HIV pre-exposure prophylaxis during the SARS-CoV-2 pandemic: Results from a prospective observational study in Germany.

Aims: Since 2017, HIV pre-exposure prophylaxis (PrEP) care has been provided through an intersectoral collaboration at WIR (Walk-in-Ruhr, Center for Sexual Health and Medicine, Bochum, Germany). The aim of this study was to establish possible impact of COVID-restrictions on the sexual behavior of PrEP users in North Rhine-Westphalia. Methods: The current PrEP study collected data of individuals using PrEP, their sexual behavior and sexually transmitted infections (STIs) before (each quarter of year 2018) and during the COVID-19 pandemic (each quarter of year 2020). Results: During the first lockdown in Germany from mid-March until May 2020, PrEP-care appointments at WIR were postponed or canceled. Almost a third of PrEP users had discontinued their PrEP intake in the 2nd quarter of 2020 due to alteration of their sexual behavior. The number of sexual partners decreased from a median of 14 partners in the previous 6 months in 1st quarter of 2020, to 7 partners in 4th quarter of 2020. Despite such a significant reduction in partner number during the pandemic in comparison to the pre-pandemic period, a steady rate of STIs was observed among PrEP users in 2020. Conclusion: The SARS-CoV-2-pandemic has impacted PrEP-using MSM in North Rhine-Westphalia with respect to their PrEP intake regimen and sexual behavior in 2020. Our study revealed a steady rate of STI among PrEP users even during the pandemic, thus highlighting the importance of ensuring appropriate HIV/STI prevention services in times of crisis.

Influence of dietary supplementation of short-chain fatty acid sodium propionate in people living with HIV (PLHIV).

BACKGROUND: Non-AIDS-associated chronic diseases in HIV+ patients have been on the rise since the advent of antiretroviral therapy. Especially cardiovascular diseases and disruption in the gastrointestinal tract have limited health-related quality of life (QoL). Several of those complications have been associated with chronic systemic inflammation. Short-chain fatty acids (SCFA), with propionate as one of the major compounds, have been described as an important link between gut microbiota and the immune system, defining the pro- and the anti-inflammatory milieu through direct and indirect regulation of T-cell homeostasis. The effects of dietary supplementation of sodium propionate (SP) in people living with HIV (PLHIV) have not yet been investigated prior to this study. OBJECTIVES: To investigate the impact of SP uptake among PLHIV and its relevance to improve QoL, the study aimed to investigate metabolic, immunological, microbiome and patient-reported QoL-related changes post-SP supplementation with follow-up. METHODS: A prospective, non-randomized, controlled, monocentric interventional study was conducted in WIR, Center for Sexual Health and Medicine, in Bochum, Germany. 32 HIV+ patients with unaltered ART-regimen in the last three months were included. Participants were given SP for a duration of 12 weeks in the form of daily oral supplementation and were additionally followed-up for another 12 weeks. RESULTS: The supplementation of SP was well tolerated. We found an improvement in lipid profiles and long-term blood glucose levels. A decrease in pro-inflammatory cytokines and a depletion of effector T cells was observed. Regulatory T cells and IL-10 decreased. Furthermore, changes in taxonomic composition of the microbiome during follow-up were observed and improvement of items of self-reported life-quality assessment. CONCLUSION: Taken together, the beneficial impact of SP in PLHIV reflects its potential in improving metabolic parameters and modulating pro-inflammatory immune responses. Thus, possibly reducing the risk of cardiovascular disorders and facilitating long-term improvement of the gut flora.

Sexual behaviour, STI knowledge and Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG) prevalence in an asymptomatic cohort in Ruhr-area, Germany: PreYoungGo study.

