast and gastrointestinal cancers. The utility of ICG in the surgical management of sarcoma surgery has primarily been studied in pre-clinical mouse models and warrants further investigation as a potential adjunct to achieving negative margins. This study is a prospective, non-randomized clinical study conducted on patients with confirmed or suspected STS. Patients younger than 18 years, with a prior adverse reaction to iodine or fluorescein, or with renal disease were excluded from the study. Intravenous ICG was infused approximately three hours prior to surgery at a dosage of 2.0–2.5 mg/kg, and following tumor resection, the excised tumor and tumor bed were imaged for fluorescence intensity. When scanning the tumor bed, a threshold of 77% calibrated to the region of maximum intensity in the resected tumor was defined as a positive ICG margin, according to published protocols from the breast cancer literature. ICG results were then compared with the surgeon’s clinical impression of margin status and permanent pathology results. Out of 26 subjects recruited for the original study, 18 soft tissue sarcomas (STS) were included for analysis. Three subjects were excluded for having bone sarcomas, and five subjects were excluded due to final pathology, which was ultimately inconsistent with sarcoma. The average age of patients was 64.1 years old (range: 28–83), with an average ICG dose of 201.8 mg. In 56% (10/18) of patients, ICG margins were consistent with the permanent pathology margins, with 89% specificity. The use of ICG as an intraoperative adjunct to obtaining negative margins in soft tissue sarcoma surgery is promising. However, studies with larger sample sizes are warranted to further delineate the accuracy, optimal dosage, timing, and types of sarcoma in which this diagnostic tool may be most useful.

Understanding viral rebound in pediatric HIV-1 infection may inform the development of alternatives to lifelong antiretroviral therapy (ART) to achieve viral remission. We thus investigated viral rebound after analytical treatment interruption (ATI) in 10 infant macaques orally infected with SHIV.C.CH505 and treated with long-term ART. Rebound viremia was detected within 7 to 35 days of ATI in 9 of 10 animals, with posttreatment control of viremia seen in 5 of 5 Mamu-A*01+ macaques. Single-genome sequencing revealed that initial rebound virus was similar to viral DNA present in CD4+ T cells from blood, rectum, and lymph nodes before ATI. We assessed the earliest sites of viral reactivation immediately following ATI using ImmunoPET imaging. The largest increase in signal that preceded detectable viral RNA in plasma was found in the gastrointestinal (GI) tract, a site with relatively high SHIV RNA/DNA ratios in CD4+ T cells before ATI. Thus, the GI tract may be an initial source of rebound virus, but as ATI progresses, viral reactivation in other tissues likely contributes to the composition of plasma virus. Our study provides potentially novel insight into the features of viral rebound in pediatric infection and highlights the application of a noninvasive technique to monitor areas of HIV-1 expression in children.

Bentonite is a natural clay that is used in different industries as a desiccant, ion-exchange material, or additive to remove impurities. For example, marketed as healing clay and as protein-fining agent in wine, bentonite is expected to adsorb specific compounds while having no negative effects on the quality of the product in which it is used. In this study, 34 commercially available bentonites for different applications were selected and analyzed for their elemental composition, extraction of heavy metals, swelling behavior, and protein removal rate under conditions relevant to wine. The results indicate that bentonites can have a very variable composition that does not correlate with the intended use. The extraction of heavy metals is not directly related to the raw material and depends on swelling behavior and surface area of the clay. Interestingly, there is a similar degree of variability in swelling behavior among wine bentonites as there is for healing clays. This correlates with the protein removal rate but also with the extraction of iron, a transition metal that is known for its catalytic activity for oxidation reactions. Even though the protein removal rate is much higher than for other clays, bentonites that are marketed for wine show an extraction behavior that can have a negative effect on the final product.

Background: Obsessive-compulsive disorder (OCD) has been related to worse performance, abnormal brain activity, and functional connectivity during response inhibition. Whether these findings are indications of stable traits that contribute to the development of the disorder, or whether they are a result of the state severity of obsessions and anxiety, remains unclear since previous research mainly has employed cross-sectional designs. The present study aimed to assess longitudinal between- and within-person relationships between symptoms, task performance, right inferior frontal gyrus brain activation, and connectivity between the right amygdala and the right pre-supplementary motor area in 29 OCD patients before and after concentrated exposure and response prevention treatment.Method: Patients received exposure and response prevention delivered during 4 consecutive days, following the Bergen 4-day Treatment format. Patients performed a Stop Signal Task during 3T functional Magnetic Resonance Imaging the day before treatment, as well as 1 week and 3 months after treatment completion. Multilevel models were used to analyze disaggregated within- and between-person effects over time. Independent variables were scores on the symptom severity scales for OCD, anxiety, depression, and state distress during scanning. Dependent variables were reaction time for go trials, stop signal response time, task-related brain activation and connectivity.Results: A positive between-person effect was found for obsessive-compulsive, anxiety, and depressive symptom severity on go trial reaction time, indicating that patients with higher symptom scores on average respond slower during accurate go trials. We also found no significant between- or within-person relations between symptom severity and task-related activation or fronto-limbic connectivity.Conclusions: The between-person findings may point toward a general association between slower processing speed and symptom severity in OCD. Longitudinal studies should disaggregate between- and within-person effects to better understand variation over time.

Different HIV vaccine regimens elicit distinct plasma antibody responses in both human and nonhuman primate models. Previous studies in human and non-human primate infants showed that adjuvants influenced the quality of plasma antibody responses induced by pediatric HIV envelope vaccine regimens. We recently reported that use of the 3M052-SE adjuvant and longer intervals between vaccinations are associated with higher magnitude of antibody responses in infant rhesus macaques. However, the impact of different adjuvants in HIV vaccine regimens on the developing infant B cell receptor (BCR) repertoire has not been studied. This study evaluated whether pediatric HIV envelope vaccine regimens with different adjuvants induced distinct antigen-specific memory B cell repertoires and whether specific immunoglobulin (Ig) immunogenetic characteristics are associated with higher magnitude of plasma antibody responses in vaccinated infant rhesus macaques. We utilized archived preclinical pediatric HIV vaccine studies PBMCs and tissue samples from 19 infant rhesus macaques immunized either with (i) HIV Env protein with a squalene adjuvant, (ii) MVA-HIV and Env protein co-administered using a 3-week interval, (iii) MVA-HIV prime/ protein boost with an extended 6-week interval between immunizations, or (iv) with HIV Env administered with 3M-052-SE adjuvant. Frequencies of vaccine-elicited HIV Env-specific memory B cells from PBMCs and tissues were similar across vaccination groups (frequency range of 0.06–1.72%). There was no association between vaccine-elicited antigen-specific memory B cell frequencies and plasma antibody titer or avidity. Moreover, the epitope specificity and Ig immunogenetic features of vaccine-elicited monoclonal antibodies did not differ between the different vaccine regimens. These data suggest that pediatric HIV envelope vaccine candidates with different adjuvants that previously induced higher magnitude and quality of plasma antibody responses in infant rhesus macaques were not driven by distinct antigen-specific memory BCR repertoires.

