Monitoring of Argatroban in Critically Ill Patients: A Prospective Study Comparing Activated Partial Thromboplastin Time, Point-of-Care Viscoelastic Testing with Ecarin Clotting Time and Diluted Thrombin Time to Mass Spectrometry.

BACKGROUND: The direct thrombin inhibitor argatroban is indicated for the treatment of heparin-induced thrombocytopenia II, but it is also used off-label to treat critically ill patients presenting with heparin resistance, severe antithrombin deficiency, or hypercoagulability. Direct drug monitoring is not routinely available, and argatroban dosing is mainly based on global coagulation assays such as activated partial thromboplastin time (PTT) or diluted thrombin time (TT), both of which have limitations in patients with hypercoagulability. METHODS: Blood samples were obtained from critically ill patients treated with argatroban. Activated PTT and diluted TT were measured with a STA R Max3 analyzer (STAGO Deutschland GmbH, Germany) using an argatroban-calibrated kit. Ecarin clotting time was measured using a point-of-care viscoelastic test device. Liquid chromatography with tandem mass spectrometry was performed using a reversed-phase column, a solvent gradient, and an API4000 mass spectrometer with electrospray. Correlation was described using Pearson correlation coefficient r and Bayesian multilevel regression to estimate relationships between outcomes and covariates. RESULTS: From June 2021 to March 2022, 205 blood samples from 22 patients were analyzed, allowing for 195 activated PTT-liquid chromatography with tandem mass spectrometry comparisons, 153 ecarin clotting time-liquid chromatography with tandem mass spectrometry comparison, and 105 diluted TT-liquid chromatography with tandem mass spectrometry comparisons. Compared to liquid chromatography with tandem mass spectrometry, performance of argatroban quantification was best for diluted TT (r = 0.91), followed by ecarin clotting time (r = 0.58) and activated PTT (r = 0.48). Regression analysis revealed that patients with sepsis were more prone to argatroban overdosing (coefficient, 4.194; 95% credible interval, 2.220 to 6.792). CONCLUSIONS: Although activated PTT monitoring of argatroban is the most commonly used test, in critically ill patients, diluted TT provides more precise measurements. Alternately, point-of-care viscoelastic ecarin clotting time also provides guidance for argatroban dosing to identify overdosing if available. The data also suggested that patients with sepsis are at greater risk for argatroban overdosing.

Development and validation of a liquid chromatography-tandem mass spectrometry method for the quantification of the acetyl-coenzyme A competitive p300/CBP catalytic inhibitor A-485 in biological samples.

The small molecule A-485 competitively inhibits the histone acetyltransferase domain of CBP (cyclic-adenosine monophosphate response element-binding protein)/p300. Apart from its antineoplastic activity, researchers are exploring its potential benefits in treating osteoporosis and its impact on energy metabolism. However, so far, only limited pharmacokinetic data are available, and the crucial determination of A-485 concentration in various biological materials with small sample volumes remains unpublished. A rapid and sensitive LC-tandem mass spectrometry method has been developed and validated to quantify A-485 in mouse serum and tissue. In this method, serum samples underwent precipitation with acetonitrile, while cell lysates were appropriately diluted. The determination of A-485 utilized a reversed-phase column with a mobile phase gradient, and detection was carried out in multiple reaction monitoring mode. The lower standard sample, with a concentration of 7.8 ng/mL, served as the lower limit of quantification, while the upper standard was established at 1000 ng/mL. A-485 concentrations were assessed in both serum samples and the lysate of all examined tissues, revealing swift metabolic clearance. The analytical method outlined here is deemed appropriate for subsequent studies. The ability to measure the active ingredient in various compartments facilitates the determination of accurate pharmacokinetic parameters. In the event of human use of A-485, the analysis method can be seamlessly transferred to human samples.

Cyclic changes of sensory parameters in migraine patients.