BACKGROUND AND OBJECTIVES: STIs present a significant threat to individual and public health, disproportionately affecting youth. The study aimed to evaluate (a) the prevalence of asymptomatic Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG) infections among youth using a rapid assay platform, (b) the participants' sexual behaviour and STI knowledge, (c) the utility of the rapid assay in reducing diagnosis-to-treatment time. METHODS: In this study, 272 subjects (14-31 years) were included between 12/2016 and 7/2018. A questionnaire was used to collect sociodemographic data, sexual behaviour and STI knowledge. Prevalence of CT and NG infections were tested from oral, vaginal and anal swabs for women and oral, anal swabs and urine for men, using the Cepheid Xpert® CT/NG assay. Time intervals between (i) test to the time the patient were informed of the result (turn around time - TAT) and (ii) test to therapy initiation was documented. RESULTS: Of the 272 subjects (48.9% female, 48.9% male, undisclosed 2.2%), 56.6 % reported university education. 46.6% were men who have sex with men (MSM), and 47.4% of women and 63.1% of men had anal intercourse. 59.9% had previously been tested for HIV, while only 39.7% had for CT, 20.6% for NG. Among these asymptomatic youth 7.7% were positive for CT and 5.5% for NG. The localization of CT were 3.7% genital, 5.5% anal and 2.2% oral, while the corresponding localization of NG were 0.4%, 2.9%, 4.4% respectively. 91.8% of the participants were informed of a positive result within 24 h with a median TAT of 03:09 h. 73.3% initiated therapy within 24 h, with a median time from testing to therapy initiation being 06:50 h. CONCLUSION: Asypmtomatic CT and NG infections are common and often not tested in persons at risk. The Cepheid Xpert® CT/NG assay is an effective strategy as it reduces STI diagnosis-to-treatment time to less than a day.

Age specific evaluation of sexual behavior, STI knowledge and infection among asymptomatic adolescents and young adults.

OBJECTIVES: Adolescents and young adults account for 50% of new infections with sexually transmitted infection (STI), while representing only 25% of the sexually active population. An evaluation of sexual behavior, STI knowledge and infection among youth of different age groups is relevant to formulate effective sexual health strategies. METHODS: In this monocentric, open, prospective cross-sectional study, 268 asymptomatic subjects (14-30 years) were partitioned into three cohorts I: 14-19 (n=42), II: 20-25 (n=147) and III: 25-30 (n=79) years. A comparative analysis of their sexual behavior and STI knowledge was performed using a 21-item questionnaire at the WIR-Center for Sexual Health and Medicine. Prevalence of chlamydia and gonococcal infections were tested, using the Cepheid Xpert® CT/NG assay. RESULTS: The three age-specific cohorts showed statistically significant differences in their relationship status, their sexual contacts and the number of life-time sexual partners. Independent of age, men who have sex with men had greater number of sexual partners across all age groups. Although >95% of participants were aware of HIV in all age groups, the corresponding awareness of non-HIV STI was consistently lower in cohort I. The awareness of trichomonas, mycoplasma and candida in particular was <50% across all agedemographies. Chlamydia screening remains poor despite current chlamydia infection among cohort I, II & III being 7.1%, 5.4%, & 11.4% respectively. CONCLUSION: Our study demonstrates a demographic divide in the knowledge on most frequent STI apart from HIV. Current education, screening and vaccination programs for STI among the younger demographic should be improved.

Pregnancy outcomes after maternal varenicline use; analysis of surveillance data collected by the European Network of Teratology Information Services.

Varenicline is a smoking cessation aid for which limited data exist concerning safety during human pregnancy. This multicentre prospective observational comparative cohort study was undertaken using surveillance data collected by the European Network of Teratology Information Services. The study sample consisted of 89 varenicline exposed pregnancies and two matched comparator groups; 267 non-teratogen exposed (NTE) controls and 78 exposed to nicotine replacement therapy or bupropion (NRT/B) for smoking cessation. For all exposed pregnancies, varenicline use only occurred in the first trimester, with a considerable proportion discontinuing use in the very early stages of pregnancy. The major congenital malformation rate (n=2/89, 2.25%) was in keeping with the expected background rate (2-4%), and was not significantly increased for first trimester varenicline-exposed infants in comparison with non-exposed controls (vs. NTE: OR 2.02, 95%CI 0.166 to 17.9, vs. NRT/B: OR 0.874, 95%CI 0.0620 to 12.3). However, the small sample size produced very imprecise risk estimates.

Genetic spatial structure of European common hamsters (Cricetus cricetus)--a result of repeated range expansion and demographic bottlenecks.

