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Even though use of antiretroviral therapy (HAART) decreases the incidence of opportunistic infections (OIs) they are continuing to be a major cause of morbidity and mortality. Studies concerning this problem are scarce in Eastern Africa. The aim of this study was to determine the incidence and predictors of OIs after initiation of HAART in Ethiopia. A health facility based single centered cohort study using structured data extraction sheet was conducted. The study population was all HIV positive ART naive adolescents and adults who started HAART between January 2009 and May 2012. Simple random sampling technique was used to select 317 patients from the record. Multivariate binary logistic regression model was used to determine factors for the occurrence of OIs after initiation of HAART. The incidence of OIs after HAART was 7.5 cases/100person years. Tuberculosis, oral candidiasis, pneumonia and toxoplasmosis were the leading OIs after HAART. A bed ridden functional status at initiation of HAART, presence of OIs before HAART, non-adherence and low hemoglobin level were predictors for the occurrence of OIs after HAART. The incidence of OIs after HAART was higher than in previous studies. Patients with the identified risk factors need strict follow up to reduce the morbidity and mortality attributed to OIs. Earlier initiation of HAART before advanced immune suppression, better management of TB and extended baseline assessment could help to reduce opportunistic infections and mortality after the initiation of HAART in Ethiopian patients.

Complete lymph node dissection is recommended in patients with positive sentinel lymph node biopsy results. To date, the effect of complete lymph node dissection on prognosis is controversial. In the DeCOG-SLT trial, we assessed whether complete lymph node dissection resulted in increased survival compared with observation. In this multicentre, randomised, phase 3 trial, we enrolled patients with cutaneous melanoma of the torso, arms, or legs from 41 German skin cancer centres. Patients with positive sentinel lymph node biopsy results were eligible. Patients were randomly assigned (1:1) to undergo complete lymph node dissection or observation with permuted blocks of variable size and stratified by primary tumour thickness, ulceration of primary tumour, and intended adjuvant interferon therapy. Treatment assignment was not masked. The primary endpoint was distant metastasis-free survival and analysed by intention to treat. All patients in the intention-to-treat population of the complete lymph node dissection group were included in the safety analysis. This trial is registered with ClinicalTrials.gov, number NCT02434107. Follow-up is ongoing, but the trial no longer recruiting patients. Between Jan 1, 2006, and Dec 1, 2014, 5547 patients were screened with sentinel lymph node biopsy and 1269 (23%) patients were positive for micrometastasis. Of these, 483 (39%) agreed to randomisation into the clinical trial; due to difficulties enrolling and a low event rate the trial closed early on Dec 1, 2014. 241 patients were randomly assigned to the observation group and 242 to the complete lymph node dissection group. Ten patients did not meet the inclusion criteria, so 233 patients were analysed in the observation group and 240 patients were analysed in the complete lymph node dissection group, as the intention-to-treat population. 311 (66%) patients (158 in the observation group and 153 in the dissection group) had sentinel lymph node metastases of 1 mm or less. Median follow-up was 35 months (IQR 20–54). Distant metastasis-free survival at 3 years was 77·0% (90% CI 71·9–82·1; 55 events) in the observation group and 74·9% (69·5–80·3; 54 events) in the complete lymph node dissection group. In the complete lymph node dissection group, grade 3 and 4 events occurred in 15 patients (6%) and 19 patients (8%) patients, respectively. Adverse events included lymph oedema (grade 3 in seven patients, grade 4 in 13 patients), lymph fistula (grade 3 in one patient, grade 4 in two patients), seroma (grade 3 in three patients, no grade 4), infection (grade 3 in three patients, no grade 4), and delayed wound healing (grade 3 in one patient, grade 4 in four patients); no serious adverse events were reported. Although we did not achieve the required number of events, leading to the trial being underpowered, our results showed no difference in survival in patients treated with complete lymph node dissection compared with observation only. Consequently, complete lymph node dissection should not be recommended in patients with melanoma with lymph node micrometastases of at least a diameter of 1 mm or smaller. German Cancer Aid.

