Age-related genes USP2 and ARG2 are involved in the reduction of immune cell infiltration in elderly patients with rheumatoid arthritis.

BACKGROUND: There are large differences in clinical manifestations and biological markers between elderly patients with rheumatoid arthritis (EPRA, age >60) and younger patients with RA (YPRA, age ≤60), partly owing to variations in the immune system of different age groups. Here, we focused on the changes of immune cell infiltration in YPRA and EPRA. METHODS: The R packages "ssGSEA" and "GSEA" were used to identify the changes in immune cell infiltration and immune-related pathways between the two groups. The R packages "WGCNA" and "DEseq2" were used to screen and verify age-related differentially expressed genes (DEGs). Hub genes were identified using Cytoscape and cytoHubba. Spearman correlation coefficient was conducted to evaluate correlations between hub age-related genes and immune cells. RESULTS: Compared with 54 established YPRA, several immune cells and immune-related pathways were markedly decreased in 29 EPRA synovial tissues. Moreover, 78 age-related DEGs related to amino acid and glycosphingolipid synthesis and metabolism were identified. USP2 and ARG2 were verified to be upregulated in EPRA, signifying that these two genes could effectively distinguish YPRA and EPRA and have potential as biomarkers. In addition, we found that USP2 was significantly negatively correlated with B cells and monocytes, while there was a significant negative association between ARG2 and T cells. CONCLUSIONS: In conclusion, this study is the first to systematically analyze changes in immune cell infiltration between YPRA and EPRA patients and obtain hub age-related genes, which may provide the basis for illuminating the pathogenesis of EPRA and informing treatment strategies.

Clinical characteristics and immune profiles of patients with immune-mediated alopecia associated with COVID-19 vaccinations.

BACKGROUND: The clinical characteristics and pathomechanism for immune-mediated alopecia following COVID-19 vaccinations are not clearly characterized. OBJECTIVE: We investigated the causality and immune mechanism of COVID-19 vaccines-related alopecia areata (AA). STUDY DESIGN: 27 new-onset of AA patients after COVID-19 vaccinations and 106 vaccines-tolerant individuals were enrolled from multiple medical centers for analysis. RESULTS: The antinuclear antibody, total IgE, granulysin, and PARC/CCL18 as well as peripheral eosinophil count were significantly elevated in the patients with COVID-19 vaccines-related AA compared with those in the tolerant individuals (P = 2.03 × 10-5-0.039). In vitro lymphocyte activation test revealed that granulysin, granzyme B, and IFN-γ released from the T cells of COVID-19 vaccines-related AA patients could be significantly increased by COVID-19 vaccine excipients (polyethylene glycol 2000 and polysorbate 80) or spike protein (P = 0.002-0.04). CONCLUSIONS: Spike protein and excipients of COVID-19 vaccines could trigger T cell-mediated cytotoxicity, which contributes to the pathogenesis of immune-mediated alopecia associated with COVID-19 vaccines.

Acquired perforating calcific collagenosis in a drug addict with rhabdomyolysis and transient hypercalcemia.

Acquired perforating calcific collagenosis (APCC), which is characterized by the calcification of dermal collagen fibers with subsequent transepidermal elimination and perforation, is an extremely rare entity. Thus far, it has only been reported in a patient with direct contact exposure to calcium chloride. Here, we report a unique case of APCC occurring in a drug addict admitted for rhabdomyolysis. The present case is a 20-year-old male patient hospitalized for drug-related rhabdomyolysis and multiple organ damage. During hospitalization, he gradually developed unusual skin rashes. There were multiple confluent umbilicated and keratotic erythematous to brownish papules and plaques with scratch-like linear plaques on his lower abdomen, inguinal areas and gluteal sulci. Also, multiple well-demarcated flesh-colored rough, hard and thin plaques with a "crepe paper"-like texture were found on the bilateral popliteal fossae, olecranon fossae and axillae. The histopathology of two biopsied lesions demonstrated acquired perforating calcific collagenosis. The lesions appeared during the rhabdomyolysis-related hypercalcemia phase and resolved spontaneously after the calcium level returned to normal. This is the first reported case of disseminated APCC occurring during transient hypercalcemia due to rhabdomyolysis.

Design, synthesis and biological evaluation of deuterated Vismodegib for improving pharmacokinetic properties.