BACKGROUND: Migraine shows a cyclic pattern with an inter-ictal-, a pre-ictal, an ictal- and a post-ictal phase. We aimed to examine changes in psychophysical parameters during the migraine cycle. METHODS: The perception of nociceptive and non-nociceptive stimuli and an electrically induced axon-reflex-erythema were assessed in 20 healthy controls and 14 migraine patients on five consecutive days according to different phases of the migraine cycle. Pain was rated three times during a 10-second electrical stimulus. The size of the axon-reflex-erythema was determined using laser-Doppler-imaging. Intensity and hedonic estimates of odours presented by Sniffin' Sticks were rated. RESULTS: In healthy controls, no significant changes over the test days were observed. In migraine patients pain thresholds at the head decreased with an ictal minimum. Less habituation after five seconds of stimulation at the head was found pre-ictally, whereas reduced habituation to 10-second electrical stimulation was present in all phases. The axon-reflex-erythema size showed an inter-ictal-specific minimum at the head. odours were perceived ictally as more unpleasant and intense. CONCLUSIONS: Somatosensory functions, pain thresholds and habituation as predominantly central parameters, axon-reflex-erythema as a peripheral function of trigeminal neurons and odour perception as a predominantly extra-thalamic sensation change specifically over the migraine cycle indicating complex variations of neuronal signal processing.

Retronasal olfactory testing in early diagnosed and suspected COVID-19 patients: a 7-week follow-up study.

OBJECTIVES: Olfactory dysfunction (OD) constitutes a major symptom in Coronavirus Disease 2019 (COVID-19). Yet, most data on smell loss rely on the evaluation of orthonasal olfactory performance. Therefore, we aimed to assess retronasal olfactory function (ROF) over a period of several weeks in proven and suspected COVID-19 patients. METHODS: One hundred and one subjects with suspected or laboratory-proven COVID-19 participated in this study. In patients with OD no longer than 4 weeks after initial symptom onset, ROF was measured with the 7-item Candy Smell Test ten times over 7 weeks. RESULTS: Olfactory function was decreased in the investigated patients and remained decreased over the course of 7 weeks. One-way repeated-measures ANOVA revealed no significant difference of ROF between different measurement time points. However, self-assessment of smell and flavour improved significantly (p = 0.013 and p = 0.043), but did not show complete recovery. CONCLUSION: The current investigation revealed significant improvements in subjective smell and flavour perception over the course of 7 weeks in proven and suspected COVID-19 patients suffering from acute OD. However, objectively measured ROF based on a screening test revealed no improvements within the same time period.

Long-lasting olfactory dysfunction in COVID-19 patients.

OBJECTIVES: Olfactory dysfunction (OD) is a common symptom of Coronavirus Disease 2019 (COVID-19). Although many patients have been reported to regain olfactory function within the first month, long-term observation reports vary. Therefore, we aimed to assess the course of chemosensory function in patients diagnosed with COVID-19 within 3-15 months after the infection. METHODS: One hundred and two patients (71 females and 31 males; mean age 38.8 years) diagnosed with laboratory-confirmed COVID-19 and subjective OD participated in this single-center study 111-457 days after onset of OD. Patients first performed chemosensory tests at home, followed by psychophysical testing (Sniffin' Sticks (TDI), 27-item Candy Smell Test (CST), Taste Strips Test (TST)) in the clinic. Questionnaires regarding importance of olfaction (IOQ) and olfactory-specific quality of life (QOD) were applied at both timepoints. RESULTS: After a mean 216 days (SD 73; range 111-457) between OD onset and follow-up testing, the mean Sniffin' Sticks (TDI) score was 27.1 points (SD 5.8; range 4.25-38.5): 4.0% were anosmic, 72.5% hyposmic, and 23.5% normosmic. At follow-up testing, 73.5% of patients reported improvement, 5.9% deterioration, and 20.6% no change in OD. Moreover, full recovery of self-perceived smell, flavor, and taste was not observed. According to questionnaires, the individual importance of smell did not change, but participants showed improvement in OD-related quality of life (p < 0.001) and had increased parosmia scores (p = 0.014) at follow-up. CONCLUSION: Our results show that long-lasting OD after SARS-CoV-2 infection is a common symptom. The majority of patients had OD in the range of hyposmia, which was confirmed by comprehensive smell tests.

