Use of Home-Based Self-Collected Dried Blood Spots to Test for Syphilis, Human Immunodeficiency Virus, Hepatitis C and B Virus Infections and Measuring Creatinine Concentration.

INTRODUCTION: Home-based self-collected dried blood spot (DBS) sampling could simplify sexual health and preexposure prophylaxis care and reduce sexually transmitted infections (STIs) clinic visits for men who have sex with men (MSM). We compared the performance of DBS to venipuncture collected blood samples to test four STIs and creatinine concentration. METHODS: We invited MSM clients of the Amsterdam STI clinic to participate. Routinely collected peripheral blood was tested for syphilis treponemal antibody, HIV (HIV Ag/Ab), HCV (antibodies), HBV (HBsAg) and creatinine concentration. Participants received a home kit for DBS sampling, a return envelope and a questionnaire to evaluate the acceptability, feasibility and usability of DBS, measured on 5-point Likert scales, 1 representing complete disagreement and 5 complete agreement. We assessed sensitivity and specificity of DBS versus peripheral blood-based testing. RESULTS: In 2020 to 2021, we included 410 participants; 211 (51.5%) returned a completed DBS card, 117 (28.5%) returned a partially filled card and 82 (20.0%) did not return a card. The sensitivity for syphilis was 90.8% and the specificity 84.3%. For both HIV Ag/Ab and HBsAg, the sensitivity and specificity were 100.0%. The sensitivity for HCV antibody was 80.0%, and the specificity was 99.2%. The DBS creatinine concentration was a mean of 5.3 µmol/L higher than in venipuncture obtained plasma. Participants' median willingness to take a future DBS was 4 (interquartile range, 3-5). DISCUSSION: Dried blood spot may be an acceptable method among MSM for STI testing and creatinine follow-up during preexposure prophylaxis use. However, collecting enough blood on DBS cards was a challenge, and sensitivities for syphilis and HCV serology were too low.

Liver X receptor alpha ensures blood-brain barrier function by suppressing SNAI2.

In Alzheimer's disease (AD) more than 50% of the patients are affected by capillary cerebral amyloid-angiopathy (capCAA), which is characterized by localized hypoxia, neuro-inflammation and loss of blood-brain barrier (BBB) function. Moreover, AD patients with or without capCAA display increased vessel number, indicating a reactivation of the angiogenic program. The molecular mechanism(s) responsible for BBB dysfunction and angiogenesis in capCAA is still unclear, preventing a full understanding of disease pathophysiology. The Liver X receptor (LXR) family, consisting of LXRα and LXRß, was reported to inhibit angiogenesis and particularly LXRα was shown to secure BBB stability, suggesting a major role in vascular function. In this study, we unravel the regulatory mechanism exerted by LXRα to preserve BBB integrity in human brain endothelial cells (BECs) and investigate its role during pathological conditions. We report that LXRα ensures BECs identity via constitutive inhibition of the transcription factor SNAI2. Accordingly, deletion of brain endothelial LXRα is associated with impaired DLL4-NOTCH signalling, a critical signalling pathway involved in vessel sprouting. A similar response was observed when BECs were exposed to hypoxia, with concomitant LXRα decrease and SNAI2 increase. In support of our cell-based observations, we report a general increase in vascular SNAI2 in the occipital cortex of AD patients with and without capCAA. Importantly, SNAI2 strongly associated with vascular amyloid-beta deposition and angiopoietin-like 4, a marker for hypoxia. In hypoxic capCAA vessels, the expression of LXRα may decrease leading to an increased expression of SNAI2, and consequently BECs de-differentiation and sprouting. Our findings indicate that LXRα is essential for BECs identity, thereby securing BBB stability and preventing aberrant angiogenesis. These results uncover a novel molecular pathway essential for BBB identity and vascular homeostasis providing new insights on the vascular pathology affecting AD patients.

Age-associated systemic factors change central and peripheral immunity in adult male mice.

