Caspofungin for treatment of invasive aspergillosis in Germany: results of a pre-planned subanalysis of an international registry

<p>Abstract</p> <p>Background</p> <p>This study is a pre-planned country-specific subanalysis of results in Germany from a multinational multicenter registry to prospectively assess real-world experience with caspofungin administered for treatment of proven or probable invasive aspergillosis (IA).</p> <p>Methods</p> <p>Data from patients treated with caspofungin for a single episode of IA were collected. Effectiveness was determined by the local investigator as favorable (complete or partial response) or unfavorable (stable disease, failure or death) at the end of caspofungin therapy. Descriptive statistics with binomial exact confidence intervals were employed.</p> <p>Results</p> <p>Forty-two consecutive patients were identified in three German centers. Three patients (7%) had proven IA and 39/42 (93%) had probable IA (modified European Organization for Research and Treatment of Cancer/Mycosis Study Group (EORTC/MSG) criteria). Forty-one patients had pulmonary IA and one had tracheal IA. Caspofungin monotherapy was received by 36/42 patients (86%); of these, 26/36 (72%) received salvage therapy. A favorable response was observed in 29/42 patients (69%; 95% CI 53 to 82%); of these, 21/29 (72%) had a complete and 8/29 (28%) a partial response. Favorable response rate was 69% in patients with monotherapy (95% CI 52% to 84%; 25/36 patients), and 67% in patients receiving combination therapy (95% CI 22% to 96%; 4/6 patients). Favorable response rate in patients with first line therapy was 64% (95% CI 31% to 89%; 7/11 patients), and 73% in patients with second line therapy (95% CI 54% to 88%; 20/30 patients). No adverse events were reported. In total, 35/42 patients (83%; 95% CI 69 to 93%) survived seven days after completion of caspofungin therapy.</p> <p>Conclusions</p> <p>These real-life findings in Germany are consistent with the international findings from this registry and with findings from randomized studies.</p

The Internet-of-Things Meets Business Process Management: Mutual Benefits and Challenges

The Internet of Things (IoT) refers to a network of connected devices collecting and exchanging data over the Internet. These things can be artificial or natural, and interact as autonomous agents forming a complex system. In turn, Business Process Management (BPM) was established to analyze, discover, design, implement, execute, monitor and evolve collaborative business processes within and across organizations. While the IoT and BPM have been regarded as separate topics in research and practice, we strongly believe that the management of IoT applications will strongly benefit from BPM concepts, methods and technologies on the one hand; on the other one, the IoT poses challenges that will require enhancements and extensions of the current state-of-the-art in the BPM field. In this paper, we question to what extent these two paradigms can be combined and we discuss the emerging challenges

Fibroblast Growth Factor 21 Response in a Preclinical Alcohol Model of Acute-on-Chronic Liver Injury

Background and Aims: Fibroblast growth factor (FGF) 21 has recently been shown to play a potential role in bile acid metabolism. We aimed to investigate the FGF21 response in an ethanol-induced acute-on-chronic liver injury (ACLI) model in Abcb4−/− mice with deficiency of the hepatobiliary phospholipid transporter. Methods: Total RNA was extracted from wild-type (WT, C57BL/6J) and Abcb4−/ − (KO) mice, which were either fed a control diet (WT-Cont and KO-Cont groups; n = 28/group) or ethanol diet, followed by an acute ethanol binge (WT-EtOH and KOEtOH groups; n = 28/group). A total of 58 human subjects were recruited into the study, including patients with alcohol-associated liver disease (AALD; n = 31) and healthy controls (n = 27). The hepatic and ileal expressions of genes involved in bile acid metabolism, plasma FGF levels, and bile acid and its precursors 7α- and 27-hydroxycholesterol (7α- and 27-OHC) concentrations were determined. Primary mouse hepatocytes were isolated for cell culture experiments. Results: Alcohol feeding significantly induced plasma FGF21 and decreased hepatic Cyp7a1 levels. Hepatic expression levels of Fibroblast growth factor receptor 1 (Fgfr1), Fgfr4, Farnesoid X-activated receptor (Fxr), and Small heterodimer partner (Shp) and plasma FGF15/FGF19 levels did not differ with alcohol challenge. Exogenous FGF21 treatment suppressed Cyp7a1 in a dose-dependent manner in vitro. AALD patients showed markedly higher FGF21 and lower 7α-OHC plasma levels while FGF19 did not differ. Conclusions: The simultaneous upregulation of FGF21 and downregulation of Cyp7a1 expressions upon chronic plus binge alcohol feeding together with the invariant plasma FGF15 and hepatic Shp and Fxr levels suggest the presence of a direct regulatory mechanism of FGF21 on bile acid homeostasis through inhibition of CYP7A1 by an FGF15-independent pathway in this ACLI model. Lay Summary: Alcohol challenge results in the upregulation of FGF21 and repression of Cyp7a1 expressions while circulating FGF15 and hepatic Shp and Fxr levels remain constant both in healthy and pre-injured livers, suggesting the presence of an alternative FGF15-independent regulatory mechanism of FGF21 on bile acid homeostasis through the inhibition of Cyp7a1