Vismodegib is an oral and high selective hedgehog (Hh) inhibitor used for the treatment of basal cell carcinoma (BCC). In this work, analogs of Vismodegib with deuterium-for-hydrogen replacement at certain metabolically active sites were prepared and found to have a better pharmacokinetic properties in mice. In particular, deuterated compound SKLB-C2211 obviously altered the blood circulation behavior compared to its prototype, which was demonstrated by significantly prolonged blood circulation half-life time (t1/2) and increased AUC0→∞. These results suggested SKLB-C2211 had the potential to be a long-acting inhibitor against Hh signaling pathway, and laid the foundation for the further research of its druggability.

Appearances may be deceptive: florid cutaneous and mucosal papillomatosis.

We present a case in which a patient presented with widespread cutaneous warty lesions misdiagnosed as warts 3 months before the diagnosis of his advanced gastric adenocarcinoma. Florid cutaneous and mucosal papillomatosis is a paraneoplastic dermatosis, following a parallel course with the underlying malignancy, which is most often gastric adenocarcinoma.

Association between Dupilumab and Conjunctivitis: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Conjunctivitis is commonly reported in dupilumab users with atopic dermatitis (AD), and few studies have compared the risk of conjunctivitis among patients with different indications. This study aimed to investigate the association between dupilumab and conjunctivitis in various diseases. The protocol of this study was registered on PROSPERO (ID CRD42023396204). The electronic search of PubMed, Embase, Cochrane Library, and ClinicalTrials.gov was conducted for the period from their inception to January 2023. Only placebo-controlled, randomized controlled trials (RCTs) were included. The main outcome was the incidence of conjunctivitis during the study period. The subgroup analysis was performed for patients with AD and non-AD indications, which include asthma, chronic rhinosinusitis with nasal polyps, and eosinophilic esophagitis. In total, 23 RCTs involving 9153 patients were included for meta-analysis. Dupilumab users exhibited significantly higher risk of conjunctivitis (risk ratio [RR], 1.89; 95% confidence interval [CI], 1.34-2.67) than placebo users. Notably, significantly increased incidence of conjunctivitis was observed in the dupilumab group relative to the placebo group among patients with AD (RR, 2.43; 95% CI, 1.84-3.12) but not among patients with non-AD indications (RR, 0.71; 95% CI, 0.43-1.13). In conclusion, only dupilumab users with AD but not those with non-AD indications reported an elevated incidence of conjunctivitis.

Lactate biosensors for spectrally and spatially multiplexed fluorescence imaging.

L-Lactate is increasingly appreciated as a key metabolite and signaling molecule in mammals. However, investigations of the inter- and intra-cellular dynamics of L-lactate are currently hampered by the limited selection and performance of L-lactate-specific genetically encoded biosensors. Here we now report a spectrally and functionally orthogonal pair of high-performance genetically encoded biosensors: a green fluorescent extracellular L-lactate biosensor, designated eLACCO2.1, and a red fluorescent intracellular L-lactate biosensor, designated R-iLACCO1. eLACCO2.1 exhibits excellent membrane localization and robust fluorescence response. To the best of our knowledge, R-iLACCO1 and its affinity variants exhibit larger fluorescence responses than any previously reported intracellular L-lactate biosensor. We demonstrate spectrally and spatially multiplexed imaging of L-lactate dynamics by coexpression of eLACCO2.1 and R-iLACCO1 in cultured cells, and in vivo imaging of extracellular and intracellular L-lactate dynamics in mice.

Biofabricating hollow microneedle array with controllable microstructure for cell transplantation.

Microneedles improve upon the direct injection method by piercing the epidermis to create microchannels for drug delivery in a painless and minimally invasive way. With these microchannels, large macromolecules can penetrate the skin barrier to reach the underlying target tissue. In this study, poly(methyl methacrylate) (PMMA) hollow microneedles (HMN) arrays were fabricated to transplant cells. The result showed that HMN arrays have good biocompatibility. Human epidermal melanocytes and follicle dermal papilla cells were shown to be successfully delivered to acellular porcine skin tissue. Similarly, human corneal keratocytes and corneal epithelial cells were shown to be successfully delivered to acellular porcine corneal tissue. The delivered cells proliferated and penetrated into the tissue. This system may have the potential in the application of cell delivery or cell transplantation.