Different HIV vaccine regimens elicit distinct plasma antibody responses in both human and nonhuman primate models. Previous studies in human and non-human primate infants showed that adjuvants influenced the quality of plasma antibody responses induced by pediatric HIV envelope vaccine regimens. We recently reported that use of the 3M052-SE adjuvant and longer intervals between vaccinations are associated with higher magnitude of antibody responses in infant rhesus macaques. However, the impact of different adjuvants in HIV vaccine regimens on the developing infant B cell receptor (BCR) repertoire has not been studied. This study evaluated whether pediatric HIV envelope vaccine regimens with different adjuvants induced distinct antigen-specific memory B cell repertoires and whether specific immunoglobulin (Ig) immunogenetic characteristics are associated with higher magnitude of plasma antibody responses in vaccinated infant rhesus macaques. We utilized archived preclinical pediatric HIV vaccine studies PBMCs and tissue samples from 19 infant rhesus macaques immunized either with (i) HIV Env protein with a squalene adjuvant, (ii) MVA-HIV and Env protein co-administered using a 3-week interval, (iii) MVA-HIV prime/ protein boost with an extended 6-week interval between immunizations, or (iv) with HIV Env administered with 3M-052-SE adjuvant. Frequencies of vaccine-elicited HIV Env-specific memory B cells from PBMCs and tissues were similar across vaccination groups (frequency range of 0.06-1.72%). There was no association between vaccine-elicited antigen-specific memory B cell frequencies and plasma antibody titer or avidity. Moreover, the epitope specificity and Ig immunogenetic features of vaccine-elicited monoclonal antibodies did not differ between the different vaccine regimens. These data suggest that pediatric HIV envelope vaccine candidates with different adjuvants that previously induced higher magnitude and quality of plasma antibody responses in infant rhesus macaques were not driven by distinct antigen-specific memory BCR repertoires.

Response inhibition has previously been suggested as an endophenotype for obsessive–compulsive disorder (OCD), evidenced by studies showing worse task performance, and altered task-related activation and connectivity. However, it’s unclear if these measures change following treatment. In this study, 31 OCD patients and 28 healthy controls performed a stop signal task during 3 T functional magnetic resonance imaging before treatment, while 24 OCD patients and 17 healthy controls were rescanned one week and three months after concentrated exposure and response prevention over four consecutive days using Bergen 4-Day Format. To study changes over time we performed a longitudinal analysis on stop signal reaction time and task-related activation and amygdala connectivity during successful and failed inhibition. Results showed that there was no group difference in task performance. Before treatment, OCD patients compared to controls showed less inhibition-related activation in the right inferior frontal gyrus, and increased functional connectivity between the right amygdala and the right inferior frontal gyrus and pre-supplementary motor area. During error-processing, OCD patients versus controls showed less activation in the pre-SMA before treatment. These group differences did not change after treatment. Pre-treatment task performance, brain activation, and connectivity were unrelated to the degree of symptom improvement after treatment. In conclusion, inferior frontal gyrus hypoactivation and increased fronto-limbic connectivity are likely trait markers of OCD that remain after effective exposure therapy.

IntroductionGiven JUUL e-cigarettes' potential for smoking cessation and its drastically increased sales in the U.S., more evidence is needed to understand the antecedents of JUUL use among adult cigarette smokers. This study assessed the relationships between awareness sources, perceptions about using JUUL, and JUUL use behavior.MethodsIn an online study with adult smokers who were aware of JUUL e-cigarettes (n = 341), respondents reported their sources for learning about JUUL, perceptions of using JUUL versus Vuse (a competitor brand), and ever and past-30-day (current) JUUL use. Multivariable logistic regressions were used to examine the associations between awareness sources, perceptions, and JUUL use, adjusting for covariates.ResultsLearning about JUUL through internet ads was associated with positive perceptions about JUUL compared to Vuse, including JUUL was more fun to use (AOR = 2.04, 95% CI = 1.21, 3.42) and tastier (AOR = 1.96, 95% CI = 1.19, 3.22). Perceiving JUUL as being tastier (AOR = 2.07, 95% CI = 1.23, 3.49), more helpful for quitting smoking (AOR = 2.07, 95% CI = 1.22, 3.53), and cooler (AOR = 2.07, 95% CI = 1.21, 3.56) than Vuse was associated with ever using JUUL. Only perceiving JUUL as being tastier (AOR = 1.98, 95% CI = 1.10, 3.59) than Vuse was associated with current use of JUUL.DiscussionAdult smokers may be more likely to focus on the sensory and social experience of using JUUL rather than JUUL's smoking cessation benefits. These positive perceptions are likely to be influenced by internet ads in general instead of JUUL's official marketing outlets. They are also more likely to sustain JUUL use than JUUL's perceived smoking cessation benefits.

Background and objectives: Gilles de la Tourette syndrome (GTS) is a neuropsychiatric disorder characterized by tics. A hallmark of GTS is the ability to voluntarily suppress tics. Our aim was to distinguish the neural circuits involved in the voluntary suppression of ocular tics in GTS patients from blink suppression in healthy subjects. Methods: Fifteen GTS patients and 22 healthy control subjects were included in a multimodal study using eye-tracker recordings during functional MRI (fMRI). The ability to suppress tics/blinks was compared both on subjective (self-rating) and objective (eye-tracker) performance. For fMRI analysis we used a novel designed performance-adapted block design analysis of tic/blink suppression and release based on eye-tracker monitoring. Results: We found that the subjective self-reported ability to suppress tics or blinks showed no significant correlation with objective task performance. In GTS during successful suppression of tics, the dorsal anterior cingulate cortex and associated limbic areas showed increased activation. During successful suppression of eye blinks in healthy subjects, the right ventrolateral prefrontal cortex and supplementary and cingulate motor areas showed increased activation. Conclusions: These findings demonstrate that GTS patients use a characteristic limbic suppression strategy. In contrast, control subjects use the voluntary sensorimotor circuits and the classical ‘stop’ network to suppress natural urges. The employment of different neural suppression networks provides support for cognitive behavioral therapy in GTS. Keywords: Gilles de la Tourette syndrome, Functional magnetic resonance imaging, Suppression, Tics, Urges