The spatial genetic structure of common hamsters (Cricetus cricetus) was investigated using three partial mitochondrial (mt) genes and 11 nuclear microsatellite loci. All marker systems revealed significant population differentiation across Europe. Hamsters in central and western Europe belong largely to two allopatric mitochondrial lineages south and northwest of the Carpathian and Sudetes. The southern group, 'Pannonia', comprises populations inside the Carpathian basin (Czech Republic, Hungary) while the second group, 'North', includes hamsters from Belgium, the Netherlands, France, and Germany. Isolation of the lineages is maintained by a combination of geographical and ecological barriers. Both main phylogeographical groups show signs of further subdivision. North is separated into highly polymorphic central German and less polymorphic western populations, which most likely split during late glacial expansion (15,000-10,000 bp). Clock estimates based on haplotype distributions predict a divergence of the two major lineages 85,000-147,000 bp. Expansion times fall during the last glaciation (115,000-10,000 bp) corroborating fossil data, which identify Cricetus cricetus as characteristic of colder climatic phases. Despite the allopatry of mt haplotypes, there is an overlap of nuclear microsatellite alleles between phylogeographical units. Although there are strong evidence that Pannonian hamsters have persisted inside the Carpathian basin over the last 50,000 years, genetic differentiation among European hamsters has mainly been caused by immigration from different eastern refugia. Possible source populations are likely to be found in the Ukrainian and the southern Russian plains--core areas of hamster distribution. From there, hamsters have repeatedly expanded during the Quaternary.

A major CYP2D6 autoepitope in autoimmune hepatitis type 2 and chronic hepatitis C is a three-dimensional structure homologous to other cytochrome P450 autoantigens.

Liver-kidney microsomal antibodies type 1 (LKM) are a diagnostic marker for autoimmune hepatitis type 2 (AIH-2), however, LKM autoantibodies are also detected in a small percentage of patients with chronic hepatitis C. The major target of LKM antibodies as evidenced by indirect immunofluorescence is cytochrome P4502D6 (CYP2D6). Anti-CYP2D6 titers of 62 LKM positive sera, 196 sera of patients with hepatic and rheumatic diseases and 33 sera of healthy blood donors (BD) were determined by an in vitro transcription/in vitro translation assay (ITT). Twenty five out of 26 AIH-2 sera and 33/36 LKM positive hepatitis C virus (HCV) sera were anti-CYP2D6 positive by ITT and antibody titers were similar in both patient groups. Epitope mapping experiments were performed by a series of truncated CYP2D6 proteins and by single epitopes of 257-269, 321-351, 373-389 and 410-419 amino acid (aa) expressed as DHFR-fusion proteins in Escherichia coli. The major linear epitope consists of 257-269 aa. This epitope is recognized with a significantly higher prevalence (64%) in AIH-2 than in LKM sera from patients with chronic hepatitis C (24%) (p < 0.001). None of the other autoepitopes showed significant differences in the prevalence of recognition by sera from both patient groups. Minor binding sites consisted of 321-351 aa, which was recognized by less than 20% of LKM sera and in the C-terminal region of 350-494 aa, which was recognized by less than 5% of LKM sera Our study revealed an epitope of 321-379 an on CYP2D6, which was shown to be conformation dependent. It was recognized by the vast majority of LKM sera, specifically by 76% of sera from HCV positive LKM patients and also by 76% of sera from patients with AIH-2. This epitope is homologous to three-dimensional epitopes detected by autoantibodies directed against hepatic cytochromes P450s in drug induced hepatitis and to an autoepitope on CYP21B associated with adrenal failure.

Hepatic autoantigens in patients with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy.