Aging coincides with major changes in brain immunity that aid in a decline in neuronal function. Here, we postulate that systemic, pro-aging factors contribute to immunological changes that occur within the brain during aging. To investigate this hypothesis, we comprehensively characterized the central and peripheral immune landscape of 20-month-old male mice using cytometry by time-of-flight (CyTOF) and investigated the role of age-associated circulating factors. We found that CD8+ T cells expressing programmed cell death protein 1 (PD1) and tissue-resident memory CD8+ T cells accumulated in the aged brain while levels of memory T cells rose in the periphery. Injections of plasma derived from 20-month-old mice into 5-month-old receiving mice decreased the frequency of splenic and circulating naïve T cells, increased memory CD8+ T cells, and non-classical, patrolling monocytes in the spleen, and elevated levels of regulatory T cells and non-classical monocytes in the blood. Notably, CD8+ T cells accumulated within white matter areas of plasma-treated mice, which coincided with the expression of vascular cell adhesion molecule 1 (VCAM-1), a mediator of immune cell trafficking, on the brain vasculature. Taken together, we here describe age-related immune cell changes in the mouse brain and circulation and show that age-associated systemic factors induce the expansion of CD8+ T cells in the aged brain.

Characteristics of mpox positive, versus mpox negative, and mpox unsuspected clients from the Centre of Sexual Health, Public Health Service of Amsterdam, 20 May to 15 September 2022.

BACKGROUND: In May 2022, an outbreak of mpox (monkeypox) in men-who-have-sex-with-men (MSM) emerged and quickly affected over 100 countries. In the early stages of the outbreak, overlap in symptoms with sexually transmitted infections (STI) made triage for mpox testing challenging. More information was needed on whom to screen and the main route of transmission. OBJECTIVES: We aimed to identify characteristics of mpox cases to further strengthen case definitions. We also compared Cycle threshold (Ct) values of the DNA positive mpox samples as a proxy for viral load by body location. METHODS: From 20 May 2022 to 15 September 2022, we tested all MSM who presented with malaise, and/or ulcerative lesions, and/or proctitis and/or a papular-vesicular-pustular eruption attending the Centre of Sexual Health in Amsterdam, the Netherlands, for mpox, with a PCR test. In the same period, 6932 MSM mpox unsuspected clients were not tested. We compared those tested positive for mpox with those tested negative and those unsuspected for mpox. RESULTS: Of the 374 MSM tested, 135 (36%) were positive for mpox. The mpox-positive MSM were older (median age, respectively, 36, 34 and 34 years, p = 0.019) and more often lived with HIV (30% vs. 16% and 7%, p < 0.001). Furthermore, mpox-positive patients more often reported receptive anal sex without a condom, sexualized drug use, more sex partners, and were more often diagnosed with bacterial STI (p < 0.001). Systemic symptoms and anogenital lesions were associated with mpox infection. For mpox-positive patients, anal samples (p = 0.009) and lesional samples (p = 0.006) showed significantly lower median mpox Ct values compared to throat samples. CONCLUSIONS: Mpox-positive patients more often reported receptive anal sex without a condom, had more sex partners and more often lived with HIV. Our results suggest that in the current mpox outbreak among MSM, sexual transmission is the main route.

Increased clonality among Neisseria gonorrhoeae isolates during the COVID-19 pandemic in Amsterdam, the Netherlands.