Abstract Background Social exclusion (SE) refers to the inability of certain groups or individuals to fully participate in society. SE is associated with socioeconomic inequalities in health, and its measurement in routine public health monitoring is considered key to designing effective health policies. In an earlier retrospective analysis we demonstrated that in all four major Dutch cities, SE could largely be measured with existing local public health monitoring data. The current prospective study is aimed at constructing and validating an extended national measure for SE that optimally employs available items. Methods In 2012, a stratified general population sample of 258,928 Dutch adults completed a version of the Netherlands Public Health Monitor (PHM) questionnaire in which 9 items were added covering aspects of SE that were found to be missing in our previous research. Items were derived from the SCP social exclusion index, a well-constructed 15-item instrument developed by the Netherlands Institute for Social Research (SCP). The dataset was randomly divided into a development sample (N =129,464) and a validation sample (N = 129,464). Canonical correlation analysis was conducted in the development sample. The psychometric properties were studied and compared with those of the original SCP index. All analyses were then replicated in the validation sample. Results The analysis yielded a four dimensional index, the Social Exclusion Index for Health Surveys (SEI-HS), containing 8 SCP items and 9 PHM items. The four dimensions: “lack of social participation”, “material deprivation”, “lack of normative integration” and “inadequate access to basic social rights”, were each measured with 3 to 6 items. The SEI-HS showed adequate internal consistency for both the general index and for two of four dimension scales. The internal structure and construct validity of the SEI-HS were satisfactory and similar to the original SCP index. Replication of the SEI-HS in the validation sample confirmed its generalisability. Conclusion This study demonstrates that the SEI-HS offers epidemiologists and public health researchers a uniform, reliable, valid and efficient means of assessing social exclusion and its underlying dimensions. The study also provides valuable insights in how to develop embedded measures for public health surveillance.

Until a few years ago, lymphatic vessels and lymphatic endothelial cells (LEC) were viewed as part of a passive conduit for lymph and immune cells to reach lymph nodes (LN). However, recent work has shown that LEC are active immunological players whose interaction with dendritic cells and T cells is of important immunomodulatory relevance. While the immunological interaction between LEC and other immune cells has taken a center stage, molecular analysis of LEC antigen processing and presentation machinery is still lagging. Herein we review the current knowledge of LEC MHC I and MHC II antigen processing and presentation pathways, Including the role of LEC in antigen phagocytosis, classical, and non-classical MHC II presentation, proteasome processing and MHC I presentation, and cross-presentation. The ultimate goal is to provide an overview of the LEC antigen processing and presentation machinery that constitutes the molecular basis for their role in MHC I and MHC II-restricted immune responses.

Impaired cognitive–motivational functioning is present in many psychiatric disorders, including alcohol use disorder (AUD). Emotion regulation is a key intermediate factor, relating to the (cognitive) regulation of emotional and motivational states, such as in regulation of craving or negative emotions that may lead to relapse in alcohol use. These cognitive–motivational functions, including emotion regulation, are a target in cognitive behavioral therapy and may possibly be improved by neurostimulation techniques. The present between-subjects, single-blind study assesses the effects of sham-controlled high-frequency neuronavigated repetitive transcranial magnetic stimulation (10 Hz) of the right dorsolateral prefrontal cortex (dlPFC) on several aspects relevant for emotion regulation (emotion processing and reappraisal abilities) and related brain activity, as well as self-reported craving in a sample of alcohol use disorder patients (AUD; n = 39) and healthy controls (HC; n = 36). During the emotion reappraisal task, participants were instructed to either attend or reappraise their emotions related to the negative, positive, neutral, and alcohol-related images, after which they rated their experienced emotions. We found that repetitive transcranial magnetic stimulation (rTMS) reduces self-reported experienced emotions in response to positive and negative images in AUD patients, whereas experienced emotions were increased in response to neutral and positive images in HCs. In the functional magnetic resonance imaging (fMRI) analyses, we found that rTMS reduces right dlPFC activity during appraisal of affective images relative to sham stimulation only in AUD patients. We could not confirm our hypotheses regarding the effect of rTMS craving levels, or on reappraisal related brain function, since no significant effects of rTMS on craving or reappraisal related brain function were found. These findings imply that rTMS can reduce the emotional impact of images as reflected in blood oxygenation level-dependent (BOLD) response, especially in AUD patients. Future studies should replicate and expand the current study, for instance, by assessing the effect of multiple stimulation sessions on both explicit and implicit emotion regulation paradigms and craving, and assess the effect of rTMS within subgroups with specific addiction-relevant image preferences.Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT02557815.

Alcohol dependence has long been related to impaired emotion regulation—including reappraisal—but little is known about the performance and associated neural activity of alcohol-dependent patients (ADPs) on an emotion reappraisal task. This study, therefore, compares reappraisal of negative, positive, neutral, and alcohol-related images at a behavioral and neural level between ADPs and healthy controls (HCs).Thirty-nine ADPs and 39 age-, gender-, and education-matched HCs performed an emotion reappraisal task during functional magnetic resonance imaging (fMRI), and craving was measured before and after the reappraisal task. During the emotion reappraisal task, participants were instructed to either attend or reappraise positive, negative, neutral, or alcohol-related images, and to indicate their experienced emotion on a visual analogue scale (VAS).Both ADPs and HCs completed the emotion reappraisal task successfully, showing significant differences in self-reported experienced emotion after attending versus reappraising visual stimuli and in brain activity in emotion processing/reappraisal relevant areas. ADPs were not impaired in cognitive reappraisal at a behavioral or neural level relative to HCs, nor did ADPs indicate any difference in self-reported emotion while attending emotional images. However, ADPs were different from HC in emotion processing: ADPs revealed a blunted response in the (posterior) insula, precuneus, operculum, and superior temporal gyrus while attending emotional images compared neutral images compared to HCs, and in ADPs, higher baseline craving levels were associated with a less blunted response to alcohol-related images than in HCs. These results reveal that ADPs do not show impaired reappraisal abilities when instructed, although future studies should assess voluntary reappraisal abilities in alcohol-dependent patients.Clinical Trial Registration:www.ClinicalTrials.gov, identifier NCT02557815.