[Diagnosis and Therapy of Olfactory Dysfunction - State of the ArtThe neglected sense-new evidence highlights the significance of the human sense of smell]. / Riechstörungen evidenzbasiert diagnostizieren und behandeln. Der unterschätzte Sinn ­ neue Erkenntnisse belegen die Bedeutung und Leistungsfähigkeit des menschlichen Geruchssinns.

Recent research shows that the human sense of smell seems to be more efficient than previously believed and to have a major impact on our health condition and quality of life. During the COVID-19 pandemic, an increased clinical interest has become evident for the SARS-CoV-2 related impact on olfactory function. This article highlights important aspects in the diagnosis and therapy of the chemical senses.

Ortho- and retronasal olfactory performance in rhinosurgical procedures: a longitudinal comparative study.

PURPOSE: Testing olfaction should be an integral part of a clinical work-up in rhinosurgical procedures. Importantly, intact olfactory experience also includes retronasally perceived odors (retronasal olfaction). This study aimed at comprehensively assessing olfaction in patients undergoing rhinosurgical procedures in a comparative manner and evaluating relations to patient-reported outcome measurements (PROMs). METHODS: Each nostril odor threshold and discrimination, and birhinal identification were tested using Sniffin' Sticks in 14 subjects assigned for septoplasty (SP), 21 for septorhinoplasty (SRP), and 30 for endoscopic sinus surgery (ESS). The 27-Candy-Smell-Test was used to quantify retronasal abilities. Tests were repeated 3 months after surgery. RESULTS: Olfactory dysfunction was preoperatively present in 21% of SP, in 47.6% of SRP, and in 80% of ESS patients. Odor threshold side differences were most frequently found in SRP. Frequently, SRP and ESS patients showed severely impaired retronasal olfaction. Half of included subjects re-visited after 3 months, but olfactory function did not improve overall and rarely on an individual basis to a meaningful extent. Subjective ratings on nasal patency and PROMs were not associated with olfaction nor with changes in olfactory scores. CONCLUSION: Olfactory function can decisively be impaired a priori not only in patients awaiting sinus surgery, but also in those assigned for functional septorhinoplasty. This impairment may not improve in the short term, which has to be taken into account in patient counseling. This study adds to the current literature on olfaction in rhinosurgery with the extension of retronasal testing.

Decrease and Recovery of Olfactory and Gustatory Function in a Case of SARS-CoV-2 Infection.

Self-reported chemosensory dysfunction in severe acute respiratory syndrome coronavirus 2 patients is common. We present a case of reversible smell loss in a young patient with mild coronavirus disease 2019 infection assessed with established testing methods over a period of 8 weeks.

Flavor education and training in olfactory dysfunction: a pilot study.

PURPOSE: Olfactory training is recommended in olfactory dysfunction (OD) showing promising results. OD patients frequently ask for training modifications in the hope of a better outcome. Also, a lack of knowledge of the flavor system is evident. This investigation sought to implement flavor education (FE) and encourage patients to experience flavors in terms of a flavor training (FT). METHODS: In included patients (n = 30), OD was either of postinfectious (86.7%) or posttraumatic (13.3%) cause. Chemosensory abilities were tested orthonasally (using Sniffin Sticks = TDI) and retronasally (using the Candy Smell Test = CST). Key points of flavor perception were demonstrated in an educative session. Subjects were instructed to consciously experience flavors out of a list of 50. Effects of FT were explored in two groups (group A and B), with group B starting FT 17 weeks later. RESULTS: FE was appreciated and drop-out rate stayed very low (one participant). Compliance was high and 30.4 ± 12.9 flavors were tried. Overall TDI scores improved in 10 patients (6 group A, 4 group B) in a clinically significant way (> 5.5). For group A (starting FT earlier) rm-ANOVA showed a significant effect of session (timepoint) on CST (p < 0.01). CONCLUSION: Flavor education is demonstrated as feasible and appreciated in a clinical setting. FT seems to be a welcomed second-line therapy in patients with olfactory dysfunction. This study shows beneficial trends of FT; however, further studies with larger sample sizes and standardized training protocols are needed.

Spatiotemporal Pattern of Human Cortical and Subcortical Activity during Early-Stage Odor Processing.

