HIV transmission by human bite: a case report and review of the literature—implications for post-exposure prophylaxis

We report a case of a probable HIV-1 transmission by human bite. The analyzed data from ten previously reported suspected or allegedly confirmed HIV transmissions revealed a deep bleeding bite wound as the primary risk factor. A high HIV plasma viral load and bleeding oral lesions are present most of the time during HIV transmission by bite. HIV post-exposure prophylaxis (PEP) should be recommended in case of a bleeding wound resulting from a bite of an HIV-infected person. PEP was missed in this presented case

Indwelling pleural catheters for non-malignant pleural effusions: report on a single centre's 10 years of experience

BACKGROUND: Recurrent pleural effusion is a common cause of dyspnoea, cough and chest pain during the course of infectious pleurisy and non-malignant diseases like congestive heart failure (CHF) or liver cirrhosis with hepatic hydrothorax (HH). With regard to the chronic character of the underlying diseases, indwelling pleural catheters (IPC) are increasingly used, not only assuring immediate symptom relief but also potentially leading to pleurodesis without sclerosing agents. PATIENTS AND METHODS: In this single-centre retrospective observational study, patient characteristics, procedural variables and outcome in patients with IPC in non-malignant pleural effusion (NMPE) were evaluated and prognostic factors for pleurodesis were identified. RESULTS: From 2006 to 2017, 54 patients received 62 IPC, of whom 48.4% with CHF and 43.5% with HH. The median length of insertion was 1.5 months (IQR 0.6-2.9 months), the median survival time after insertion 3.2 months (IQR 1.1-16.0). An adequate symptom relief was achieved in 93.2% with no need for subsequent interventions. In patients surviving ≥30 days after IPC insertion, pleurodesis was observed in 45.9%, being associated to age (<55 years, p=0.02), the primary diagnosis (p=0.03) and interventions for the underlying disease (p<0.001). Complications occurred in 24.2% of all procedures (n=15), the majority concerning mechanical obstructions (n=10) and infections (n=4). Patients with HH had an excess risk for complications (37.3%). CONCLUSION: Efficacy in symptom relief and a generally manageable safety profile recommend IPC as a first-line treatment option in NMPE, where disease-specific treatments are exhausted. Caution is warranted in patients with HH due to an excess risk for complications

Role of IL‐17 in atopy—A systematic review

Purpose of Review: Atopy is defined as the genetic predisposition to react with type I allergic diseases such as food-, skin-, and respiratory allergies. Distinct molecular mechanisms have been described, including the known Th2 driven immune response. IL-17A (IL-17) is mainly produced by Th17 cells and belongs to the IL-17 family of cytokines, IL-17A to F. While IL-17 plays a major role in inflammatory and autoimmune disorders, more data was published in recent years elucidating the role of IL-17 in allergic diseases. The present study aimed to elaborate specifically the role of IL-17 in atopy. Methods: A systematic literature search was conducted in MEDLINE, Embase, and Cochrane Central Register of Controlled Trials, regarding IL-17 and atopy/allergic diseases. Results: In total, 31 novel publications could be identified (food allergy n = 3, allergic asthma n = 7, allergic rhinitis [AR] n = 10, atopic dermatitis [AD] n = 11). In all allergic diseases, the IL-17 pathway has been investigated. Serum IL-17 was elevated in all allergic diseases. In AR, serum and nasal IL-17 levels correlated with the severity of the disease. In food allergies, serum IL-17E was also elevated in children. In AD, there is a trend for higher IL-17 values in the serum and skin specimen, while it is more expressed in acute lesions. In allergic asthma, serum IL-17 levels were increased. In two studies, higher serum IL-17 levels were found in severe persistent asthmatic patients than in intermittent asthmatics or healthy controls. Only one therapeutic clinical study exists on allergic diseases (asthma patients) using a monoclonal antibody against the IL-17 receptor A. No clinical efficacy was found in the total study population, except for a subgroup of patients with (post-bronchodilator) high reversibility. Summary: The role of IL 17 in the pathogenesis of allergic diseases is evident, but the involvement of the Th17 cytokine in the pathophysiological pathway is not conclusively defined. IL-17 is most likely relevant and will be a clinical target in subgroups of patients. The current data indicates that IL-17 is elevated more often in acute and severe forms of allergic diseases