BackgroundThe recently developed Social Exclusion Index for Health Surveys (SEI-HS) revealed particularly strong social exclusion in non-Western immigrant groups compared to the native Dutch population. To qualify such results, cross-cultural validation of the SEI-HS in non-Western immigrant groups is called for.MethodsA sequential explanatory mixed methods design was used, employing quantitative data from the Netherlands Public Health Monitor along with qualitative interviews. Data from 1,803 adults aged 19 years or older of Surinamese, 1,009 of Moroccan and 1,164 of Turkish background and 19,318 native Dutch living in the four largest cities in the Netherlands were used to test the factorial structure of the SEI-HS and differential item functioning across immigrant groups. Additionally, 52 respondents with a high score on the SEI-HS and from different background were interviewed on the item content of the SEI-HS and subjective feelings of exclusion. For each SEI-HS item the semantic, conceptual and contextual connotations were coded and compared between the immigrant groups and native Dutch.ResultsHigh levels of social exclusion were found in 20.0% of the urban population of Surinamese origin, 20.9% of Moroccan, 28.7% of Turkish and 4.2% of native Dutch origin. The 4-factor structure of the SEI-HS was confirmed in all three immigrant groups. None of the items demonstrated substantial differential item functioning in relation to immigration background. The interviews uncovered some methodological shortcomings, but these did not substantially impact the observed excess of social exclusion in immigrant groups.ConclusionsThe present study provides evidence in support of the validity of the SEI-HS in adults of Surinamese, Moroccan and Turkish background and confirms the major social exclusion of these immigrant groups in the main cities in the Netherlands. Policy measures to enhance social inclusion and reduce exclusion are urgently needed.

Shared decision making (SDM) is not widely practiced in routine care due to a variety of organizational, provider, patient, and contextual factors. This article explores how implementation science—which encourages attention to the multilevel contextual factors that influence the adoption, implementation, and sustainment of health care practices—can provide useful insights for increasing SDM use in routine practice. We engaged with stakeholders representing different organizations and geographic locations over three phases: 1) multidisciplinary workgroup meeting comprising researchers and clinicians ( n = 11); 2) survey among a purposive sample of 47 patient advocates, clinicians, health care system leaders, funders, policymakers, and researchers; and 3) working session among diverse stakeholders ( n = 30). The workgroup meeting identified priorities for action and research, which included targeting multiple audiences and levels, shifting culture toward valuing and supporting SDM, and considering contextual factors influencing SDM implementation. Survey respondents provided recommendations for increasing adoption, implementation, and maintenance of SDM in practice including providing tools to support SDM, obtaining stakeholders’ involvement, and raising awareness of the importance of SDM. Stakeholders in the working session provided recommendations on the design of a guide for implementation of SDM in clinical settings, strategies to disseminate educational curricula on SDM, and strategies to influence policies to increase SDM use. These specific recommendations serve as a call to action to pursuing specific promising strategies aimed at increasing SDM use in practice and enhance understanding of the perspectives of diverse stakeholders at multiple levels from an implementation science perspective that appear fruitful for further study and application.

Introduction: Brain regions are anatomically and functionally interconnected in order to facilitate important functions like cognition and movement. It remains incompletely understood how brain connectivity contributes to the pathophysiology of Tourette’s disorder (TD). By using resting-state functional MRI, we aimed to identify alterations in the default mode network (DMN), frontal-parietal network (FPN), sensori-motor network (SMN), and salience network (SN) in TD compared with healthy control (HC) subjects.Method: In 23 adult TD patients and 22 HC, 3T-MRI resting-state scans were obtained. Independent component analysis was performed comparing TD and HC to investigate connectivity patterns within and between resting-state networks.Results: TD patients showed higher involvement of the dorsal medial prefrontal cortex in the connectivity of the DMN and less involvement of the inferior parietal cortex in the connectivity of the FPN when compared to HC. Moreover, TD patients showed a stronger coupling between DMN and left FPN than HC. Finally, in TD patients, functional connectivity within DMN correlated negatively with tic severity.Conclusion: We tentatively interpret the increased functional connectivity within DMN in TD patients as compensatory to the lower functional connectivity within left FPN. The stronger coupling between DMN and left FPN, together with the finding that higher DMN intrinsic connectivity is associated with lower tic severity would indicate that DMN is recruited to exert motor inhibition.

The social exclusion of children is problematic for two reasons. Young people typically inherit their marginal position from their family, and therefore cannot be held responsible for their hardship themselves; and social exclusion in childhood may affect their wellbeing and subsequent development, possibly leading to a “scarring effect” in later life. In this contribution we develop an instrument for measuring social exclusion among children. Social exclusion is regarded as a theoretical construct with four sub-dimensions: material deprivation, limited social participation, inadequate access to social rights, and a lack of normative integration. First we analyse data from a survey of 2,200 Dutch children, which contains a large set of social exclusion items. We applied nonlinear principal components analysis in order to construct a multidimensional scale. Measured in this way, the prevalence of social exclusion among children is 4.5%. Boys and children living in large families are more likely to experience social exclusion than girls and children with few siblings. The parental level of education and dependency on social security benefits are also important driving factors of childhood social exclusion. Subsequently we investigate the scarring effect. Longitudinal administrative income and household data covering 25 years were combined with a new survey of just under 1,000 Dutch adults, a third of whom were poor as a child. The survey assessed their past and current degree of social exclusion, and their health and psychosocial development, educational career, past family circumstances, etc. In an absolute sense scarring turns out to have been limited during this period: a very large majority of those who were poor or excluded as a child are above the threshold values in adult life. However, the “descendants of hardship” are still more likely to be socially excluded as adults than people who grew up in more favourable conditions. A causal analysis suggests that low educational achievements are the main mediator of scarring risks.

Abstract Objective: Case‐control studies have linked mobile phone use to an increased risk of glioma in the most exposed brain areas, the temporal and parietal lobes, although inconsistently. We examined time trends in the incidence rates of brain malignancies in New Zealand from 1995 to 2010. Methods: Data from the New Zealand Cancer Registry was used to calculate incidence rates of primary brain cancer, by age, gender, morphology and anatomical site. Log‐linear regression analysis was used to assess trends in the annual incidence of primary brain cancer; annual percentage changes and their 95% confidence intervals were estimated. Results: No consistent increases in all primary brain cancer, glioma, or temporal or parietal lobe glioma were seen. At ages 10–69, the incidence of all brain cancers declined significantly. Incidence of glioma increased at ages over 70. Conclusion: In New Zealand, there has been no consistent increase in incidence rates of primary brain cancers. An increase in glioma at ages over 70 is likely to be due to improvements in diagnosis. As with any such studies, a small effect, or one with a latent period of more than 10 to 15 years, cannot be excluded.