The dynamics of early-stage cortical and subcortical responses in the human brain to odor stimulation are currently unknown. The objective of the present study was to analyze spatiotemporal patterns of human brain activity during odor perception using magnetoencephalography (MEG). In 12 normosmic healthy subjects, we investigated the onset of brain activity in relation to ipsilateral and contralateral stimulation with 2 odorants. Olfactory stimuli (200ms duration) were applied using an olfactometer, and brain activity was recorded with a 248-magnetometer whole-head MEG system. Olfactory responses were identified shortly (within 150ms) after stimulus onset in both hemispheres. Stimulation on the ipsilateral side yielded signals earlier (starting at 90ms) compared with contralateral stimulation in the primary olfactory cortex, hippocampus, parahippocampal gyrus, amygdala, and orbitofrontal cortex ( P < 0.001). The duration and peak amplitude of olfactory evoked magnetic fields were found to increase with increasing poststimulus time in the majority of the investigated cortical structures ( P ≤ 0.019 and P ≤ 0.021). The study showed the locations of early olfactory brain activity in humans within 150ms after the onset of stimuli. Olfactory activation is processed on the ipsilateral side of stimulation in early stages. After a short delay of 34ms a corresponding pattern of activation was also seen in the contralateral hemisphere, indicating the functional connectivity between the 2 hemispheres in the anterior commissure.

A new extension to the Taste Strips test.

OBJECTIVE: Assessment of gustatory function in human subjects using the 'taste strips' test is an easy and validated procedure. The aim of this study was to extend this test in order to detect subjects with superior gustatory sensitivity. METHODS: The investigation included 134 subjects (29.5±12.6 years, range 18-84 years) with normal gustatory function. Four concentrations of sweet, sour, salty, and bitter were augmented with additional low concentrations (sweet: 25/12.5 mg/ml sucrose; sour: 27/15 mg/ml citric acid; salty: 6.4/2.6 mg/ml sodium chloride, bitter: 0.15/0.06 mg/ml quinine hydrochloride), resulting in a maximum extended taste score (ETS) of 24. RESULTS: The mean ETS was 14.5 ± 3.2. Specifically, it was 4.5 ± 1.2 for sweet, 2.8 ± 1.0 for sour, 4.0 ± 1.3 for salty, and 3.2 ± 1.2 for bitter. In contrast to the original version of the taste strips test, no ceiling effect was observed. Cluster analysis separated three groups of subjects by ETS, whereas test scores derived from the original four concentrations were insufficient to discriminate the subgroup with higher gustatory sensitivity. CONCLUSIONS: The extended taste strips test seems to be a useful tool for the detection of patients with low gustatory thresholds for sweet, sour, salty, or bitter taste.

Germline genetic variations in methotrexate candidate genes are associated with pharmacokinetics, toxicity, and outcome in childhood acute lymphoblastic leukemia.

The pharmacogenetics of methotrexate (MTX) was investigated in a large cohort of pediatric patients with acute lymphoblastic leukemia (ALL). Four hundred ninety-nine children with ALL from the ALL-BFM (Berlin-Frankfurt-Münster) 2000 trial who received 1996 courses of MTX at 5 g/m(2) were genotyped for 8 single nucleotide polymorphisms in 5 candidate genes of the MTX/folate pathway. Patients' MTX pharmacokinetics, MTX toxicities, and outcomes were correlated with the genotypes. The interindividual variability in MTX kinetics had a substantial genetic component between 68% and 75%. The SLCO1B1 rs4149056 variant was significantly associated with MTX kinetics. In a multiple regression model, MTX area under the concentration time curve (AUC)0-48h increased by 26% (P < .001) per SLCO1B1 rs4149056 C allele. MTX AUC0-48h was a significant predictor of overall toxic adverse events during MTX courses (R(2) = 0.043; P < .001), whereas the thymidylate synthase rs34743033 tandem repeat polymorphism was predictive of stomatitis (R(2) = 0.018; P = .009), a frequent side effect of high-dose MTX. Multiple Cox regression analyses revealed an association of minimal residual disease (hazard ratio 7.3; P < .001) and methylenetetrahydrofolate reductase rs1801131 (hazard ratio 3.1; P = .015) with event-free survival in the ALL-BFM 2000 study population. Genetic variations substantially influence the kinetics and response to high-dose MTX therapy in childhood ALL.

