Dihydropyrimidine Dehydrogenase Testing prior to Treatment with 5-Fluorouracil, Capecitabine, and Tegafur: A Consensus Paper

Background: 5-Fluorouracil (FU) is one of the most commonly used cytostatic drugs in the systemic treatment of cancer. Treatment with FU may cause severe or life-threatening side effects and the treatment-related mortality rate is 0.2–1.0%. Summary: Among other risk factors associated with increased toxicity, a genetic deficiency in dihydropyrimidine dehydrogenase (DPD), an enzyme responsible for the metabolism of FU, is well known. This is due to variants in the DPD gene (DPYD). Up to 9% of European patients carry a DPD gene variant that decreases enzyme activity, and DPD is completely lacking in approximately 0.5% of patients. Here we describe the clinical and genetic background and summarize recommendations for the genetic testing and tailoring of treatment with 5-FU derivatives. The statement was developed as a consensus statement organized by the German Society for Hematology and Medical Oncology in cooperation with 13 medical associations from Austria, Germany, and Switzerland. Key Messages: (i) Patients should be tested for the 4 most common genetic DPYD variants before treatment with drugs containing FU. (ii) Testing forms the basis for a differentiated, risk-adapted algorithm with recommendations for treatment with FU-containing drugs. (iii) Testing may optionally be supplemented by therapeutic drug monitorin

Incidence of sexually transmitted infections and association with behavioural factors: Time-to-event analysis of a large pre-exposure prophylaxis (PrEP) cohort.

OBJECTIVES Our objective was to obtain long-term data on the incidence of sexually transmitted infections (STIs) and their association with behavioural factors after widespread pre-exposure prophylaxis (PrEP) implementation. METHODS This was a time-to-event analysis of a national PrEP cohort in Switzerland (SwissPrEPared study). Participants were people without HIV interested in taking PrEP with at least two STI screening visits. Primary outcomes were incidence rate of gonorrhoea, chlamydia, and syphilis. The association between behavioural factors and STI diagnosis was expressed using hazard ratios. We adjusted for testing frequency and calendar year. RESULTS This analysis included 3907 participants enrolled between April 2019 and April 2022, yielding 3815.7 person-years of follow-up for gonorrhoea (15 134 screenings), 3802.5 for chlamydia (15 141 screenings), and 3858.6 for syphilis (15 001 screenings). The median age was 39 years (interquartile range [IQR] 32-47), 93.8% (n = 3664) identified as men who have sex with men (MSM). The incidence was 22.8 (95% confidence interval [CI] 21.3-24.4) per 100 person-years for gonorrhoea, 26.3 (95% CI 24.7-28.0) for chlamydia, and 4.4 (95% CI 3.8-5.1) for syphilis. Yearly incidence rates decreased between 2019 (all bacterial STIs: 81.6; 95% CI 59.1-109.9) and 2022 (all bacterial STIs: 49.8; 95% CI 44.6-55.3). Participants reporting chemsex substance use were at higher risk of incident STIs, as were those reporting multiple sexual partners. Younger age was associated with a higher risk of gonorrhoea and chlamydia. CONCLUSIONS Incidence rates of bacterial STIs decreased over time. Young MSM, those with multiple partners, and those using chemsex substances were at increased risk of STIs

Incidence of sexually transmitted infections and association with behavioural factors: Time-to-event analysis of a large pre-exposure prophylaxis (PrEP) cohort