According to the norm-based version of the multidimensional face space model (nMDFS, Valentine, 1991), any given face and its corresponding anti-face (which deviates from the norm in exactly opposite direction as the original face) should be equidistant to a hypothetical prototype face (norm), such that by definition face and anti-face should bear the same level of perceived typicality. However, it has been argued that familiarity affects perceived typicality and that representations of familiar faces are qualitatively different (e.g., more robust and image-independent) from those for unfamiliar faces. Here we investigated the role of face familiarity for rated typicality, using two frequently used operationalisations of typicality (deviation-based: DEV), and distinctiveness (face in the crowd: FITC) for faces of celebrities and their corresponding anti-faces. We further assessed attractiveness, likeability and trustworthiness ratings of the stimuli, which are potentially related to typicality. For unfamiliar faces and their corresponding anti-faces, in line with the predictions of the nMDFS, our results demonstrate comparable levels of perceived typicality (DEV). In contrast, familiar faces were perceived much less typical than their anti-faces. Furthermore, familiar faces were rated higher than their anti-faces in distinctiveness, attractiveness, likability and trustworthiness. These findings suggest that familiarity strongly affects the distribution of facial representations in norm-based face space. Overall, our study suggests (1) that familiarity needs to be considered in studies of mental representations of faces, and (2) that familiarity, general distance-to-norm and more specific vector directions in face space make different and interactive contributions to different types of facial evaluations.

Abstract:Objective: Obsessive-compulsive disorder (OCD) is a common neuropsychiatric disorder with moderate genetic influences and white matter abnormalities in frontal-striatal and limbic regions. Inconsistencies in reported white matter results from diffusion tensor imaging (DTI) studies can be explained, at least partly, by medication use and between-group differences in disease profile and stage. We used a family design aiming to establish whether white matter abnormalities, if present in un-medicated OCD patients, also exist in their unaffected siblings.Method: Forty-four OCD patients, un-medicated for at least the past 4 weeks, 15 of their unaffected siblings and 37 healthy controls (HC) underwent DTI using a 3-Tesla MRI-scanner. Data analysis was done using tract-based spatial statistics (TBSS). Fractional anisotropy (FA), axial diffusivity (AD), radial diffusivity (RD), and mean diffusivity (MD) values were compared within seven skeletonised regions of interest (ROIs), i.e., corpus callosum, bilateral cingulum bundle, bilateral inferior longitudinal fasciculus/frontal-occipital fasciculus (ILF/FOF) and bilateral superior longitudinal fasciculus (SLF).Results: Un-medicated OCD patients, compared with HC, had significantly lower FA in the left cingulum bundle. FA was trend-significantly lower in all other ROIs, except for the corpus callosum. Significant three-group differences in FA (and in RD at trend-significant level) were observed in the left cingulum bundle, with the unaffected siblings representing an intermediate group between OCD patients and HC. Conclusions: OCD patients showed lower FA in the left cingulum bundle, partly driven by trend-significantly higher values in RD. Since the unaffected siblings were found to be an intermediate group between OCD patients and HC, this white matter alteration may be considered an endophenotype for OCD.

The concept of "enabling conditions" centers on conditions that facilitate approaches to addressing social and ecological challenges. Although multiple fields have independently addressed the concept of enabling conditions, the literature lacks a shared understanding or integration of concepts. We propose a more synthesized understanding of enabling conditions beyond disciplinary boundaries by focusing on the enabling conditions that influence the implementation of a range of environmental policies termed payments for ecosystem services (PES). Through an analysis of key literature from different disciplinary perspectives, we examined how researchers and practitioners refer to and identify enabling conditions within the context of PES. Through our synthesis, we identified 24 distinct enabling conditions organized within 4 broad themes: biophysical, economic, governance, and social-cultural conditions. We found that the literature coalesces around certain enabling conditions, such as strong ecosystem science and existing institutions, regardless of disciplinary background or journal audience. We also observed key differences in how authors perceive the direction of influence for property type, program objectives, and number of actors. Additionally, we noted an emphasis on the importance of the contextual nature of many enabling conditions that may cause certain conditions to have a disproportionate impact on successful implementation in some circumstances. Unraveling the relative importance of specific enabling conditions in diverse contexts remains a research frontier. Ultimately, no single disciplinary perspective is likely to provide all necessary insights for PES creation, and given the intertwined nature of enabling conditions, practitioners need to consider insights from multiple dimensions. Our work suggests opportunities to better connect diverse conversations through integration of concepts, a common vocabulary, and a synthetic framework.

ABSTRACT Kaposi’s sarcoma (KS) is an unusual neoplasia wherein the tumor consists primarily of endothelial cells infected with human herpesvirus 8 (HHV-8; Kaposi’s sarcoma-associated herpesvirus) that are not fully transformed but are instead driven to excess proliferation by inflammatory and angiogenic factors. This oncogenic process has been postulated but unproven to depend on a paracrine effect of an abnormal excess of host cytokines and chemokines produced by HHV-8-infected B lymphocytes. Using newly developed measures for intracellular detection of lytic cycle proteins and expression of cytokines and chemokines, we show that HHV-8 targets a range of naive B cell, IgM memory B cell, and plasma cell-like populations for infection and induction of interleukin-6, tumor necrosis factor alpha, macrophage inhibitory protein 1α, macrophage inhibitory protein 1β, and interleukin-8 in vitro and in the blood of HHV-8/HIV-1-coinfected subjects with KS. These B cell lineage subsets that support HHV-8 infection are highly polyfunctional, producing combinations of 2 to 5 of these cytokines and chemokines, with greater numbers in the blood of subjects with KS than in those without KS. Our study provides a new paradigm of B cell polyfunctionality and supports a key role for B cell-derived cytokines and chemokines produced during HHV-8 infection in the development of KS. IMPORTANCE Kaposi’s sarcoma (KS) is the most common cancer in HIV-1-infected persons and is caused by one of only 7 human cancer viruses, i.e., human herpesvirus 8 (HHV-8). It is unclear how this virus causes neoplastic transformation. Development and outgrowth of endothelial cell lesions characteristic of KS are hypothesized to be dependent on virus replication and multiple immune mediators produced by the KS cells and inflammatory cells, yet the roles of these viral and cell factors have not been defined. The present study advances our understanding of KS in that it supports a central role for HHV-8 infection of B cells inducing multiple cytokines and chemokines that can drive development of the cancer. Notably, HIV-1-infected individuals who developed KS had greater numbers of such HHV-8-infected, polyfunctional B cells across a range of B cell phenotypic lineages than did HHV-8-infected persons without KS. This intriguing production of polyfunctional immune mediators by B cells serves as a new paradigm for B cell function and classification.