N(1)-methylnicotinamide as an endogenous probe for drug interactions by renal cation transporters: studies on the metformin-trimethoprim interaction.

PURPOSE: N(1)-methylnicotinamide (NMN) was proposed as an in vivo probe for drug interactions involving renal cation transporters, which, for example, transport the oral antidiabetic drug metformin, based on a study with the inhibitor pyrimethamine. The role of NMN for predicting other interactions with involvement of renal cation transporters (organic cation transporter 2, OCT2; multidrug and toxin extrusion proteins 1 and 2-K, MATE1 and MATE2-K) is unclear. METHODS: We determined inhibition of metformin or NMN transport by trimethoprim using cell lines expressing OCT2, MATE1, or MATE2-K. Moreover, a randomized, open-label, two-phase crossover study was performed in 12 healthy volunteers. In each phase, 850 mg metformin hydrochloride was administered p.o. in the evening of day 4 and in the morning of day 5. In phase B, 200 mg trimethoprim was administered additionally p.o. twice daily for 5 days. Metformin pharmacokinetics and effects (measured by OGTT) and NMN pharmacokinetics were determined. RESULTS: Trimethoprim inhibited metformin transport with K i values of 27.2, 6.3, and 28.9 µM and NMN transport with IC50 values of 133.9, 29.1, and 0.61 µM for OCT2, MATE1, and MATE2-K, respectively. In the clinical study, trimethoprim increased metformin area under the plasma concentration-time curve (AUC) by 29.5 % and decreased metformin and NMN renal clearances by 26.4 and 19.9 %, respectively (p ≤ 0.01). Moreover, decreases of NMN and metformin renal clearances due to trimethoprim correlated significantly (r S=0.727, p=0.010). CONCLUSIONS: These data on the metformin-trimethoprim interaction support the potential utility of N(1)-methylnicotinamide as an endogenous probe for renal drug-drug interactions with involvement of renal cation transporters.

Chemo-somatosensory evoked potentials: a sensitive tool to assess conditioned pain modulation?

UNLABELLED: Abstract Background: Chemo-somatosensory evoked potentials (CSSEPs) elicited by chemical stimulation (CO2 gas) of the nasal mucosa have been shown to be sensitive enough to pick up even weak analgesic effects. With the present study we wanted to investigate whether CSSEPs are also a sensitive tool to capture endogenous pain inhibitory mechanisms elicited by conditioned pain modulation (CPM; where a first conditioning stimulus reduces the sensitivity for a second test stimulus) with a conditioning stimulus of rather low noxious load. METHODS: Seventeen healthy participants were tested for CPM effects (conditioning stimulus: tonic heat pain with intensities around the pain threshold induced via a thermode; test stimulus: chemonasal stimulation (73% and 78% CO2)) on CSSEPs and on self-report ratings. RESULTS: We found significant CPM effects in the CSSEPS, with reduced amplitudes and prolonged latencies at several electroencephalogram (EEG) recording positions when using the lower CO2 concentration (73% CO2). In contrast to the visible inhibitory effects on the CSSEPs, subjective ratings of the test stimulus did not reflect CPM action. DISCUSSION: The experimental pain model using CO2 stimuli to elicit CSSEPs proved to be sensitive enough to capture weak CPM effects elicited by a conditioning stimulus of rather low noxious load. The usage of such mild noxious conditioning stimuli-in contrast to stimuli of higher noxious load (e.g., cold pressor test)-has the advantage that the activation of other types of pain inhibitory mechanisms in parallel (like attentional distraction, stress-induced analgesia) can be avoided.

A novel device for the clinical assessment of intranasal trigeminal sensitivity.