Analysis on the intention and influencing factors of free influenza vaccination among the elderly people aged 70 and above in Hangzhou in 2022.

Background: Although influenza vaccination is recommended for people aged 70 and above in Hangzhou, and the vaccine is provided free of charge, the elderly influenza vaccination rate is still low. The purpose of this study was to understand the barriers and motivations of older people in deciding to receive free influenza vaccine through questionnaires. Methods: The method of stratified random sampling was adopted to take samples. A questionnaire survey was conducted among the elderly aged 70 years and above by face-to-face interview or telephone interview. Results: A total of 11,663 elderly people aged 70-100 years were successfully and effectively interviewed. 85.98% of the respondent were willing to get the influenza shot, 8.91% were unwilling to get the influenza shot, and 5.11% were on vaccine hesitancy. The people of age of 70-79 years old (hesitancy: OR 70~79 = 0.668, 95%CI: 0.571 0.782, Unwilling: OR 70 - 79 = 0.755, 95%CI: 0.622 0.916), primary school degree or below (hesitancy: OR Secondary school degree or above = 1.467, 95%CI: 1.249 1.724, Unwilling: OR Secondary school degree or above = 1.255, 95%CI: 1.028 1.535), remote areas (hesitancy: OR near central urban area = 2.111, 95%CI: 1.604 2.778, OR central urban area = 2.957, 95%CI: 2.255 3.877, Unwilling: OR near central urban area = 1.687, 95%CI: 1.230 2.313. OR centralurbanarea = 2.218, 95%CI: 1.626 3.027), and convenient for movement (hesitancy: OR yes = 0.494, 95%CI: 0.420 0.580, Unwilling: OR yes = 0.585, 95%CI: 0.480 0.713), understanding of the free vaccine policy (hesitancy: OR understand = 0.204, 95%CI: 0.171 0.245, Unwilling: OR understand = 0.164, 95%CI: 0.128 0.210), influenza knowledge level≥ 13 points (hesitancy: OR ≥13points = 0.628, 95%CI: 0.533 0.739, Unwilling: OR ≥13points = 0.538, 95%CI: 0.437 0.662), influenza vaccine knowledge level≥ 12 points (hesitancy: OR ≥12points = 0.422, 95%CI: 0.350 0.508, Unwilling: OR ≥12points = 0.370, 95%CI: 0.290 0.472), and social trust level ≥ 12 points (hesitancy: OR ≥12points = 0.134, 95%CI: 0.112 0.160, Unwilling: OR ≥12points = 0.220, 95%CI: 0.180 0.269) are more willing to receive free influenza vaccine. Conclusion: The proportion of elderly people aged 70 and above who are willing to receive free influenza vaccine is high in Hangzhou. But the level of knowledge about influenza, vaccine and trust in society is low. The government should continue to improve the elderly's awareness and trust in society through medical staff, family members, television and radio media, and guide the elderly to actively vaccinate against influenza. Effective publicity should be carried out through the above channels to guide the elderly to actively vaccinate against influenza.

Diabetic Patients With Rosacea Increase the Risks of Diabetic Macular Edema, Dry Eye Disease, Glaucoma, and Cataract.

PURPOSE: Inflammation plays a role in diabetic eye diseases, but the association between rosacea and eye diseases in patients with diabetes remains unknown. DESIGN: This retrospective cohort study used claims data from the National Health Insurance Research Database in Taiwan to investigate the association between rosacea and eye diseases in patients with diabetes. MATERIALS AND METHODS: Taiwanese patients diagnosed as having diabetes mellitus between January 1, 1997, and December 31, 2013, and using any hypoglycemic agents were included and divided into rosacea and nonrosacea groups. After applying 1:20 sex and age matching and exclusion criteria, 1:4 propensity score matching (PSM) was conducted to balance the covariate distribution between the groups. The risk of time-to-event outcome between rosacea and nonrosacea groups in the PSM cohort was compared using the Fine and Gray subdistribution hazard model. RESULTS: A total of 4096 patients with rosacea and 16,384 patients without rosacea were included in the analysis. During a mean follow-up period of 5 years, diabetic patients with rosacea had significantly higher risks of diabetic macular edema [subdistribution hazard ratio (SHR): 1.31, 95% confidence interval (CI): 1.05-1.63], glaucoma with medical treatment (SHR: 1.11, 95% CI: 1.01-1.21), dry eye disease (SHR: 1.55, 95% CI: 1.38-1.75), and cataract surgery (SHR: 1.13, 95% CI: 1.02-1.25) compared with diabetic patients without rosacea. A cumulative incidence analysis performed up to 14 years after the index date revealed that the risks of developing ocular diseases consistently increased over time. No significant differences in diabetic retinopathy, age-related macular degeneration, retinal vascular occlusion, ischemic optic neuropathy, optic neuritis, uveitis, or retinal detachment were identified according to rosacea diagnosis. However, we observed significant associations between rosacea and psoriasis, irritable bowel syndrome, anxiety, and major depressive disorder among patients with diabetes. CONCLUSIONS: Rosacea is associated with diabetic macular edema, glaucoma, dry eye disease, and cataract development in diabetic patients, as well as increased risks of psoriasis, irritable bowel syndrome, anxiety, and depression in diabetic patients.