Distancing measures during the COVID-19 lockdown led to a temporary decrease of casual sex partners among clients of the Centre for Sexual Health (CSH) in Amsterdam, the Netherlands. We investigated the effect of this change on the genotypic and phenotypic distribution of Neisseria gonorrhoeae (Ng) isolates from CSH patients. From each Ng-positive patient we sequenced one isolate, resulting in 322 isolates which constituted two groups: 181 isolates cultured from 15 January to 29 February 2020 (before the first lockdown) and 141 cultured from 15 May to 30 June 2020 (during the first lockdown). Patient characteristics showed significantly more symptomatic patients and significantly fewer reported sex partners during the lockdown. Phenotypic data showed an increase in low-level azithromycin resistance and ceftriaxone susceptibility during the lockdown, and this remained after the study period. The diversity in sequence types (STs) decreased slightly during the lockdown. A shift occurred from ST 8156 being predominant before lockdown to ST 9362 during lockdown and a remarkably low median SNP distance of 17 SNPs was found between ST 9362 isolates obtained during lockdown. These findings reflect restricted travel and the change in sexual behaviour of CSH clients during the lockdown, with a potentially increased local transmission of the ST 9362 strain during this period, which led to genotypic and phenotypic changes in the Ng population. This shows that public health measures have far-reaching consequences and should be considered in the surveillance of other infectious diseases.

Markers of aging: Unsupervised integrated analyses of the human plasma proteome.

Aging associates with an increased susceptibility for disease and decreased quality of life. To date, processes underlying aging are still not well understood, leading to limited interventions with unknown mechanisms to promote healthy aging. Previous research suggests that changes in the blood proteome are reflective of age-associated phenotypes such as frailty. Moreover, experimentally induced changes in the blood proteome composition can accelerate or decelerate underlying aging processes. The aim of this study is to identify a set of proteins in the human plasma associated with aging by integration of the data of four independent, large-scaled datasets using the aptamer-based SomaScan platform on the human aging plasma proteome. Using this approach, we identified a set of 273 plasma proteins significantly associated with aging (aging proteins, APs) across these cohorts consisting of healthy individuals and individuals with comorbidities and highlight their biological functions. We validated the age-associated effects in an independent study using a centenarian population, showing highly concordant effects. Our results suggest that APs are more associated to diseases than other plasma proteins. Plasma levels of APs can predict chronological age, and a reduced selection of 15 APs can still predict individuals' age accurately, highlighting their potential as biomarkers of aging processes. Furthermore, we show that individuals presenting accelerated or decelerated aging based on their plasma proteome, respectively have a more aged or younger systemic environment. These results provide novel insights in the understanding of the aging process and its underlying mechanisms and highlight potential modulators contributing to healthy aging.

Effects of providing tailored information about e-cigarettes in a digital smoking cessation intervention: randomized controlled trial.

The effectiveness of e-cigarettes in smoking cessation is under debate. Informing smokers who are motivated to quit smoking about e-cigarettes may help them to make an informed decision about their use for smoking cessation, which, however, may also lead to unintended effects such as less quitting. This experimental study assessed the influence of providing tailored information about e-cigarettes in a web-based tailored smoking cessation intervention on participants' decision-making and smoking behavior. Adult smokers (N = 331) were randomized into a personalized eHealth intervention on (i) smoking cessation (control condition) or (ii) smoking cessation and information about e-cigarettes (intervention condition). Directly postintervention, participants in the intervention condition had more knowledge about e-cigarettes than participants in the control condition. Attitudes toward e-cigarettes were more positive among intervention participants than control participants, but the differences in attitude were less pronounced than the differences in knowledge and not consistent across items. At a 6-month follow-up, no between-condition differences were observed in the use of e-cigarettes as a smoking cessation method, the number of tobacco cigarettes smoked in the past 7 days, or other smoking outcomes.

Role of bile acid receptor FXR in development and function of brown adipose tissue.