OBJECTIVE: Despite the significance of trigeminal pathology, practical clinical tests that accurately evaluate intranasal trigeminal function are scarce. The aim of the present study is to introduce a practical procedure for the assessment of intranasal trigeminal sensitivity. METHODS: We developed a device to stimulate the nasal mucosa using carbon dioxide, which is self-administered intranasally by holding down a timed button until the required sensory response has been triggered. The trigeminal sensitivity is derived from the measured administration time in conjunction with the concentration of carbon dioxide administered. Sixty-three healthy participants were used to validate the device, after which the new device was compared with a standard lateralization task in an additional 16 participants. In 20 participants, the experiment was repeated to verify test-retest reliability. RESULTS: Statistical analysis showed significant consistency in administration-duration in healthy individuals, including those in the test-retest group. Those participants with higher scores in the lateralization task were found to show higher intranasal sensitivity measured by the new device. CONCLUSION: Herein, we present the design and validation of a novel device for the practical assessment of intranasal trigeminal sensitivity. In this study, we demonstrate the efficacy and reliability of this device.

The olfactory diary: Tracking awareness and consciousness of the sense of smell throughout the day.

Objectives: The aim of the present study was to follow the daily course of patients with olfactory dysfunction and healthy controls and to assess (i) how many times a day, (ii) at which time, and (iii) in which aspect of daily life participants are conscious about their sense of smell. Methods: In this longitudinal study, 49 patients with smell loss and 30 healthy participants were enrolled. Olfactory function was assessed using the Sniffin' Sticks. All participants received paper diaries designed for a 14-day period, featuring 12 rows representing 12 daily hours and six columns for various daily life aspects. They were instructed to mark their awareness of smell by indicating the relevant row and column in the diary. Following the return of the diaries, a second olfactory test was conducted within the patient group. Results: On average, patients were consciously aware of their sense of smell around 8 times daily, while healthy participants noted it about 6.5 times a day. Both groups primarily focused on their sense of smell during activities related to "eating," followed by considerations in "social life" and "personal hygiene." Interestingly, distinct patterns emerged: patients peaked in awareness at 8 a.m. and 7 p.m., whereas healthy individuals showed peaks at 6 a.m., 12 p.m., and 7 p.m. Despite regular diary use, we observed no improvement in patients' olfactory function or related quality of life. Conclusion: The olfactory diary is a valuable tool unveiling individual smell awareness patterns in patients with smell loss, aiding in counseling and patient management. Level of Evidence: 4.

Tonic stimulation of the pharyngeal mucosa causes pain and a reversible increase of inflammatory mediators.

OBJECTIVE AND DESIGN: To develop a model of the inflammatory component of non-infectious sore throat using tonic stimulation and quantification of inflammatory mediators in pharyngeal lavage fluid. MATERIAL OR SUBJECTS: Forty-five healthy volunteers. TREATMENT: Cold dry air. METHOD: Tonic stimulation of the pharynx was achieved using a constant stream of cold dry air to the back of the throat. Following optimization of stimulation conditions (phase 1), pharyngeal pain, irritation, and swallowing discomfort were assessed using visual analog scales, and the concentration of inflammatory markers were measured in pharyngeal lavage fluid (phase 2). RESULTS: Optimum conditions for tonic pharyngeal stimulation were cold dry air at 12 °C, relative humidity 20 %, at a flow rate of 12 L/min for 15 min. Analysis of pharyngeal lavage fluid collected 5 min after stimulation showed significant increases in prostaglandin E2 (P = 0.018), thromboxane B2 (P < 0.001), and substance P (P < 0.001), but no increase in peptidoleukotriene. When the stimulus was removed, the level of inflammatory markers in pharyngeal lavage fluid returned to baseline by 30 min post-stimulation. These objective measures mirrored subjective pain ratings. CONCLUSIONS: Tonic stimulation of the pharyngeal mucosa with cold dry air causes pain and an increase of inflammatory mediators which are reversible.

Drug consumption in German cities and municipalities during the COVID-19 lockdown: a wastewater analysis.