BACKGROUND & AIMS: Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is caused by mutations of both copies of the autoimmune regulator (AIRE) gene. It is characterized by susceptibility to mucocutaneous candidiasis and multiple autoimmune lesions. A serious disease component is hepatitis. To identify diagnostic autoantibodies for APECED hepatitis, sera from 64 patients with APECED were screened for autoantibodies established in the diagnosis of idiopathic autoimmune hepatitis, and for autoantibodies against 10 cytochrome P450s. METHODS: Screening methods were indirect immunofluorescence, Western blot, Ouchterlony gel diffusion, enzyme-linked immunosorbent assay, and immunoprecipitation. RESULTS: Anti-liver microsomal antibodies were detected in 50% of the patients with APECED hepatitis and 11% of those without hepatitis. Prevalences of antinuclear, smooth muscle, anti-liver cytosol, anti-soluble liver protein/liver pancreas, and anti-CYP2D6 autoantibodies were 9%, 6%, 3%, 0%, and 0%, respectively. CYP1A1, CYP2B6, CYP1A2, and CYP2A6 were identified as autoantigens. Thirty percent of patients with anti-CYP2A6 and 100% of patients with anti-CYP1A2 were affected by hepatitis. Despite the high specificity of anti-CYP1A2 for APECED hepatitis, its sensitivity was low (50%). Anti-CYP2A6 and anti-CYP1A2 were not detected in patients with autoimmune hepatitis (N = 68) or nonhepatitic controls (N = 81). CONCLUSIONS: Anti-CYP1A2 is a highly specific but insensitive marker for APECED hepatitis. No clinical correlation was observed for anti-CYP2A6. Autoimmune hepatitis and APECED hepatitis are characterized by different molecular targets of autoantibodies with no overlap.

Contrast-dependent nonlinearities arise locally in a model of contrast-invariant orientation tuning.

We study a recently proposed "correlation-based," push-pull model of the circuitry of layer 4 of cat visual cortex. This model was previously shown to explain the contrast-invariance of cortical orientation tuning. Here we show that it can simultaneously account for several contrast-dependent (c-d) "nonlinearities" in cortical responses. These include an advance with increasing contrast in the temporal phase of response to a sinusoidally modulated stimulus; a change in shape of the temporal frequency tuning curve, so that higher temporal frequencies may give little or no response at low contrast but reasonable responses at high contrast; and contrast saturation that occurs at lower contrasts in cortex than in the lateral geniculate nucleus (LGN). In the context of the model circuit, these properties arise from a mixture of nonlinear cellular and synaptic mechanisms: short-term synaptic depression, spike-rate adaptation, contrast-induced changes in cellular conductance, and the nonzero spike threshold. The former three mechanisms are sufficient to explain the experimentally observed increase in c-d phase advance in cortex relative to LGN. The c-d changes in temporal frequency tuning arise as a threshold effect: voltage modulations in response to higher-frequency inputs are only slightly above threshold at lower contrast, but become robustly suprathreshold at higher contrast. The other three nonlinear mechanisms also play a crucial role in this result, allowing contrast dependence of temporal frequency tuning to coexist with contrast-invariance of orientation tuning. Contrast saturation, and the observation that responses to stimuli of increasing temporal frequency saturate at increasingly high contrasts, can be induced both by the model's push-pull inhibition and by synaptic depression. Previous proposals explained these nonlinear response properties by assuming contrast-invariant orientation tuning as a starting point, and adding normalization by shunting inhibition derived equally from cells of all preferred orientations. The present proposal simultaneously explains both contrast-invariant orientation tuning and these contrast-dependent nonlinearities and requires only processing that is local in orientation, in agreement with intracellular measurements.

Is the development of orientation selectivity instructed by activity?

Is the development of orientation selectivity in visual cortex instructed by the patterns of neural activity of input neurons? We review evidence as to the role of activity, review models of activity-instructed development, and discuss how these models can be tested. The models can explain the normal development of simple cells with binocularly matched orientation preferences, the effects of monocular deprivation and reverse suture on the orientation map, and the development of a full intracortical circuit sufficient to explain mature response properties including the contrast-invariance of orientation tuning. Existing experiments are consistent with the models, in that (a) selective blockade of ON-center ganglion cells, which will degrade or eliminate the information predicted to drive development of orientation selectivity, in fact prevents development of orientation selectivity; and (b) the spontaneous activities of inputs serving the two eyes are correlated in the lateral geniculate nucleus at appropriate developmental times, as was predicted to be required to achieve binocular matching of preferred orientations. However, definitive tests remain to be done to firmly establish the instructive rather than simply permissive role of activity and determine whether the retinotopically and center type-specific patterns of activity predicted by the models actually exist. We conclude by critically examining alternative scenarios for the development of orientation selectivity and maps, including the idea that maps are genetically prespecified.