Impact of Ventilation Modes on Bronchoscopic Chartis Assessment Outcome in Candidates for Endobronchial Valve Treatment

Background: Endobronchial valve therapy has proven to reduce lung hyperinflation and decrease disease burden in patients with severe lung emphysema. Exclusion of collateral ventilation (CV) of the targeted lobe by using an endobronchial assessment system (Chartis; PulmonX, Drive Redwood City, CA, USA) in combination with software-based fissure integrity analysis (FCS [fissure completeness score]) of computed tomography scans of the lung are established tools to select appropriate patients for endobronchial valve treatment. So far, there is no conclusive evidence if the ventilation mode during bronchoscopy impacts the outcome of Chartis assessments. Methods: Patients with Chartis assessments and software-based quantification of FCS (StratX; PulmonX, Drive Redwood City, CA, USA) were enrolled in this retrospective study. During bronchoscopy, pulmonary fissure integrity was evaluated with the Chartis assessment system in each patient first under spontaneous breathing and subsequently under high-frequency (HF) jet ventilation. Results: In total, 102 patients were analyzed. Four Chartis phenotypes CV positive (CV+), CV negative (CV-), low flow, and low plateau in spontaneous breathing and HF jet ventilation were identified. The frequency of each Chartis phenotype per lobe was similar in both settings. When comparing Chartis assessments in spontaneous breathing and HF jet ventilation, there was an overall good concordance rate for all analyzed fissures. In agreement, receiver operating characteristic analysis of the FCS showed an almost similar prediction for CV+ and CV- status independent of the ventilation modes. Conclusion: Chartis assessment in spontaneous breathing and HF jet ventilation had similar rates in detecting CV in lung emphysema. Our results suggest that both modes are equivalent for the assessment of CV

CD169/SIGLEC1 is expressed on circulating monocytes in COVID-19 and expression levels are associated with disease severity

Coronavirus disease 2019 (COVID-19) is caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Type I interferons are important in the defense of viral infections. Recently, neutralizing IgG auto-antibodies against type I interferons were found in patients with severe COVID-19 infection. Here, we analyzed expression of CD169/SIGLEC1, a well described downstream molecule in interferon signaling, and found increased monocytic CD169/SIGLEC1 expression levels in patients with mild, acute COVID-19, compared to patients with severe disease. We recommend further clinical studies to evaluate the value of CD169/SIGLEC1 expression in patients with COVID-19 with or without auto-antibodies against type I interferons

A time-resolved proteomic and prognostic map of COVID-19.

COVID-19 is highly variable in its clinical presentation, ranging from asymptomatic infection to severe organ damage and death. We characterized the time-dependent progression of the disease in 139 COVID-19 inpatients by measuring 86 accredited diagnostic parameters, such as blood cell counts and enzyme activities, as well as untargeted plasma proteomes at 687 sampling points. We report an initial spike in a systemic inflammatory response, which is gradually alleviated and followed by a protein signature indicative of tissue repair, metabolic reconstitution, and immunomodulation. We identify prognostic marker signatures for devising risk-adapted treatment strategies and use machine learning to classify therapeutic needs. We show that the machine learning models based on the proteome are transferable to an independent cohort. Our study presents a map linking routinely used clinical diagnostic parameters to plasma proteomes and their dynamics in an infectious disease

Clinical and virological characteristics of hospitalised COVID-19 patients in a German tertiary care centre during the first wave of the SARS-CoV-2 pandemic: a prospective observational study