ABSTRACT HIV-1-infected nonprogressors (NP) inhibit disease progression for years without antiretroviral therapy. Defining the mechanisms for this resistance to disease progression could be important in determining strategies for controlling HIV-1 infection. Here we show that two types of professional antigen-presenting cells (APC), i.e., dendritic cells (DC) and B lymphocytes, from NP lacked the ability to mediate HIV-1 trans infection of CD4+ T cells. In contrast, APC from HIV-1-infected progressors (PR) and HIV-1-seronegative donors (SN) were highly effective in mediating HIV-1 trans infection. Direct cis infection of T cells with HIV-1 was comparably efficient among NP, PR, and SN. Lack of HIV-1 trans infection in NP was linked to lower cholesterol levels and an increase in the levels of the reverse cholesterol transporter ABCA1 (ATP-binding cassette transporter A1) in APC but not in T cells. Moreover, trans infection mediated by APC from NP could be restored by reconstitution of cholesterol and by inhibiting ABCA1 by mRNA interference. Importantly, this appears to be an inherited trait, as it was evident in APC obtained from NP prior to their primary HIV-1 infection. The present study demonstrates a new mechanism wherein enhanced lipid metabolism in APC results in remarkable control of HIV-1 trans infection that directly relates to lack of HIV-1 disease progression. IMPORTANCE HIV-1 can be captured by antigen-presenting cells (APC) such as dendritic cells and transferred to CD4 helper T cells, which results in greatly enhanced viral replication by a mechanism termed trans infection. A small percentage of HIV-1-infected persons are able to control disease progression for many years without antiretroviral therapy. In our study, we linked this lack of disease progression to a profound inability of APC from these individuals to trans infect T cells. This effect was due to altered lipid metabolism in their APC, which appears to be an inherited trait. These results provide a basis for therapeutic interventions to control of HIV-1 infection through modulation of cholesterol metabolism.

Over the past twenty years, motor response inhibition and interference control have received considerable scientific effort and attention, due to their important role in behavior and the development of neuropsychiatric disorders. Results of neuroimaging studies indicate that motor response inhibition and interference control are dependent on cortical-striatal-thalamic-cortical (CSTC) circuits. Structural and functional abnormalities within the CSTC circuits have been reported for many neuropsychiatric disorders, including obsessive-compulsive disorder (OCD) and related disorders, such as attention deficit hyperactivity disorder (ADHD), Tourette’s syndrome (TS) and trichotillomania. These disorders also share impairments in motor response inhibition and interference control, which may underlie some of their behavioral and cognitive symptoms. Results of task-related neuroimaging studies on inhibitory functions in these disorders show that impaired task performance is related to altered recruitment of the CSTC circuits. Previous research has shown that inhibitory performance is dependent upon dopamine, noradrenaline and serotonin signaling, neurotransmitters that have been implicated in the pathophysiology of these disorders. In this review we discuss the common and disorder-specific pathophysiological mechanisms of inhibition-related dysfunction in OCD and related disorders.

INTRODUCTION: Social exclusion is considered a major factor in the causation and maintenance of health inequalities, but its measurement in health research is still in its infancy. In the Netherlands the Institute for Social Research (SCP) developed an instrument to measure the multidimensional concept of social exclusion in social and economic policy research. Here, we present a method to construct a similar measure of social exclusion using available data from public health surveys. METHODS: Analyses were performed on data from the health questionnaires that were completed by 20,877 adults in the four largest cities in the Netherlands. From each of the four questionnaires we selected the items that corresponded to those of the SCP-instrument. These were entered into a nonlinear canonical correlation analysis. The measurement properties of the resulting indices and dimension scales were assessed and compared to the SCP-instrument. RESULTS: The internal consistency of the indices and most of the dimension scales were adequate and the internal structure of the indices was as expected. Both generalisabiliy and construct validity were good: in all datasets strong associations were found between the index and a number of known risk factors of social exclusion. A limitation of content validity was that the dimension "lack of normative integration" could not be measured, because no relevant items were available. CONCLUSIONS: Our findings indicate that a measure for social exclusion can be constructed with available health questionnaires. This provides opportunities for application in public health surveillance systems in the Netherlands and elsewhere in the world.

Assessing liking is one of the most intriguing and influencing types of processing we experience day by day. We can decide almost instantaneously what we like and are highly consistent in our assessments, even across cultures. Still, the underlying mechanism is not well understood and often neglected by vision scientists. Several potential predictors for liking are discussed in the literature, among them very prominently typicality. Here, we analysed the impact of subtle changes of two perceptual dimensions (shape and colour saturation) of three-dimensional models of chairs on typicality and liking. To increase the validity of testing, we utilized a test-adaptation–retest design for extracting sensitivity data of both variables from a static (test only) as well as from a dynamic perspective (test–retest). We showed that typicality was only influenced by shape properties, whereas liking combined processing of shape plus saturation properties, indicating more complex and integrative processing. Processing the aesthetic value of objects, persons, or scenes is an essential and sophisticated mechanism, which seems to be highly sensitive to the slightest variations of perceptual input.

Little is known about mate choice preferences outside Western, educated, industrialised, rich and democratic societies, even though these Western populations may be particularly unrepresentative of human populations. To our knowledge, this is the first study to test which facial cues contribute to African perceptions of African female attractiveness and also the first study to test the combined role of facial adiposity, skin colour (lightness, yellowness and redness), skin homogeneity and youthfulness in the facial attractiveness preferences of any population. Results show that youthfulness, skin colour, skin homogeneity and facial adiposity significantly and independently predict attractiveness in female African faces. Younger, thinner women with a lighter, yellower skin colour and a more homogenous skin tone are considered more attractive. These findings provide a more global perspective on human mate choice and point to a universal role for these four facial cues in female facial attractiveness.

Abstract Intravital 2P-microscopy enables the longitudinal study of brain tumor biology in superficial mouse cortex layers. Intravital microscopy of the white matter, an important route of glioblastoma invasion and recurrence, has not been feasible, due to low signal-to-noise ratios and insufficient spatiotemporal resolution. Here, we present an intravital microscopy and artificial intelligence-based analysis workflow (Deep3P) that enables longitudinal deep imaging of glioblastoma up to a depth of 1.2 mm. We find that perivascular invasion is the preferred invasion route into the corpus callosum and uncover two vascular mechanisms of glioblastoma migration in the white matter. Furthermore, we observe morphological changes after white matter infiltration, a potential basis of an imaging biomarker during early glioblastoma colonization. Taken together, Deep3P allows for a non-invasive intravital investigation of brain tumor biology and its tumor microenvironment at subcortical depths explored, opening up opportunities for studying the neuroscience of brain tumors and other model systems.