Kaposi's sarcoma–associated herpesvirus (KSHV) can infect endothelial cells, leading to the development of Kaposi's sarcoma in some individuals. The mechanisms underlying cell entry by KSHV are not fully elucidated. ahn et al. now report that ephrin receptor tyrosine kinase A2 (EphA2) acts as a cellular receptor for KSHV and show that blocking EphA2 inhibits infection of endothelial cells. Kaposi's sarcoma–associated herpesvirus (KSHV) is the causative agent of Kaposi's sarcoma 1 , a highly vascularized tumor originating from lymphatic endothelial cells, and of at least two different B cell malignancies 2 , 3 . A dimeric complex formed by the envelope glycoproteins H and L (gH-gL) is required for entry of herpesviruses into host cells 4 . We show that the ephrin receptor tyrosine kinase A2 (EphA2) is a cellular receptor for KSHV gH-gL. EphA2 co-precipitated with both gH-gL and KSHV virions. Infection of human epithelial cells with a GFP-expressing recombinant KSHV strain, as measured by FACS analysis, was increased upon overexpression of EphA2. Antibodies against EphA2 and siRNAs directed against EphA2 inhibited infection of endothelial cells. Pretreatment of KSHV with soluble EphA2 resulted in inhibition of KSHV infection by up to 90%. This marked reduction of KSHV infection was seen with all the different epithelial and endothelial cells used in this study. Similarly, pretreating epithelial or endothelial cells with the soluble EphA2 ligand ephrinA4 impaired KSHV infection. Deletion of the gene encoding EphA2 essentially abolished KSHV infection of mouse endothelial cells. Binding of gH-gL to EphA2 triggered EphA2 phosphorylation and endocytosis, a major pathway of KSHV entry 5 , 6 . Quantitative RT-PCR and in situ histochemistry revealed a close correlation between KSHV infection and EphA2 expression both in cultured cells derived from human Kaposi's sarcoma lesions or unaffected human lymphatic endothelium, and in situ in Kaposi's sarcoma specimens, respectively. Taken together, our results identify EphA2, a tyrosine kinase with known functions in neovascularization and oncogenesis, as an entry receptor for KSHV.

Biological barriers remain a major obstacle for the development of innovative therapeutics. Depending on a disease’s pathophysiology, the involved tissues, cell populations, and cellular components, drugs often have to overcome several biological barriers to reach their target cells and become effective in a specific cellular compartment. Human biological barriers are incredibly diverse and include multiple layers of protection and obstruction. Importantly, biological barriers are not only found at the organ/tissue level, but also include cellular structures such as the outer plasma membrane, the endolysosomal machinery, and the nuclear envelope. Nowadays, clinicians have access to a broad arsenal of therapeutics ranging from chemically synthesized small molecules, biologicals including recombinant proteins (such as monoclonal antibodies and hormones), nucleic-acid-based therapeutics, and antibody-drug conjugates (ADCs), to modern viral-vector-mediated gene therapy. In the past decade, the therapeutic landscape has been changing rapidly, giving rise to a multitude of innovative therapy approaches. In 2018, the FDA approval of patisiran paved the way for small interfering RNAs (siRNAs) to become a novel class of nucleic-acid-based therapeutics, which—upon effective drug delivery to their target cells—allow to elegantly regulate the post-transcriptional gene expression. The recent approvals of valoctocogene roxaparvovec and etranacogene dezaparvovec for the treatment of hemophilia A and B, respectively, mark the breakthrough of viral-vector-based gene therapy as a new tool to cure disease. A multitude of highly innovative medicines and drug delivery methods including mRNA-based cancer vaccines and exosome-targeted therapy is on the verge of entering the market and changing the treatment landscape for a broad range of conditions. In this review, we provide insights into three different disease entities, which are clinically, scientifically, and socioeconomically impactful and have given rise to many technological advancements: acquired immunodeficiency syndrome (AIDS) as a predominant infectious disease, pancreatic carcinoma as one of the most lethal solid cancers, and hemophilia A/B as a hereditary genetic disorder. Our primary objective is to highlight the overarching principles of biological barriers that can be identified across different disease areas. Our second goal is to showcase which therapeutic approaches designed to cross disease-specific biological barriers have been promising in effectively treating disease. In this context, we will exemplify how the right selection of the drug category and delivery vehicle, mode of administration, and therapeutic target(s) can help overcome various biological barriers to prevent, treat, and cure disease.