The shortened dental arch concept and its implications for oral health care.

The minimum number of teeth needed to satisfy functional demands has been the subject of several studies. However, since functional demands--and consequently the number of teeth needed--can vary from individual to individual, this minimum number cannot be defined exactly. In general, occlusion of a complete dental arch is preferable. However, this goal might be neither attainable, for general, dental or financial reasons, nor necessary. Many studies demonstrate that shortened dental arches comprising the anterior and premolar regions can meet the requirements of a functional dentition. Consequently, when priorities have to be set, restorative therapy should be aimed at preserving the most strategic parts of the dental arch: the anterior and premolar regions. This also implies that in cases of a shortened dental arch, the prompt replacement of absent posterior molars by free-end removable partial dentures leads to overtreatment and discomfort. The shortened dental arch concept is based on circumstantial evidence: it does not contradict current theories of occlusion and fits well with a problem-solving approach. The concept offers some important advantages and may be considered a strategy to reduce the need for complex restorative treatment in the posterior regions of the mouth.

Epitope mapping of cytochrome P4502D6 autoantigen in patients with chronic hepatitis C during alpha-interferon treatment.

BACKGROUND/AIMS: Cytochrome P450 2D6 (CYP2D6) has been documented as the major target antigen of liver kidney microsomal autoantibodies type-1 (anti-LKM-1) in both autoimmune hepatitis type-2 (AIH-2) and hepatitis C (HCV). In HCV/anti-LKM-1-positive patients, the choice between alpha-interferon (alpha-IFN) or immunosuppression may be difficult. This study was conducted to evaluate the course and outcome of alpha-IFN therapy in HCV/anti-LKM-1-positive and -negative patients and the alterations in these autoantibody titers by the indirect immunofluorescence and a novel radioligand assay. Epitope mapping was also performed to screen for a potential shift in anti-LKM-1 binding towards small linear epitopes, which are more often detected in AIH-2 patients. METHODS: Twenty-one patients with HCV infection received alpha-IFN. Seven patients were anti-LKM-1 positive (study group) and 14 patients were anti-LKM-1 negative (disease control group). Anti-CYP2D6 detection was based on immunoprecipitation of [35S]-methionine-labeled CYP2D6 recombinant protein (rCYP2D6) produced by in vitro transcription/translation. RESULTS: Four out of seven (57%) patients in the study group and 5/14 (36%) in the disease control group initially responded, but subsequently relapsed. During follow-up, alanine aminotransferase significantly increased in the study group compared to the disease control group (p<0.01). A slight increase, followed by a plateau of autoantibody titers was recorded by the radioligand assay and by indirect immunofluorescence during therapy and follow-up in most cases. In one patient, however, gamma-globulins and anti-LKM-1 titers increased, reaching very high levels (1:40 960). alpha-IFN was interrupted and immunosuppression was started. HCV/anti-CYP2D6 positive sera recognized CYP2D6 expressed in E. coli and two truncated proteins (aa 250-494 and 321-494). Two out of seven sera, in addition reacted with a small linear epitope of aa 257-269 (one of which also reacted with a C-terminal domain of aa 350-494). CONCLUSIONS: A rather mild deterioration in liver disease was observed in only 1/7 HCV/anti-LKM-1-positive patients during alpha-IFN treatment. This patient showed high anti-CYP2D6 titers before the initiation of therapy, a sharp increase in anti-LKM-1 titers during treatment, and reactivities to a small linear epitope and an infrequently recognized C-terminal domain of CYP2D6. After switching to immunosuppressive treatment, a complete and sustained response was recorded. Further prospective studies from many centers are needed to define whether these features have general, clinical significance or not.

The nucleotide sequence of Saccharomyces cerevisiae chromosome V.

Here we report the sequence of 569,202 base pairs of Saccharomyces cerevisiae chromosome V. Analysis of the sequence revealed a centromere, two telomeres and 271 open reading frames (ORFs) plus 13 tRNAs and four small nuclear RNAs. There are two Tyl transposable elements, each of which contains an ORF (included in the count of 271). Of the ORFs, 78 (29%) are new, 81 (30%) have potential homologues in the public databases, and 112 (41%) are previously characterized yeast genes.