Purpose: Adequate patient allocation is pivotal for optimal resource management in strained healthcare systems, and requires detailed knowledge of clinical and virological disease trajectories. The purpose of this work was to identify risk factors associated with need for invasive mechanical ventilation (IMV), to analyse viral kinetics in patients with and without IMV and to provide a comprehensive description of clinical course. Methods: A cohort of 168 hospitalised adult COVID-19 patients enrolled in a prospective observational study at a large European tertiary care centre was analysed. Results: Forty-four per cent (71/161) of patients required invasive mechanical ventilation (IMV). Shorter duration of symptoms before admission (aOR 1.22 per day less, 95% CI 1.10-1.37, p < 0.01) and history of hypertension (aOR 5.55, 95% CI 2.00-16.82, p < 0.01) were associated with need for IMV. Patients on IMV had higher maximal concentrations, slower decline rates, and longer shedding of SARS-CoV-2 than non-IMV patients (33 days, IQR 26-46.75, vs 18 days, IQR 16-46.75, respectively, p < 0.01). Median duration of hospitalisation was 9 days (IQR 6-15.5) for non-IMV and 49.5 days (IQR 36.8-82.5) for IMV patients. Conclusions: Our results indicate a short duration of symptoms before admission as a risk factor for severe disease that merits further investigation and different viral load kinetics in severely affected patients. Median duration of hospitalisation of IMV patients was longer than described for acute respiratory distress syndrome unrelated to COVID-19

New therapeutic options in gastrointestinal neuroendocrine tumours

Die Behandlung von metastasierten gastroenteropankreatischen neuroendokrinen Tumoren (GEP-NETs) ist weiterhin eine große klinische Herausforderung. Zusätzliche medikamentöse Interventionsmöglicheiten werden dringend benötigt. Die vermehrte Aktivierung des intrazellulären Phosphatidylinsositol-3-kinase (PI3K)-AKT Signalweg führt zu einem vermehrten Tumorwachstum und verhindert Apoptose bei verchiedenen Tumorarten. Weiterhin spielt der Signalweg eine wichtige Rolle in der Resistenzentwicklung gegenüber Zytostatika sowie bei der Angiogenese. Das Hitzeschockprotein 90 (HSP90) ist ein wichtiger Regulator von AKT. Außerdem konnte bei vielen Tumoren eine Überexpression von HSP90 gezeigt werden. Auch hat die vermehrte Expression von HSP90 in Tumoren eine wichtige prognostische Bedeutung. Mittels Echtzeit-Proliferations-Assays untersuchten wir die Wirkung von Triciribine, einem AKT-Inhibitor, und IPI504, ein Inhibitor von HSP90, auf drei verschiedene gastroenteropankreatische neuroendokrine Tumorzelllinien. Wir analysierten die Induktion von Apoptose und die Effekte der Substanzen auf verschiedene krebsassoziierte Genprodukte. Weiterhin untersuchten wir die Rolle des Enzymes PTEN als ein möglicher Prediktor für die Wirksamkeit einer AKT-Inhibition. Mögliche additive antineoplastische Effekte durch Kombination mit zytostatischen oder anderen enzymspezifischen Inhibitoren wurden untersucht. Auch die in vivo Effekte wurden mittels einer Hühnermembranuntersuchung analysiert. Dabei zeigte sowohl die Inhibition von AKT, als auch die Hemmung von HSP90 einen antiproliferativen Effekt bei gastroenteropankreatischen neuroendokrinen Tumoren. Die Kombination mit klassischen Zytostatika, also auch die Kombination mit anderen signalwegspezifischen Substanzen zeigten synergistische antiproliferative Effekte. In vivo Versuche bestätigten die antiproliferative Wirkung der beiden Substanzen. Die Expression von PTEN konnte als Prädiktor bezüglich der Sensitivität von GEP-NET-Zellen gegenüber einer AKT-Inhibition nachgewiesen werden. Zusammenfassend konnten wir zeigen, dass sowohl die AKT-Inhibition, als auch die HSP90-Inhibition in der Lage ist, das Wachstum von gastroenteropankreatischen neuroendokrinen Tumorzellen zu hemmen.Treatment of gastroenteropancreatic neuroendocrine tumors (GEP-NET) is still unsatisfactory and innovative thera¬peutic approaches are urgently needed. Up- regulation of phosphatidylinositol-3-kinase (PI3K)-AKT signaling facilitates tumor cell growth and inhibits cell demise. The AKT-pathway also plays an important role in cytostatic therapy resistance and response to hypoxia and angiogenesis. The Heat shock protein 90 (Hsp90) is an important regulator of AKT-activity. Furthermore, it is overexpressed in a wide range of tumors and an emerging target for the treatment of cancer. We therefore examined the potency of triciribine, an AKT inhibitor, and IPI504, a HSP90 inhibitor, in three distinct neuroendocrine gastrointestinal tumor cell lines, using real- time cell proliferation assays. Also, we investigated the induction of apoptosis and effects on a broad range of cancer-associated gene products. Furthermore, we characterized the role of PTEN as a possible predictor of sensitivity to triciribine in GEP-NETs. We looked for additive anti-neoplastic effects of the drugs when combined with conventional cytostatic drugs or other targeted drugs, affecting different molecules of the PI3K-AKT-pathway. We also assessed the potency of AKT- and HSP90 inhibition to slow tumor growth in vivo, by using the chick chorioallantoic membrane assay. Both, AKT- and HSP90 inhibition significantly suppressed growth in different neuroendocrine cell lines. Combinations with classic cytostatic drugs as well as drugs targeting other molecules of the PI3K-AKT-pathway led to synergistic anti-proliferative effects. Additional in vivo-evaluations confirmed the anti-neoplastic potency of triciribine and IPI504. Expression of PTEN was shown to predict sensitivity of cells towards AKT inhibition. Thus, our data show that inhibition of the AKT-pathway as well as inhibition of HSP90 potently reduces the growth of GEP- NET cells alone or in combination therapies