Despite the development of vaccines, which protect healthy people from severe and life-threatening Covid-19, the immunological responses of people with secondary immunodeficiencies to these vaccines remain incompletely understood. Here, we investigated the humoral and cellular immune responses elicited by mRNA-based SARS-CoV-2 vaccines in a cohort of people living with HIV (PLWH) receiving anti-retroviral therapy. While antibody responses in PLWH increased progressively after each vaccination, they were significantly reduced compared to the HIV-negative control group. This was particularly noteworthy for the Delta and Omicron variants. In contrast, CD4+ Th cell responses exhibited a vaccination-dependent increase, which was comparable in both groups. Interestingly, CD4+ T cell activation negatively correlated with the CD4 to CD8 ratio, indicating that low CD4+ T cell numbers do not necessarily interfere with cellular immune responses. Our data demonstrate that despite the lower CD4+ T cell counts SARS-CoV-2 vaccination results in potent cellular immune responses in PLWH. However, the reduced humoral response also provides strong evidence to consider PLWH as vulnerable group and suggests subsequent vaccinations being required to enhance their protection against COVID-19.

We assess long-term changes in lipid levels in human immunodeficiency disease- (HIV-) infected patients undergoing highly active antiretroviral treatment (HAART) and their association with diabetes mellitus (DM) and thyroid dysfunction. We observed changes in the levels of total cholesterol (TC) and total triglyceride (TG) of 63 HIV-infected patients in the 6 years from starting HAART and analyzed correlations between relevant parameters. TC levels of patients with normal baseline TC levels as well as those diagnosed with DM or impaired fasting glucose (IFG) increased significantly (P < 0.05) as did the TG levels of patients with normal baseline TG levels (P < 0.05). TC levels of patients with hypercholesterolemia in the year HAART was initiated were significantly higher than those of patients with normal baseline TC levels (P < 0.05) for all 6 years. TC levels of patients diagnosed with DM were significantly higher than those with euglycemia (P < 0.05) 2 and 4 years after HAART commencement. Levels of TC, high-density lipoprotein-cholesterol (HDL-C), and low-density lipoprotein-cholesterol (LDL-C) were correlated negatively with viral load, whereas levels of TC and very-low-density lipoprotein-cholesterol (VLDL-C) were correlated positively with CD4+ cell counts before HAART commencement. Linear mixed-effect model demonstrated disturbance of glucose metabolism and HAART containing nevirapine and CD4+ cell count were positively correlated with TC levels after HAART commencement. These findings suggest that there are changes in the lipid levels of patients undergoing HAART, with the potential risk of dyslipidemia.