Rosacea, Germs, and Bowels: A Review on Gastrointestinal Comorbidities and Gut-Skin Axis of Rosacea.

Rosacea is a chronic inflammatory disease with complicated pathophysiology that involves genetic and environmental elements and dysregulation of innate and adaptive immunity, neurovascular responses, microbiome colonization or infection, resulting in recurrent inflammation. Rosacea has been reported associated with various gastrointestinal diseases including inflammatory bowel disease, celiac disease, irritable bowel syndrome, gastroesophageal reflux disease, Helicobacter pylori (HP) infection, and small intestine bacterial overgrowth (SIBO). The link may involve common predisposing genetic, microbiota, and immunological factors, comprising the theory of the gut-skin axis. Although the evidence is still controversial, interestingly, medications for eradicating SIBO and HP provided an effective and prolonged therapeutic response in rosacea, and conventional therapy for which is usually disappointing because of frequent relapses. In this article, we review the current evidence and discuss probable mechanisms of the association between rosacea and gastrointestinal comorbidities.

Transdermal drug delivery systems for fighting common viral infectious diseases.

Transdermal drug delivery systems (TDDS) have many advantages and represent an excellent alternative to oral delivery and hypodermic injections. TDDS are more convenient and less invasive tools for disease and viral infection treatment, prevention, detection, and surveillance. The emerging development of microneedles for TDDS has facilitated improved skin barrier penetration for the delivery of macromolecules or hydrophilic drugs. Microneedle TDDS patches can be fabricated to deliver virus vaccines and potentially provide a viable alternative vaccine modality that offers improved immunogenicity, thermostability, simplicity, safety, and compliance as well as sharp-waste reduction, increased cost-effectiveness, and the capacity for self-administration, which could improve vaccine distribution. These advantages make TDDS-based vaccine delivery an especially well-suited option for treatment of widespread viral infectious diseases including pandemics. Because microneedle-based bioassays employ transdermal extraction of interstitial fluid or blood, they can be used as a minimally invasive approach for surveying disease markers and providing point-of-care (POC) diagnostics. For cutaneous viral infections, TDDS can provide localized treatment with high specificity and less systemic toxicity. In summary, TDDS, especially those that employ microneedles, possess special attributes that can be leveraged to reduce morbidity and mortality from viral infectious diseases. In this regard, they may have considerable positive impact as a modality for improving global health. In this article, we introduce the possible role and summarize the current literature regarding TDDS applications for fighting common cutaneous or systemic viral infectious diseases, including herpes simplex, varicella or herpes zoster, warts, influenza, measles, and COVID-19.

Association of rosacea with inflammatory bowel disease: A MOOSE-compliant meta-analysis.