Bile acids act as signalling molecules that contribute to maintenance of energy homeostasis in mice and humans. Activation of G-protein-coupled bile acid receptor TGR5 induces energy expenditure in brown adipose tissue (BAT). However, a role for the nuclear bile acid receptor Farnesoid X receptor (FXR) in BAT has remained ambiguous. We aimed to study the potential role of FXR in BAT development and functioning. Here we demonstrate low yet detectable expression of the α1/2 isoforms of FXR in murine BAT that markedly decreases upon cold exposure. Moderate adipose tissue-specific FXR overexpression in mice induces pronounced BAT whitening, presenting with large intracellular lipid droplets and extracellular collagen deposition. Expression of thermogenic marker genes including the target of Tgr5, Dio2, was significantly lower in BAT of chow-fed aP2-hFXR mice compared to wild-type controls. Transcriptomic analysis revealed marked up-regulation of extracellular matrix formation and down-regulation of mitochondrial functions in BAT from aP2-hFXR mice. In addition, markers of cell type lineages deriving from the dermomyotome, such as myocytes, as well as markers of cellular senescence were strongly induced. The response to cold and ß3-adrenergic receptor agonism was blunted in these mice, yet resolved BAT whitening. Newborn cholestatic Cyp2c70-/- mice with a human-like bile acid profile also showed distinct BAT whitening and upregulation of myocyte-specific genes, while thermogenic markers were down-regulated. Ucp1 expression inversely correlated with plasma bile acid levels. Therefore, bile acid signalling via FXR has a role in BAT function already early in tissue development. Functionally, FXR activation appears to oppose TGR5-mediated thermogenesis.

The Associations Between Illness Perceptions and Expectations About Return to Work of Workers With Chronic Diseases and Their Significant Others: A Dyadic Analysis.

Purpose To examine the associations between illness perceptions and expectations about full return to work (RTW) of workers with chronic diseases and their significant others. Methods This study used cross-sectional data of 94 dyads consisting of workers with chronic diseases and their significant others. We performed dyadic analyses based on the Actor-Partner Interdependence Model (APIM), estimating associations of illness perceptions of the two members of the dyad with their own expectations about the worker's full RTW within six months (actor effect) as well as with the other dyad member's expectations about the worker's RTW (partner effect). Results Illness perceptions of one dyad member were significantly associated with his or her own RTW expectations (actor effect composite illness perceptions score; B = -0.05, p < .001; rd = .37) and with the other dyad member's RTW expectations (partner effect composite illness perceptions score; B = -0.04, p < .001; rd = .35). That is, more negative illness perceptions of one member of the dyad were associated with more negative RTW expectations in both dyad members. For most illness perception domains, we found small to moderate actor and partner effects on RTW expectations (rd range: .23-.44). Conclusions This study suggests that illness perceptions and RTW expectations should be considered at a dyadic level as workers and their significant others influence each other's beliefs. When trying to facilitate adaptive illness perceptions and RTW expectations, involving significant others may be more effective than an individualistic approach targeted at the worker only.

Crossing borders in Alzheimer's disease: A T cell's perspective.

Alzheimer's disease (AD) is the most common form of dementia affecting millions of people worldwide. While different immunotherapies are imminent, currently only disease-modifying medications are available and a cure is lacking. Over the past decade, immunological interfaces of the central nervous system (CNS) and their role in neurodegenerative diseases received increasing attention. Specifically, emerging evidence shows that subsets of circulating CD8+ T cells cross the brain barriers and associate with AD pathology. To gain more insight into how the adaptive immune system is involved in disease pathogenesis, we here provide a comprehensive overview of the contribution of T cells to AD pathology, incorporating changes at the brain barriers. In addition, we review studies that provide translation of these findings by targeting T cells to combat AD pathology and cognitive decline. Importantly, these data show that immunological changes in AD are not confined to the CNS and that AD-associated systemic immune changes appear to affect brain homeostasis.

Treponema pallidum Subspecies Pallidum Intrapatient Homogeneity at Various Body Locations in Men with Infectious Syphilis.