Fit of direct retainers in removable partial dentures after 8 years of use.

In a cross-sectional study the fit of direct retainers was assessed after 8 years of use. A total of 101 metal frame removable partial dentures (RPD) were investigated, including 54 extension base prostheses without any tooth supported replacement and 47 tooth supported prostheses that replaced only premolars and molars. Of the frameworks studied, about 60% of the clasps showed a space between retainers and abutments. Logistic regression analyses demonstrated that the age of the RPD and the type of opposing dentition significantly influenced the fit of the clasps. The relative risks and a backward regression analysis revealed that the variable non-rigid extension base RPD had the greatest influence on clasp fit. It was concluded that in extension base RPDs a rigid design should be preferred.

Dentists' attitudes to the shortened dental arch concept.

The aim of restorative dentistry in high-risk groups tends to shift over time from the preservation of complete dental arches towards the preservation of functional dental arches, using a functionally oriented approach. An example of this approach, aimed at limited treatment goals, is the shortened dental arch (SDA) concept. The objective of this study was to investigate dentists' attitudes to the SDA concept in general practice. A questionnaire seeking information pertaining to the attitudes and application of the SDA concept in clinical practice was sent to all dentally qualified members of staff in the field of restorative dentistry in the Nijmegen School of Dentistry (n = 64). From a 64% response, it was found that all but one of the respondents view the SDA concept as having a useful place in clinical practice. Although the respondents indicated only regular or occasional use of SDA in < 10% of patients, the outcome of SDA management was generally satisfactory or at least sufficient, notably in the care of special category patients. The findings support the view that the SDA concept has a role in contemporary clinical practice.

[Occlusion repair or occlusion loss? Results of preliminary treatment as the starting point]. / Occlusieherstel of occlusieverlies? Resultaat van voorbereidende behandeling geldt als uitgangspunt.

Epidemiological data confirm that the number of elderly with an impaired dentition is increasing. The treatment of patients with an impaired dentition should be focused on maintaining oral function during life-time. However this goal is hardly achievable because of the complicating factors in an impaired dentition. This article describes the Nijmegen Dental School approach in the treatment of impaired dentition and stresses the importance of the preliminary treatment in order to answer the question whether restoring or extracting teeth is the most appropriate treatment modality.

[Partial models in fixed prosthodontics]. / Partiële modellen, indicatie en aandachtspunten.

In general there is consensus regarding the required criteria for crown- and bridge restorations. However, the variety in methods used for their fabrication is large. Textbooks and courses tend to advocate the use of full arch impressions without supplying objective data indicating better clinical behaviour of these restorations compared with the use of quadrant impressions. This article presents advantages, disadvantages, indication and essential steps when using quadrant models.

Ten-year evaluation of removable partial dentures: survival rates based on retreatment, not wearing and replacement.

From a group of 1480 patients, 1036 were treated with metal frame removable partial dentures (RPDs) at least 5 years before this analysis. Of those, 748 patients who wore 886 RPDs were followed up between 5 and 10 years; 288 patients dropped out. The 748 patients in the study groups were wearing 703 conventionally designed metal frame RPDs and 183 RPDs with attachments. When dropout patients and patients who remained in the study were compared, no differences were shown in the variables analyzed, which indicated that the dropouts did not bias the results. Survival rates of the RPDs were calculated by different failure criteria. Taking abutment retreatment as failure criterion, 40% of the conventional RPDs survived 5 years and more than 20% survived 10 years. In RPDs with attachments crowning abutments seemed to retard abutment retreatment. Fracture of the metal frame was found in 10% to 20% of the RPDs after 5 years and in 27% to 44% after 10 years. Extension base RPDs needed more adjustments of the denture base than did tooth-supported base RPDs. Taking replacement or not wearing the RPD as failure criteria, the survival rate was 75% after 5 years and 50% after 10 years (half-life time). The treatment approach in this study was characterized by a simple design of the RPD and regular surveillance of the patient in a recall system.