OBJECTIVES: Our objective was to obtain long-term data on the incidence of sexually transmitted infections (STIs) and their association with behavioural factors after widespread pre-exposure prophylaxis (PrEP) implementation. METHODS: This was a time-to-event analysis of a national PrEP cohort in Switzerland (SwissPrEPared study). Participants were people without HIV interested in taking PrEP with at least two STI screening visits. Primary outcomes were incidence rate of gonorrhoea, chlamydia, and syphilis. The association between behavioural factors and STI diagnosis was expressed using hazard ratios. We adjusted for testing frequency and calendar year. RESULTS: This analysis included 3907 participants enrolled between April 2019 and April 2022, yielding 3815.7 person-years of follow-up for gonorrhoea (15 134 screenings), 3802.5 for chlamydia (15 141 screenings), and 3858.6 for syphilis (15 001 screenings). The median age was 39 years (interquartile range [IQR] 32-47), 93.8% (n = 3664) identified as men who have sex with men (MSM). The incidence was 22.8 (95% confidence interval [CI] 21.3-24.4) per 100 person-years for gonorrhoea, 26.3 (95% CI 24.7-28.0) for chlamydia, and 4.4 (95% CI 3.8-5.1) for syphilis. Yearly incidence rates decreased between 2019 (all bacterial STIs: 81.6; 95% CI 59.1-109.9) and 2022 (all bacterial STIs: 49.8; 95% CI 44.6-55.3). Participants reporting chemsex substance use were at higher risk of incident STIs, as were those reporting multiple sexual partners. Younger age was associated with a higher risk of gonorrhoea and chlamydia. CONCLUSIONS: Incidence rates of bacterial STIs decreased over time. Young MSM, those with multiple partners, and those using chemsex substances were at increased risk of STIs

Beziehung von Hintergrundaktivität, Variabilität evozierter Aktivität und behaviorale Leistung im menschlichen Gehirn

The question of the function and meaning of brain rhythms, especially in the processing of stimuli and generation of stimulus–based (evoked) brain signals, has long been and still is a topic of great interest and debate. We tested different aspects of putative interactions between ongoing activity, evoked activity, and behavioral performance, using electroencephalography (EEG) and, partly, simultaneous functional magnetic resonance imaging (fMRI). We employed novel, online data analysis approaches allowing to maximize the signal of interest and the difference across conditions in a noisy, artefact–prone en- vironment. We discovered interactions between ongoing α and μ rhythms and the re- spective evoked potentials (EPs) in the examined sensory systems, indicating their involvement in stimulus processing and higher cognitive functions. Furthermore, we found effects of α rhythm power on evoked fMRI responses, both by linear superposition and by more complex, non–linear relationships, helping to explain the source of trial–by–trial variance in functional neuroimaging data and cast further light on the origin and nature of these rhythms. Finally, we observed increased spatial acuity and changes in resting–state functional connectivity of the μ rhythm after a specific form of high–frequency repetitive somatosensory stimulation, showing that this form of stimulation changes intrinsic network properties of distant brain regions without the need for active participation of the subject. These data might provide a neurophysiological basis for the previously observed improvements in sensorimotor training in response to that stimulation, which make it a candidate for rehabilitation paradigms for e.g. stroke patients. Importantly, it also shows that assessment of functional connectivity might be used as a tool to study the efficacy of different sensory and motor training paradigms.Die Frage nach der Funktion und Bedeutung von Hintergrundrhythmen, insbesondere in Bezug auf die Verarbeitung von Reizen und die Entstehung stimulusbezogener (evozierter) Hirnsignale, ist seit langem Gegenstand wissenschaftlichen Interesses. Wir haben mittels Elektroenzephalographie (EEG) sowie funktioneller Magnetresonanztomographie (fMRT) verschiedene Aspekte der Interaktion von Hintergrundaktivität, evozierter Aktivität, und Verhalten untersucht. Dabei wurde ein neuartiger Echtzeit-Datenanalyse-Ansatz gewählt, um in einer artefaktanfälligen Umgebung die Signalstärke sowie den Unterschied zwischen experimentellen Bedingungen zu maximieren. Wir fanden Interaktionen von spontanen α- und μ-Rhythmen und den jeweiligen evozierten Potentialen (EPs) der untersuchten sensorischen Systeme. Diese Interaktionen deuten auf eine Beteiligung der Rhythmen an der Verarbeitung von Reizen und an höheren kognitiven Funktionen hin. Weiterhin fanden wir Effekte des α-Rhythmus auf evozierte fMRT-Antworten, sowohl durch lineare Superposition als auch durch nicht-lineare Interaktion. Diese Ergebnisse helfen, die hohe Variabilität neuronaler Antworten auf konstante Reize zu erklären, und ermöglichen weitere Einsicht in die Herkunft und Funktion von Hintergrundrhythmen. Ausserdem konnten wir zeigen, dass eine bestimmte Art hochfrequenter, somatosensorischer Stimulation, neben einer Verbesserung taktiler Diskriminationsfähigkeit Veränderungen in der funktionellen Konnektivität des μ-Rhythmus im Ruhezustand bewirkt. Diese Stimulation verändert Netzwerkeigenschaften von Hirnregionen ohne die Notwendigkeit aktiver Teilnahme des Probanden. Diese geänderten Netzwerkeigenschaften sind möglicherweise die Grundlage für die beschriebenen behavioralen Verbesserungen, die diese Art der Stimulation als mögliche Behandlung für z.B. durch Schlaganfall bedingte sensomotorische Ausfälle erscheinen lässt. Auch könnte funktionelle Konnektivität herangezogen werden, um die Effektivität verschiedener sensomotorischer Trainingsprotokolle zu beurteilen