Syphilis, caused by Treponema pallidum subspecies pallidum (TP), is a complex multistage infectious disease. Systematic dissemination occurs within a few hours of transmission. We determined the molecular variation of TP at various body locations and peripheral blood within patients in different stages of syphilis to assess the distribution of TP strains at these locations. We included 162 men who have sex with men (MSM) with syphilis visiting the Sexual Health Center in Amsterdam between 2018 to 2019, who had TP DNA detected in at least one sample type (anal swab, urine sample, peripheral blood, pharyngeal swab, and/or ulcer swab). TP DNA was detected in 287 samples using a qPCR targeting the polA gene. With multilocus sequence typing (TP-MLST) based on partial sequence analysis of three genetic regions (tp0136, tp0548, tp0705), we characterized all TP DNA positive samples. Samples could be typed (119/287) from at least one anatomical location or peripheral blood from 93/162 (57%) patients in the following stages: 48 (52%) primary, 35 (38%) secondary, and 10 (11%) early latent stage syphilis. The TP-MLST type was identical within each of the 12 patients with typed samples at ≥2 different body locations. The most prevalent TP strains were 1.3.1 (39/93, 42%) and 1.1.1 (17/93, 18%) belonging to the SS14 lineage; 80% (74/93) of the patients carried a SS14 lineage TP strain and 20% (19/93) Nichols lineage. The distribution of TP-MLST types did not differ between patients by syphilis stage. We found intrapatient TP strain homogeneity and no TP strain variation between anatomical location or syphilis stages. More early latent samples should be typed and added in future studies to investigate this in more detail. IMPORTANCE Syphilis, caused by Treponema pallidum subspecies pallidum, is a complex multistage infectious disease. Systematic dissemination is known to occur within a few hours of transmission. Despite the effective antibiotic penicillin, syphilis remains prevalent worldwide. Men who have sex with men are disproportionally affected in high income countries like the Netherlands where 96% of the syphilis cases in 2020 were among this population. The inability to in vitro culture T. pallidum directly from patient samples limits whole-genome sequencing efforts. Fortunately, in 2018 a multilocus sequence typing technique was developed for T. pallidum allowing the monitoring of circulating strains. The significance of our research is in the investigation of T. pallidum molecular variation at various body locations and blood within patients in different stages of syphilis in order to assess the distribution of strains at these locations.

Detection of Treponema pallidum DNA During Early Syphilis Stages in Peripheral Blood, Oropharynx, Ano-Rectum and Urine as a Proxy for Transmissibility.

BACKGROUND: Syphilis diagnosis may be challenging, especially in the asymptomatic and early clinical stages. We evaluated the presence of Treponema pallidum DNA (TP-DNA) in various sample types to elucidate transmissibility during various syphilis stages. METHODS: The study was conducted at the Amsterdam Centre for Sexual Health. We included adult men who have sex with men (MSM), who were suspected of having syphilis. The 2020 European guidelines definitions were followed for the diagnosis and staging of syphilis. Using a polymerase chain reaction (PCR) targeting the polA gene of Treponema pallidum (TP-PCR), we tested the following study samples on TP-DNA: peripheral blood, oropharyngeal swab, ano-rectal swab, and urine. RESULTS: From November 2018 to December 2019 we included 293 MSM. Seventy clients had primary syphilis, 73 secondary syphilis, 86 early latent syphilis, 14 late latent syphilis, 23 treated syphilis, and 27 had no syphilis. TP-DNA was detected in at least 1 study sample in 35/70 clients with primary syphilis (2/70 peripheral blood, 7/70 oropharynx, 13/70 ano-rectum, and 24/70 urine); in 62/73 clients with secondary syphilis (15/73 peripheral blood, 47/73 oropharynx, 37/73 ano-rectum, and 26/73 urine); and in 29/86 clients with early latent syphilis (5/86 peripheral blood, 21/86 oropharynx, 11/86 ano-rectum, and 6/86 urine). TP-DNA was not detected in clients with late latent syphilis or treated syphilis, nor in clients without syphilis. CONCLUSIONS: TP-DNA was frequently detected in various sample types in the absence of lesions. This is in line with the high transmission rate of syphilis and opens diagnostic opportunities for early presymptomatic syphilis stages.

Adjunctive cytoprotective therapies in acute ischemic stroke: a systematic review.