ABSTRAK Al-MCM-41 adalah material padatan berpori yang tersusun dari silika amorf, memiliki struktur membentuk susunan heksagonal dengan ukuran pori antara 2-50 nm, sehingga dikategorikan sebagai material mesopori. Dalam pembuatan Al-MCM-41 membutuhkan sumber silika dan alumina yang tinggi sebagai bahan pembuatannya, sehingga dibutuhkan bahan yang kaya akan kedua senyawa tersebut sebagai bahan alternatif dalam pembuatan Al-MCM-41. Rumus formula kaolin adalah Al4(Si4O10)(OH)8 dengan komponen mineral utamanya adalah SiO2 dan Al2O3 Kaolin yang digunakan berasal dari bangka belitung dengan kandungan SiO2 sebesar 61% dan Al2O3 sebesar 31%, kandungan SiO2 dan Al2O3 yang cukup tinggi dimanfaatkan sebagai bahan pada sintesis material aluminosilikat seperti Al-MCM-41. Sintesis Al-MCM-41 dari kaolin dilakukan dengan metode hidrotermal. pH yang digunakan sebesar 10, dengan suhu 80°C selama 12 jam pada proses hidrotermalnya. Al-MCM-41 hasil sintesis dianalisa menggunakan XRD dan FTIR dimana pada analisa XRD sudut pendek menunjukkan 3 puncak pada 2θ= 2.237°, 3.921°, 4.449° dan XRD sudut panjang pada 2θ= 21.449°. Analisa FTIR untuk Al-MCM-41 menunjukkan pita serapan pada bilangan gelombang 436.49; 802.47; 1146.41; 1630.61; 3389.79 cm-1. Kata kunci: Al-MCM-41, hidrotermal, lempung, kaolin, mesopori, pH ABSTRACT Al-MCM-41 is a porous solid material composed of amorphous silica, has a structure forming a hexagonal array with a pore size between 2-50 nm, so it is categorized as a mesoporous material. The manufacture of Al-MCM-41 requires a high source of silica and alumina as materials, so materials rich in both compounds are needed as the development of materials used in the manufacture of Al-MCM-41. Kaolin (Al4(Si4O10)(OH)8) is a white clay mineral, the main minerals are SiO2 and Al2O3. The kaolin used comes from bangka belitung with a SiO2 content of 61% and Al2O3 of 31%, the high content of SiO2 and Al2O3 is utilized as an ingredient in the synthesis of aluminosilicate materials such as Al-MCM-41. The synthesis of Al-MCM-41 from kaolin was carried out by hydrothermal method. The pH used was 10, with a temperature of 80°C for 12 hours in the hydrothermal process. The synthesized Al-MCM-41 was analyzed using XRD and FTIR where the short angle XRD analysis showed 3 peaks at 2θ = 2.237°, 3.921°, 4.449° and long angle XRD at 2θ = 21.449°. FTIR analysis for Al-MCM-41 showed absorption bands at wave numbers 436.49; 802.47; 1146.41; 1630.61; 3389.79 cm-1. Keywords: Al-MCM-41, clay, hydrothermal, kaolin, mesopore, pH

Abstract Digital measures may provide objective, sensitive, real-world measures of disease progression in Parkinson’s disease (PD). However, multicenter longitudinal assessments of such measures are few. We recently demonstrated that baseline assessments of gait, tremor, finger tapping, and speech from a commercially available smartwatch, smartphone, and research-grade wearable sensors differed significantly between 82 individuals with early, untreated PD and 50 age-matched controls. Here, we evaluated the longitudinal change in these assessments over 12 months in a multicenter observational study using a generalized additive model, which permitted flexible modeling of at-home data. All measurements were included until participants started medications for PD. Over one year, individuals with early PD experienced significant declines in several measures of gait, an increase in the proportion of day with tremor, modest changes in speech, and few changes in psychomotor function. As measured by the smartwatch, the average (SD) arm swing in-clinic decreased from 25.9 (15.3) degrees at baseline to 19.9 degrees (13.7) at month 12 (P = 0.004). The proportion of awake time an individual with early PD had tremor increased from 19.3% (18.0%) to 25.6% (21.4%; P

Mesoporous silica was synthesized using biosurfactant templates to tailor the mesoporosity and catalytic activity in waste cooking oil conversion to liquid hydrocarbon. Facile maceration of Sapindus rarak fruit produced extract with amphiphilic properties. The effect of saponin biosurfactant in controlling mesoporosity was determined by varying silica to extract at 1:0.5, 1:1, and 1:2 w/w ratios. The silica formed sponge-like morphology with 3D intraparticle disordered mesopores. The mesoporosity reaches optimum with 6.08 nm pore size, 541 m2/g surface area, and 0.57 cc/g pore volume. High mesoporosity in silica enhances waste cooking oil conversion during deoxygenation reaction, achieving 80.60 % hydrocarbon selectivity and reducing carbon coke.

Lactic acid recovery and reusability for hydrolysis of cellulose offers an economical method and produces fewer waste streams. Successful lactic acid recovery up to three recycle times efficiently hydrolyzed NCs with rod-shape morphology. However, after four cycles, the nanocrystalline cellulose yield reduced from 72.3 % to 48.2 %, forming large nanocelluloses with high crystalline index. Large-size nanocellulose with high zeta potential and thermal stability were obtained with increasing cycles due to inefficient acid diffusion into the rigid crystalline network compared to amorphous cellulose. This study offers a green pathway for hydrolysis nanocellulose using a less corrosive and low toxicity lactic acid than inorganic acids.

The catalytic thermal conversion of carbon dioxide is essential for carbon capture, storage, and utilization, helping to reduce CO2 emissions and potentially stimulating future economic activities. Zeolite Y, ZSM-5, BEA, and A were synthesized using the hydrothermal technique from Indonesian kaolin to examine the potential use of zeolite as a catalyst without metal nanoparticles. In the absence of metal, catalytic activity for CO2 methanation relies solely on textural properties and basicity-acidity. Zeolite Y exhibits the highest CO2 conversion at 36.64 % and attained 100 % of CH4 selectivity at 400 °C. The exceptional CO2 conversion of zeolite Y relies on a high basicity level of 1.02 mmol/g, as shown by CO2-TPD analysis, and a relatively low acid site concentration of 1.48 mmol/g, as determined by NH3-TPD analysis. ZSM-5, BEA, and zeolite A, demonstrated CO2 conversion of 29.85 %, 23.86 %, and 12.15 %, respectively. Stability studies revealed ZSM-5 maintains methane (CH4) selectivity of 94 %, which is only slightly lowered by 6 % for 30 hours, while zeolite Y achieved 90 % selectivity for 26 hours. The presence of mesopores in zeolite ZSM-5 reduced coke or carbon production, maintaining crystalline framework.