Cenicriviroc for the treatment of COVID-19: first interim results of a randomised, placebo-controlled, investigator-initiated, double-blind phase II trial

Objectives: C-C-chemokine receptors (CCRs) are expressed on a variety of immune cells and play an important role in many immune processes, particularly leukocyte migration. Comprehensive preclinical research demonstrated CCR2/CCR5-dependent pathways as pivotal for the pathophysiology of severe COVID-19. Here we report human data on use of a chemokine receptor inhibitor in patients with COVID-19. Methods: Interim results of a 2:1 randomised, placebo-controlled, investigator-initiated trial on the CCR2/CCR5-inhibitor Cenicriviroc (CVC) 150 mg BID orally for 28 d in hospitalised patients with moderate to severe COVID-19 are reported. The primary endpoint is the subject's responder status defined by achieving grade 1 or 2 on the 7-point ordinal scale of clinical improvement on day 15. Results: Of the 30 patients randomised, 18 were assigned to receive CVC and 12 to placebo. Efficient CCR2- and CCR5 inhibition was demonstrated through CCL2 and CCL4 elevation in CVC-treated patients (485% and 80% increase on day 3 compared to the baseline, respectively). In the modified intention-to-treat population, 82.4% of patients (14/17) in the CVC group met the primary endpoint, as did 91.7% (11/12) in the placebo group (OR = 0.5, 95% CI = 0.04–3.41). One patient treated with CVC died of progressive acute respiratory distress syndrome, and the remaining had a favourable outcome. Overall, treatment with CVC was well tolerated, with most adverse events being grade I or II and resolving spontaneously. Conclusions: Our interim analysis provides proof-of-concept data on CVC for COVID-19 patients as an intervention to inhibit CCR2/CCR5. Further studies are warranted to assess its clinical efficacy

CD169/SIGLEC1 is expressed on circulating monocytes in COVID-19 and expression levels are associated with disease severity

Coronavirus disease 2019 (COVID-19) is caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Type I interferons are important in the defense of viral infections. Recently, neutralizing IgG auto-antibodies against type I interferons were found in patients with severe COVID-19 infection. Here, we analyzed expression of CD169/SIGLEC1, a well described downstream molecule in interferon signaling, and found increased monocytic CD169/SIGLEC1 expression levels in patients with mild, acute COVID-19, compared to patients with severe disease. We recommend further clinical studies to evaluate the value of CD169/SIGLEC1 expression in patients with COVID-19 with or without auto-antibodies against type I interferons