Influence of Radiotherapy on Ossification of Vascularized Osseous Reconstruction of the Jaw: A Radiological Retrospective Cohort Study Based on Panoramic Radiographs

Background: The aim of this study was to evaluate the impact of irradiation and time of irradiation on the ossification of jaws reconstructed with free bone grafts. Methods: In total, 100 reconstructions of the jaw were retrospectively evaluated for ossification between bone segments by two raters based on postoperative panoramic radiographs (immediate postOP, approximately 6, 12 and 24 months follow-up). Three subgroups were divided according to the time of irradiation: preoperative radiation therapy (n = 41), postoperative radiation therapy (n = 26) and patients without any radiation therapy (n = 33) as the control group. Ossification time and influencing factors were documented. Results: The fastest ossification with a median of 304 ± 37 days was observed (p < 0.001) in the nonirradiated control group. No significant difference (p = 0.087) in ossification was found between the pre- (447 ± 136 days) and postoperative (510 ± 112 days) radiation groups. Ossification between two graft segments (336 ± 38 days) showed significantly (p < 0.001) faster ossification than between the original and grafted bone (448 ± 85 days). Moreover, closer initial contact between the segments resulted in faster ossification (p < 0.001). When analyzing cofactors, tobacco consumption was the only negative factor aggravating ossification (p = 0.006). Conclusion: Head and neck radiation corresponded with the impaired and prolonged ossification of jaw reconstructions with free bone grafts. There was no difference in ossification if radiotherapy was performed before or after reconstructive surgery. A close bony contact was particularly important for ossification between the original and grafted bone

Antiresorptive agents enhance ossification of free flap reconstructions of the mandible: a radiological retrospective cohort study

Background: The aim of this study was to investigate the effect of antiresorptive agents on the ossification of reconstructed mandibles by free bone grafts for the first time. Methods: A total of 38 reconstructions of the jaw were retrospectively evaluated for ossification between bone segments by two raters based on postoperative panoramic radiographs. The study group (n = 13) had segmental resection of the mandible and free bone flap reconstruction due to medication-related osteonecrosis of the jaw (MRONJ). The control group (noMRONJ, n = 25) comprised segmental mandibular resections and free bone flap reconstructions due to tumors, chronic osteomyelitis, or trauma without any radiation. Ossification time and influencing factors were evaluated. Results: Both duration of surgery (346 ± 90 min. vs. 498 ± 124 min.; p < 0.001) and hospitalization (8.7 ± 2.8 days vs. 13.4 ± 5.3 days, p = 0.006) were shorter in the MRONJ group compared to the noMRONJ group. Ossification after mandibular reconstruction was significantly faster in the MRONJ study group [224 days, interquartile range (IQR) 175–287] compared to the control group (288 days, IQR 194–445; p < 0.001). Moreover, good initial contact between the segments resulted in faster ossification (p < 0.001) in the MRONJ group. Ossification rate between original and grafted bone or between grafted bone segments only did not differ in both the study and control groups (MRONJ, p = 0.705 vs. control, p = 0.292). The type of antiresorptive agent did not show any significance for ossification. The rate of wound healing disturbances did also not differ between the study and control groups (p = 0.69). Conclusion: Advanced MRONJ (stage 3) can be resected and reconstructed safely with free microvascular bone flaps. Antiresorptive agents enhance the ossification of the bone segments. Optimal initial contact of the bone segments accelerates bone healing. Surgery and hospitalization are markedly shortened in this vulnerable group of MRONJ patients compared to oncologic patients