Analysis of illicit drugs, medicines, and pathogens in wastewater is a powerful tool for epidemiological studies to monitor public health trends. The aims of this study were to (i) assess spatial and temporal trends of population-normalized mass loads of illicit drugs and nicotine in raw wastewater in the time of regulations against SARS-CoV-2 infections (2020-21) and (ii) find substances that are feasible markers for characterizing the occurrence of selected drugs in wastewater. Raw sewage 24-h composite samples were collected in catchment areas of 15 wastewater treatment plants (WWTPs) in urban, small-town, and rural areas in Germany during different lockdown phases from April 2020 to December 2021. Parent substances (amphetamine, methamphetamine, MDMA, carbamazepine, gabapentin, and metoprolol) and the metabolites of cocaine (benzoylecgonine) and nicotine (cotinine) were measured. The daily discharge of WWTP influents were used to calculate the daily load (mg/day) normalized by population equivalents (PE) in drained catchment areas (in mg/1,000 persons/day). A weekend trend for illicit drugs was visible with higher amounts on Saturdays and Sundays in larger WWTPs. An influence of the regulations to reduce SARS-CoV-2 infections such as contact bans and border closures on drug consumption has been proven in some cases and refuted in several. In addition, metoprolol and cotinine were found to be suitable as marker substances for the characterization of wastewater. A change in drug use was visible at the beginning of the SARS-CoV-2 crisis. Thereafter from mid-2020, no obvious effect was detected with regard to the regulations against SARS-CoV-2 infections on concentration of drugs in wastewater. Wastewater-based epidemiology is suitable for showing changes in drug consumption during the COVID-19 lockdown.

Chemosensory Functions After Glossectomy-A Cross-Sectional Pilot Study.

OBJECTIVE: To evaluate potential interactions and compensatory mechanisms of subjectively impaired taste function with ortho- and retronasal olfaction after glossectomy. STUDY DESIGN: In this cross-sectional pilot study, chemosensory functions were assessed in 25 patients with tongue carcinomas after glossectomy. The orthonasal-, retronasal-, and gustatory functions were tested with a mean time of 25 months after surgery with the Sniffin' Sticks odor identification test kit (ISST), the Candy Smell-27 test (CST-27) and the Taste strip test (TST). Visual analog scales (VAS) were additionally used for self-assessment of taste, flavor perception, and odor ranging from 0 (no perception) to 10 (excellent perception) and further correlated with our psychophysical evaluated outcome measures. RESULTS: The TST, ISST, and CST-27 tests revealed that only eight (32%) and 13 (52%) glossectomy patients had normal taste and orthonasal function, e 21 (84%) patients showed normal retronasal function. Importantly, neither extent of resection and reconstruction nor prior radiotherapy affected chemosensory functions. Contrary, 20 (80%) patients rated their taste and flavor perception as acceptable (VAS >5). Results of the TST, ISST, and CST-27 tests did not correlate with the equivalent self-assessments of taste (p = 0.260, r = 0.234), odor (p = 0.588, r = -0.114), and flavor (p = 0.728, r = 0.073) perception. CONCLUSION: There was a significant discrepancy between self-perception of taste and flavor and assessed gustatory function after glossectomy. A contribution of the intact retronasal olfactory system could be a possible explanation of our results. LEVEL OF EVIDENCE: 4 Laryngoscope, 133:375-382, 2023.

Regional and temporal differences in the relation between SARS-CoV-2 biomarkers in wastewater and estimated infection prevalence - Insights from long-term surveillance.

Wastewater-based epidemiology provides a conceptual framework for the evaluation of the prevalence of public health related biomarkers. In the context of the Coronavirus disease-2019, wastewater monitoring emerged as a complementary tool for epidemic management. In this study, we evaluated data from six wastewater treatment plants in the region of Saxony, Germany. The study period lasted from February to December 2021 and covered the third and fourth regional epidemic waves. We collected 1065 daily composite samples and analyzed SARS-CoV-2 RNA concentrations using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Regression models quantify the relation between RNA concentrations and disease prevalence. We demonstrated that the relation is site and time specific. Median loads per diagnosed case differed by a factor of 3-4 among sites during both waves and were on average 45 % higher during the third wave. In most cases, log-log-transformed data achieved better regression performance than non-transformed data and local calibration outperformed global models for all sites. The inclusion of lag/lead time, discharge and detection probability improved model performance in all cases significantly, but the importance of these components was also site and time specific. In all cases, models with lag/lead time and log-log-transformed data obtained satisfactory goodness-of-fit with adjusted coefficients of determination higher than 0.5. Back-estimation of testing efficiency from wastewater data confirmed state-wide prevalence estimation from individual testing statistics, but revealed pronounced differences throughout the epidemic waves and among the different sites.