Background: Overprescribing of potentially harmful medication in UK general practice has a complex association with socioeconomic deprivation. Aim: To assess trends in general practice prescribing of five high-risk medications and their relationship with deprivation. Design & setting: An observational study was conducted using general practice data from three English regions with varied sociodemographic factors: West Yorkshire and Harrogate (WY), Black Country and West Birmingham (BC), and Surrey and East Sussex (SE). Method: Practice-level prescribing data were obtained from 2016–2021 for five drug classes: opioids, hypnotics, gabapentinoids, non-steroidal anti-inflammatory drugs (NSAIDs), and antibacterials. Prescribing trends were demonstrated using a linear model. Results: Reduction in NSAID, opioid, hypnotic and antibacterial prescriptions, and the increase in gabapentinoid prescriptions, were significant at each financial year time period. Index of Multiple Deprivation (IMD) was positively associated with all drug classes except antibacterials, which showed a positive association when incorporating the interaction term between IMD and age. When adjusting for IMD and population, region was independently associated with prescribing rate. Compared with WY, IMD had a smaller association with prescribing in BC for NSAIDs (coefficient = −0.01578, P = 0.004) and antibacterials (coefficient = −0.02769, P = 0.007), whereas IMD had a greater association with prescribing in SE for NSAIDs (coefficient = 0.02443, P

Abstract Objective To investigate the trends in antiseizure medications (ASMs) use following ischemic stroke and to examine factors associated with use of newer‐ and older‐generation ASMs. Methods A retrospective cohort study was conducted using state‐wide linked health datasets. Patients who were hospitalized with a first‐ever ischemic stroke between 2013 and 2017 and were dispensed ASM within 12 months from discharge were included. Logistic regression was used to examine the predictors of receiving newer‐generation ASMs. Generalized linear modeling was used to identify factors associated with ASM use after ischemic stroke. Results Of 19 601 people hospitalized with a first‐ever ischemic stroke, 989 were dispensed an ASM within 12 months from discharge. The most prevalent first ASMs were levetiracetam (38.0%), valproate (25.8%), and carbamazepine (10.3%). Most people were dispensed ASM monotherapy (86.9%). There was a shift toward the use of newer‐generation ASMs between 2013 and 2017 (odds ratio [OR] 2.82, 95% confidence interval [CI] 1.92–4.16). Metropolitan residents were more likely to be dispensed newer‐generation ASMs as a first‐line treatment (OR 1.79, 95% CI 1.31–2.45). People over 85 years (OR 0.38, 95% CI 0.23–0.64), with dementia (OR 0.35, 95% CI 0.19–0.63) and psychotic comorbidities (OR 0.29, 95% CI 0.09–0.96) were less likely to be dispensed newer‐generation ASMs. Older age (coefficient [β] 0.23, P = 0.030), history of beta blocker use (β 0.17, P = 0.029), multiple ASMs (β 0.78, P

El presente artículo estudia el esquema centro-periferia del sistema internacional en el doble nivel de análisis, estatal y subestatal, a través de la agenda paradiplomática de las provincias argentinas con respecto a China entre 2014 y 2022. El objetivo plantea analizar la reconfiguración de la doble periferia de las unidades subestatales argentinas en la relación con China desde la suscripción del Acuerdo de Relaciones Estratégicas Integrales hasta el ingreso de Argentina en la Belt & Road Initiative (BRI). El abordaje parte de los aportes del estructuralismo para explicar la relación de dependencia centro-periférica en los distintos niveles del sistema internacional; y de los estudios de paradiplomacia para comprender el accionar internacional de las provincias argentinas condicionadas por la doble periferia en la que se insertan. La metodología es cualitativa con estudio de caso para el análisis de las provincias argentinas. Los resultados evidencian la proliferación de iniciativas provinciales en relación a actores chinos produciendo la reconfiguración de la doble periferia subestatal argentina. China se perfila como promotor del desarrollo local de la doble periferia de Argentina, pero mantiene la asimetría interestatal entre ambos países.

Abstract Background Intimate partner violence (IPV) is a prevalent public health issue associated with multiple physical and mental health consequences for survivors. Digital interventions can provide low-threshold support to those experiencing IPV, but existing digital interventions have limited efficacy in improving the safety and mental health of IPV survivors. Digitally adapting an integrative intervention with advocacy-based and psychological content holds promise for increasing the efficacy of digital interventions in the context of IPV. Methods This study examines the needs, acceptability and usability of an integrative digital intervention for people affected by IPV. We used the think-aloud method and semi-structured interviews with a sample of six people with lived experiences of IPV and six service providers. We analyzed the data using thematic analysis. Results We identified the increasing general acceptance of digital support tools and the limited capacity of the current support system as societal context factors influencing the acceptance of and needs regarding digital interventions in the context of IPV. An integrative digital self-help intervention offers several opportunities to complement the current support system and to meet the needs of people affected by IPV, including the reduction of social isolation, a space for self-reflection and coping strategies to alleviate the situation. However, potentially ongoing violence, varying stages of awareness and psychological capacities, and as well as the diversity of IPV survivors make it challenging to develop a digital intervention suitable for the target group. We received feedback on the content of the intervention and identified design features required for intervention usability. Conclusion An integrative digital self-help approach, with appropriate security measures and trauma-informed design, has the potential to provide well-accepted, comprehensive and continuous psychosocial support to people experiencing IPV. A multi-modular intervention that covers different topics and can be personalized to individual user needs could address the diversity of the target population. Providing guidance for the digital intervention is critical to spontaneously address individual needs. Further research is needed to evaluate the efficacy of an integrative digital self-help intervention and to explore its feasibility it in different settings and populations.

Abstract The increase in water holding capacity of the atmosphere with temperature, given by the Clausius‐Clapeyron (CC) relationship, describes the changes in extreme rainfall intensities at warmer atmospheric states. We study the characteristics of extreme rainfall events (EREs) during the Indian summer monsoon season with respect to thermodynamic changes and precipitation‐scaling over the Indian subcontinent and its homogeneous rainfall zones. We utilize outputs from a present‐day climate simulation and a time‐slice future climate change projection experiments of a high‐resolution global climate model. Large changes are seen for very EREs (vEREs) which suggests their sensitivity to warmer temperatures. In future, the altered radiative forcing will heat up the upper atmosphere, stabilize it and offset the effect of increasing humidity on precipitation intensity. Our analysis also suggests that more convective clouds and the interplay of increased moisture content and circulation will result in future changes in EREs.