With the introduction of endovascular thrombectomy (EVT), a new era for treatment of acute ischemic stroke (AIS) has arrived. However, despite the much larger recanalization rate as compared to thrombolysis alone, final outcome remains far from ideal. This raises the question if some of the previously tested neuroprotective drugs warrant re-evaluation, since these compounds were all tested in studies where large-vessel recanalization was rarely achieved in the acute phase. This review provides an overview of compounds tested in clinical AIS trials and gives insight into which of these drugs warrant a re-evaluation as an add-on therapy for AIS in the era of EVT. A literature search was performed using the search terms "ischemic stroke brain" in title/abstract, and additional filters. After exclusion of papers using pre-defined selection criteria, a total of 89 trials were eligible for review which reported on 56 unique compounds. Trial compounds were divided into 6 categories based on their perceived mode of action: systemic haemodynamics, excitotoxicity, neuro-inflammation, blood-brain barrier and vasogenic edema, oxidative and nitrosative stress, neurogenesis/-regeneration and -recovery. Main trial outcomes and safety issues are summarized and promising compounds for re-evaluation are highlighted. Looking at group effect, drugs intervening with oxidative and nitrosative stress and neurogenesis/-regeneration and -recovery appear to have a favourable safety profile and show the most promising results regarding efficacy. Finally, possible theories behind individual and group effects are discussed and recommendation for promising treatment strategies are described.

2021 European Guideline on the management of proctitis, proctocolitis and enteritis caused by sexually transmissible pathogens.

This guideline intents to offer guidance on the diagnosis and management of patients with gastrointestinal symptoms and a suspected sexually transmitted cause. Proctitis is defined as an inflammatory syndrome of the anal canal and/or the rectum. Infectious proctitis can be sexually transmitted via genital-anal mucosal contact, but some also via digital contact and toys. Neisseria gonorrhoeae, Chlamydia trachomatis (including lymphogranuloma venereum), Treponema pallidum and herpes simplex virus are the most common sexually transmitted anorectal pathogens. Shigellosis can be transferred via oral-anal contact and may lead to proctocolitis or enteritis. Although most studies on these infections have concentrated on men who have sex with men (MSM), women having anal intercourse may also be at risk. A presumptive clinical diagnosis of proctitis can be made when there are symptoms and signs, and a definitive diagnosis when the results of laboratory tests are available. The symptoms of proctitis include anorectal itching, pain, tenesmus, bleeding, constipation and discharge in and around the anal canal. The majority of rectal chlamydia and gonococcal infections are asymptomatic and can only be detected by laboratory tests. Therefore, especially when there is a history of receptive anal contact, exclusion of anorectal infections is generally indicated as part of standard screening for sexually transmitted infections (STIs). Condom use does not guarantee protection from STIs, which are often spread without penile penetration. New in this updated guideline is: (i) lymphogranuloma venereum proctitis is increasingly found in HIV-negative MSM, (ii) anorectal Mycoplasma genitalium infection should be considered in patients with symptomatic proctitis after exclusion of other common causations such N. gonorrhoeae, C. trachomatis, syphilis and herpes, (iii) intestinal spirochetosis incidentally found in colonic biopsies should not be confused with syphilis, and (iv) traumatic causes of proctitis should be considered in sexually active patients.

Hereditary diseases and child wish: exploring motives, considerations, and the (joint) decision-making process of genetically at-risk couples.

Couples who are at risk of transmitting a genetic disease to their offspring may face difficult challenges regarding reproductive decision-making. Deciding if, and how, to purse their child wish can be a demanding process. This study aims to describe the reproductive joint decision-making process of genetically at-risk couples. A qualitative study was conducted with 16 couples (N=31) at risk of transmitting a genetic disease to their offspring and who received genetic counseling. Most couples were not aware of all available reproductive options in the Netherlands. A variety of motives was reported with almost all couples expressing a preference towards a reproductive option in which the child is genetically related to both parents. Only a few couples considered other options such as the use of donor gametes, adoption, and foster parenting. All couples indicated that they had multiple conversations to reach a mutually supported reproductive decision. Several carriers reported feelings of guilt and in some couples, the woman appeared to have a greater impact in the decision-making process as she should carry a pregnancy and should undergo medical treatments. This study provides insight in the extensive decision-making process of genetically at-risk couples and the role of both partners in this process. These findings can guide the development of genetic counseling (e.g., increase awareness of available reproductive options) and decision support for these couples.