Background: Patients with atopic dermatitis (AD) are prone to have skin infections. We aimed to investigate mRNA expression levels of various antimicrobial peptides and proteins (AMPs) in AD patients, and compare it with psoriasis vulgaris (PV) patients and healthy subjects. Methods: Skin biopsies were obtained from healthy subjects and patients with AD and PV. Quantitative real-time RT-PCR was used to determine the mRNA levels of human β-defensin (hBD)-1, hBD-2, hBD-3, LL-37, psoriasin, RNase 7, interferon-γ, and interleukin-10 (IL-10). Results: Except for LL-37, mRNA of hBDs, psoriasin, and RNase 7 was significantly higher expressed in AD (n = 42) and/or PV (n = 35) patients when compared to controls (n = 18). While PV lesions showed significantly higher mRNA hBD-2 levels than lesions of AD, the latter was associated with significantly higher mRNA levels of RNase 7 when compared to PV. A significant positive correlation of hBD expression was observed both in AD patients and PV patients. hBD mRNA levels of AD skin correlated with psoriasin and RNase 7 levels. hBD-1 mRNA expression correlated with AD activity and IL-10 mRNA expression. Conclusions: Most AMPs investigated in this study proved to be overexpressed in AD as well as PV when compared to controls. However, a statistically significant difference in AMP mRNA expression between AD and PV was only found for hBD-2 and RNase 7. A moderate-to-strong linear relationship between the mRNA expression of particular AMPs appears to exist in AD, and to a lesser extent in PV as well.

Anal intraepithelial neoplasia (AIN), a human papillomavirus (HPV)-associated precursor lesion of anal carcinoma, is highly prevalent in HIV-infected men having sex with men (MSM). This prospective follow-up study evaluated the long-term results of imiquimod treatment of AIN in 19 HIV-infected MSM. Standardized follow-up examinations included high-resolution anoscopy, anal cytology/histology, HPV typing, and DNA load determination for HPV types 16, 18, 31, and 33. Mean follow-up time was 30.3 months. A total of 74% (14/19) of the patients remained free of AIN at the previously treated site. Five patients (26%) had recurrent high-grade AIN after a mean time of 24.6 months. At the end of follow-up, the numbers of HPV types as well as high-risk HPV–DNA loads were significantly lower than before therapy. During follow-up, 58% of all patients (11/19) developed new anal cytological abnormalities in previously normal, untreated anal regions. 55% of these new AIN lesions were high-grade lesions and most of them were located intra-anally and associated with high-risk HPV types not detectable before therapy. These results demonstrate that imiquimod leads to a high rate of long-term clearance of AIN in HIV-positive men together with a prolonged decrease of high-risk HPV–DNA load. However, new AIN lesions associated with previously undetected HPV types frequently occur in untreated areas.

Objectives Prolonged QT interval is associated with arrhythmias and sudden death. An increased prevalence of QT interval prolongation in human immunodeficiency virus-infected (HIV) subjects was previously described. The impact of different medications and HIV infection itself on the QT interval is rarely investigated in large HIV+ cohorts. Methods We compared QT interval measurement in 496 HIV(+) patients of the HIV-HEART study (HIVH) and 992 sex- and age-matched controls of the population-based German Heinz Nixdorf Recall study (HNR). QT corrected for heart rate (QTc) >440 ms in male and >460 ms in female was considered pathological. We analysed the impact of HIV status and HIV medication on QTc prolongation in the HIVH subjects. Results We observed longer QTc in HIVH subjects compared with HNR controls: 424.1 ms ± 23.3 vs. 411.3 ± 15.3 ms for male and 435.5 ms ± 19.6 vs. 416.4 ms ± 17.3 for female subjects ( p  < 0.0001 for both sexes). Adjusting for QT prolonging medication the mean differences in QTc between the two studies remained significant with 12.6 ms (95% CI 10.5–14.8; p value <0.0001) for male and 19.3 ms (95% CI 14.5–24.2; p value <0.0001) for female subjects. Prolongation of QTc was pathologic in 22.8 vs. 3.9% of HIV(+) and non-infected males and in 12.1 vs. 1.8% of the females [OR of 7.9 (5.0–12.6) and OR of 6.7 (1.8–24.2), respectively]. Smoking behaviour was an independent factor to lengthen QTc in HIV(+) patients. Diabetes mellitus was not a risk factor itself, but might be associated with medication which was associated with LQT. We could not observe any influence of the HIV status, ART, or any co-medication on the QTc. Conclusions Our study showed that HIV(+) patients had significantly longer QTc intervals compared to the general population. The number of patients with pathologic QTc prolongation was significantly increased in HIV(+) population.