Rosacea has been reported with several systemic comorbidities, but its relationship with inflammatory bowel disease (IBD) is unclear. Thus, our objective is to conduct a meta-analysis on the association of rosacea with IBD.We conduct a meta-analysis and searched MEDLINE, CENTRAL, and Embase databases for case-controlled and cohort studies that assessed the association of rosacea with IBD from inception to July 2nd, 2018. Two authors independently selected studies, extracted data, and assessed the risk of bias of included studies. Disagreement was resolved by discussion. We performed random-effects model meta-analysis to obtain the pooled risk estimates for Crohn disease (CD) and ulcerative colitis (UC) in patients with rosacea.We included three case-control and three cohort studies. The risk of bias of included studies was generally low. The meta-analysis on case-control studies showed marginally increased odds of CD (pooled odds ratio (OR) 1.30, 95% confidence interval (CI) 0.99-1.69) and a significantly increased odds of UC (pooled OR 1.64, 95% CI 1.43-1.89) in patients with rosacea. The meta-analysis on cohort studies demonstrated significant increased risk of CD (pooled hazard ratio (HR) 1.58, 95% CI 1.14-2.20) and UC (pooled HR 1.18, 95% CI 1.01-1.37) in patients with rosacea.The evidence indicates an association of rosacea with IBD. If patients with rosacea suffer from prolonged abdominal pain, diarrhea, and bloody stool, referral to gastroenterologists may be considered.

Smartphone wallpapers for dermoscopy training in medical students and residents.

BACKGROUND: Several dermoscopy training programs have found the accuracy of dermoscopy examination depends on adequate training of practitioners. Smartphones are readily available and time-efficient tools for dermoscopy training. AIM: To evaluate the learning efficacy of utilizing dermoscopy smartphone wallpapers to train medical students, PGY (postgraduate year)-1 trainees, and junior dermatological residents without prior dermoscopy training. METHODS: We designed smartphone wallpapers with dermoscopy pictures and features of several common melanocytic and nonmelanocytic conditions. Pretests and posttests were performed before and after a 10-day-long smartphone wallpaper training program to evaluate their diagnostic accuracy using dermoscopy images. RESULTS: Significant progressions were noted between the pretest and posttest scores both in the nonmelanocytic (P < 0.001) and the melanocytic (P = 0.003) sections. Medical students and PGY-1 trainees demonstrated more significant improvement in nonmelanocytic lesions, compared to dermatology residents. Residents of dermatology showed more progression in the melanocytic section than nonresidents. LIMITATIONS: There were limited participants. The frequency and time allotted by each participant in perusing the wallpapers were variable. Further study of the application on clinical practice is still needed. CONCLUSION: Smartphone wallpapers training improves dermoscopic interpretation significantly in medical students, PGY-1 trainees, and dermatological residents. The background knowledge of dermatology has an effect on the degree of improvement in the training course.

Tinea blepharo-ciliaris in a 13-year-old girl caused by Trichophyton benhamiae.

Tinea blepharo-ciliaris is a rare form of dermatophyte infection which involves eyelids and associated eyelashes. We report a 13-year-old girl with type I diabetes mellitus who had right eyelid swelling and eyelash loss for two weeks. The lesions were presented as erythematous patches with scales and tiny pustules on the right upper and lower eyelids with broken eyelashes. Two additional annular erythematous patches with scaly active borders were found on her right forearm and right thigh. Microscopic examination of broken eyelashes demonstrated many chains of arthroconidia and hyaline hyphae in an endothrix invasion pattern. Fungal cultures of right eyelid scales, eyelashes, and right thigh lesions all grew Trichophyton benhamiae, which was diagnosed by both morphological characters and sequencing of internal transcribed spacer region of the ribosomal DNA. The patient had a contact history with rabbits. To the best of our knowledge, this is the first case of tinea blepharo-ciliaris caused by T. benhamiae, and also the first formal report of infection by this fungus in Taiwan.

A new mobile learning module using smartphone wallpapers in identification of medical fungi for medical students and residents.

INTRODUCTION: Medical students and residents will encounter many cutaneous fungal infections in medical practice. However, the training for identification of medical fungi has been insufficient due to limited lecture-based courses. The objective of this study was to evaluate the impact of using smartphone-based wallpapers in learning the microscopic morphology and colony characteristics of medical fungi for medical students and residents. METHODS: A smartphone-based wallpaper learning module using a wallpaper-changing software application (app) was introduced in this 3-week training course. Twenty-six participants were enrolled and divided into two groups: nondermatology trainees, including medical students and postgraduate year one (PGY-1) doctors who have not yet specialized, and dermatology trainees (dermatology residents). All of the participants completed a 3-week training course, and the effectiveness of the module was evaluated by pre- and post-course multiple-choice examinations. RESULTS: Both nondermatology and dermatology trainees scored significantly higher in post-course examinations than pre-course examinations (P < 0.001). The dermatology trainees performed better than nondermatology trainees in the pre-course examinations (P < 0.001). In the post-course examinations, no significant difference in scores was noted between dermatology and nondermatology trainees (P = 0.573). DISCUSSION: The smartphone-based wallpaper learning module was effective in helping medical students and residents learn and memorize morphologic characteristics of fungi. In comparison to conventional lecture-based learning, this new mobile module was more readily accessible and convenient for learners to engage in learning.