[Lymphogranuloma venereum, an STI that is sometimes recognized late in secondary care]. / Lymphogranuloma venereum.

Lymphogranuloma venereum (LGV) is an invasive sexually transmitted infection caused by Chlamydia trachomatis genotypes L1, L2 and L3. Until recently, LGV was rarely seen in developed countries. However, an outbreak of LGV infections in Europe amongst men who have sex with men (MSM) has been reported in the past decades. Diagnosing LGV can be challenging since there is no pathognomic clinical presentation. Most patients are diagnosed with LGV by Community Healthcare Services and general practitioners. Recent data show that a significant diagnostic delay can occur when patients present in a hospital with symptoms due to LGV infection. This can result in unnecessary additional diagnostic procedures and a subsequent diagnostic delay. In order to create more awareness, we describe 3 cases in our hospital with an initially unrecognized LGV infection. We also discuss the epidemiology, clinical manifestations, diagnostic process and treatment of LGV infection.

Changes in mental health and drug use among men who have sex with men using daily and event-driven pre-exposure prophylaxis: Results from a prospective demonstration project in Amsterdam, the Netherlands.

BACKGROUND: Gay, bisexual and other men who have sex with men (GBMSM) are at increased risk of mental health disorders and drug use. In GBMSM taking pre-exposure prophylaxis (PrEP) for HIV, the proportion engaging in risk behaviors could increase due to decreased perception in HIV risk. In turn, this could leave them further susceptible to mental health disorders. METHODS: The AMsterdam PrEP study (AMPrEP) is a demonstration project offering a choice of daily PrEP or event-driven PrEP regimen at the STI clinic of the Public Health Service of Amsterdam. Eligible participants were HIV-negative GBMSM and transgender people at risk of HIV, aged ≥18 years. We assessed anxiety and depressive mood disorders (Mental Health Inventory 5), sexual compulsivity (Sexual Compulsivity Scale), alcohol use disorder (Alcohol Use Disorder Identification Test), and drug use disorder (Drug Use Disorder Identification Test) using yearly self-administered assessments (August 2015-September 2018). The proportion of mental health problems were analyzed and changes over time and between regimen were assessed using a logistic regression model. Variables associated with the development or recovery of disorders were assessed using a multistate Markov model. OUTCOMES: Of 376 enrolled, we analyzed 341 participants with data at baseline and at least one follow-up visit. During a median follow-up of 2.5 years (IQR=2.3-2.7), the proportion assessed with sexual compulsivity decreased from 23% at baseline to 10% at the last visit (p<0.001) and drug use disorder decreased from 38% at baseline to 31% at the last visit (p = 0.004). No changes occurred in proportion assessed with anxiety/depressive mood disorders (20% at baseline, 18% at last visit, p = 0.358) or alcohol use disorder (28% at baseline, 22% at the last visit, p = 0.106). During follow-up, participants reported significant less use of alcohol (p<0.001), nitrites (p<0.001) and ecstasy (p<0.001). We found no differences between daily and event-driven PrEP users. The development and recovery of disorders during follow-up were highly interrelated. INTERPRETATION: Mental health disorders are prevalent among those initiating PrEP. We did not find increases in mental health disorders during PrEP use, but rather a decrease in sexual compulsivity and drug use disorders. The initial prevalence of mental health disorders in our study point at the continuous need to address mental health disorders within PrEP programs. FUNDING: ZonMw, H-TEAM, Internal GGD research funds, Aidsfonds, Stichting AmsterdamDiner Foundation, Gilead Sciences, Janssen Pharmaceutica, M A C AIDS Fund, and ViiV Healthcare.