Hippocampal theta phases organize the reactivation of large-scale electrophysiological representations during goal-directed navigation

Humans are adept in simultaneously following multiple goals, but the neural mechanisms for maintaining specific goals and distinguishing them from other goals are incompletely understood. For short time scales, working memory studies suggest that multiple mental contents are maintained by theta-coupled reactivation, but evidence for similar mechanisms during complex behaviors such as goal-directed navigation is scarce. We examined intracranial electroencephalography recordings of epilepsy patients performing an object-location memory task in a virtual environment. We report that large-scale electrophysiological representations of objects that cue for specific goal locations are dynamically reactivated during goal-directed navigation. Reactivation of different cue representations occurred at stimulus-specific hippocampal theta phases. Locking to more distinct theta phases predicted better memory performance, identifying hippocampal theta phase coding as a mechanism for separating competing goals. Our findings suggest shared neural mechanisms between working memory and goal-directed navigation and provide new insights into the functions of the hippocampal theta rhythm

Changes in mental and sexual health among MSM using HIV pre-exposure prophylaxis during the SARS-CoV-2 pandemic: longitudinal analysis of the SwissPrEPared cohort study.

BACKGROUND: Changes in mental and sexual health among men having sex with men (MSM) due to the SARS-CoV-2 pandemic remain unclear. METHODS: Design: Longitudinal analysis of an ongoing, multicentre, pre-exposure prophylaxis (PrEP) cohort (NCT03893188) in Switzerland. Participants: HIV-negative MSM aged ≥18 who completed at least one questionnaire before and one after the start of the SARS-CoV-2 pandemic. Outcomes: Primary: mental health, defined as anxiety and depression scores assessed by the Patient Health Questionnaire-4. Secondary: sexual behaviour, well-being, PrEP use and disruption of care. Outcomes were assessed over seven periods corresponding to different SARS-CoV-2 prevention measures in Switzerland. We performed pairwise comparisons between periods (Wilcoxon signed rank test). RESULTS: Data from 1,043 participants were included. Whilst anxiety scores remained stable over time, depression scores worsened in the second wave and the second lockdown period compared to pre-pandemic scores. This was confirmed by pairwise comparisons (pre-SARS-CoV-2/second wave and pre-SARS-CoV-2/second lockdown: p <0.001). Downward trends in sexual activity,sexualized substance use, and a switch from daily to "event-driven" PrEP were found. Disruption of care affected 42.6% (790/1856) of daily PrEP users' follow-up visits. CONCLUSION: In this longitudinal analysis of a PrEP cohort enrolling MSM, depression scores worsened in the second wave and the second lockdown compared to the pre-pandemic period

TFAP2E-DKK4 and chemoresistance in colorectal cancer

Chemotherapy for advanced colorectal cancer leads to improved survival; however, predictors of response to systemic treatment are not available. Genomic and epigenetic alterations of the gene encoding transcription factor AP-2 epsilon (TFAP2E) are common in human cancers. The gene encoding dickkopf homolog 4 protein (DKK4) is a potential downstream target of TFAP2E and has been implicated in chemotherapy resistance. We aimed to further evaluate the role of TFAP2E and DKK4 as predictors of the response of colorectal cancer to chemotherapy