Discovery of a novel class of pyridine derivatives that selectively inhibits mutant isocitrate dehydrogenase 2.

This paper presents synthesis and structure-activity relationship of pyridine derivatives as inhibitors of mutant isocitrate dehydrogenase 2 (IDH2). A series of 2,4,6-trisubstituted pyridine derivatives have been prepared and evaluated in vitro. Among these compounds, 14n exhibited excellent inhibition activity with the IC50 of 54.6 nm, which is approximately onefold improvement compared to drug candidate AG-221 (Enasidenib) that is in Phase III trial. Exquisite selectivity of 14n for IDH2 R140Q mutant isoform was demonstrated by the poor activity against the wild-type IDH1 and IDH2.

Synthesis and evaluation of novel thiazole-based derivatives as selective inhibitors of DNA-binding domain of the androgen receptor.

A series of thiazole-based inhibitors selectively targeting DNA-binding domain of the androgen receptor (AR) were synthesized and evaluated, and the SAR data were summarized. We identified a novel compound SKLB-C2807 that effectively inhibited the human prostate cancer cell line LNCaP/AR with the IC50 value of 0.38 µm without significant antiproliferative effects on other cell lines PC-3 (AR-negative), SW620, MCF-7 (ER-positive), and L-O2 (non-cancerous). This compound also considerably decreased the expression of prostate-specific antigen. Its binding mode to the AR-DBD was studied. These efforts lay the foundation for developing the next generation of anti-androgens.

Design, Synthesis, and Biological Evaluation of Dimorpholine Substituted Thienopyrimidines as Potential Class I PI3K/mTOR Dual Inhibitors.

Dysfunctional signaling of the PI3K/AKT/mTOR pathway in cancer and its crucial role in cell growth and survival have made it a much desired target for cancer therapeutics. A series of dimorpholine substituted thienopyrimidine derivatives had been prepared and evaluated in vitro and in vivo. Among them, compound 14o was identified as a dual Class I PI3K and mTOR kinase inhibitor, which had an approximately 8-fold improvement in mTOR inhibition relative to the class I PI3K inhibitor 1 (pictilisib, GDC-0941). Western blot analysis confirmed the 14o mechanistic modulation of the cellular PI3K/AKT/mTOR pathway through inhibiting phosphorylation of both AKT and S6 in human cancer cell lines. In addition, 14o demonstrated significant efficacy in SKOV-3 and U87MG tumor xenograft models without causing significant weight loss and toxicity.

HPLC Determination of Enantiomeric Purity of Letermovir Based on CHIRALPAK AD.

A precise and sensitive LC method was developed and further validated for the determination of enantiomeric purity of {(4S)-8-Fluoro-2-[4-(3-methoxyphenyl)-1-piperazinyl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydro-4-quinazolinyl} acetic acid (Letermovir). Baseline separation with a resolution >2.8 was accomplished within 10 min using a CHIRALPAK AD (250 mm × 4.6 mm; particle size 5 µm) column, with n-hexane/2-propanol (80:20 v/v) as mobile phase at a flow rate of 1 mL min-1. The eluted analytes were monitored by UV detection at 260 nm. The effects of mobile phase composition and temperature on enantiomeric selectivity as well as resolution of enantiomers were thoroughly investigated. The calibration curves were plotted within the concentration range between 0.003 and 1 mg mL-1 (n = 14), and the recoveries between 98.24 and 101.43% were obtained, with relative standard deviation <1.29%. The limit of detection (LOD) and limit of quantitation (LOQ) for Letermovir were 0.96 and 3.15 µg mL-1; those for its enantiomer were 1.01 and 3.39 µg mL-1, respectively. The developed method was demonstrated to be accurate, robust and sensitive for the determination of enantiomeric purity of Letermovir, especially for the analysis of bulk samples.