NERNST: a genetically-encoded ratiometric non-destructive sensing tool to estimate NADP(H) redox status in bacterial, plant and animal systems

NADP(H) is a central metabolic hub providing reducing equivalents to multiple biosynthetic, regulatory and antioxidative pathways in all living organisms. While biosensors are available to determine NADP+ or NADPH levels in vivo, no probe exists to estimate the NADP(H) redox status, a determinant of the cell energy availability. We describe herein the design and characterization of a genetically-encoded ratiometric biosensor, termed NERNST, able to interact with NADP(H) and estimate E NADP(H). NERNST consists of a redox-sensitive green fluorescent protein (roGFP2) fused to an NADPH-thioredoxin reductase C module which selectively monitors NADP(H) redox states via oxido-reduction of the roGFP2 moiety. NERNST is functional in bacterial, plant and animal cells, and organelles such as chloroplasts and mitochondria. Using NERNST, we monitor NADP(H) dynamics during bacterial growth, environmental stresses in plants, metabolic challenges to mammalian cells, and wounding in zebrafish. NERNST estimates the NADP(H) redox poise in living organisms, with various potential applications in biochemical, biotechnological and biomedical research

The Folded Radial Forearm Flap in Lip and Nose Reconstruction—Still a Unique Choice

(1) Background: The radial forearm flap (RFF) has evolved as the flap of choice for intraoral mucosal reconstructions, providing thin and pliable skin with a safe blood supply. Perforator flaps such as the anterolateral thigh (ALT) flap are increasingly being discussed for the same applications. (2) Methods: Patient history, treatment details, and outcome of 12 patents with moderate to extended defects of the lip and/or nose area that were reconstructed by a folded radial forearm flap were retrospectively evaluated for oncologic and functional outcomes. (3) Results: The mean oncologic and functional follow-up were 21.1 (min. 3.8; max. 83.3) and 31.2 (min. 6; max. 96) months, respectively. All flaps survived without revision. In eight cases, major lip defects were reconstructed by an RFF; in six patients, the palmaris longus tendon was included for lip suspension. The functional results in terms of eating, drinking, and mouth opening were good in five cases, while three patients were graded as fair due to moderate drooling. In seven cases, the major parts of the nose were reconstructed with two good and five fair (nostril constriction in three cases) functional results. (4) Conclusions: The folded RFF remains a unique free flap option for complex three-dimensional lip and nose reconstructions in terms of flexibility, versatility, and robustness

Patient’s Perception of Outcome after Extracapsular Fractures of the Mandibular Condyle Differs from Objective Evaluation—Experience of a Third-Level Hospital

Background: The aim of this study is to assess patients’ subjective perception of treatment outcome after extracapsular fractures of the mandibular condyle. Methods: A questionnaire survey regarding facial nerve palsy (FNP), malocclusion, pain, reduction in maximum mouth opening (MMO) and further discomfort after 3, 6, and 12 months was carried out. Patients aged 18 or more presenting with an extracapsular condylar fracture between 2006 and 2020 were identified by purposive sampling Questionnaires were received from 115 patients. Fractures were classified on the basis of the pre-treatment imaging, the way of treatment was obtained from patients’ medical records. Data were analyzed using Pearsons’ chi-square-test, descriptive statistics and Student’s t-test. Results: 93.0% of the fractures were treated by open reduction and internal fixation (ORIF). MMO reduction was the most common post-treatment complication (55.6%). ORIF was associated with less pain after 3 months (p = 0.048) and lower VAS scores compared to conservative treatment (p = 0.039). Comminuted fractures were more frequently associated with post-treatment malocclusion (p = 0.048), FNP (p = 0.016) and MMO reduction (p = 0.001). Bilateral fractures were significantly accompanied by malocclusion (p = 0.029), MMO reduction (p = 0.038) and pain occurrence (p < 0.001). Conclusions: Patients report less pain after ORIF. Comminuted and bilateral fractures seem to be major risk factors for complications. Subjective perception of complications after extracapsular condylar fractures differs from objectively assessed data

Animal Bite Injuries to the Face: A Retrospective Evaluation of 111 Cases

The treatment of bite wounds to the face is discussed controversially in relation to surgery and antibiotics. The aim of this study is a retrospective evaluation of 111 cases of animal bite injuries to the face that presented to our unit of oral and maxillofacial surgery over a 13-year period. Children under 10 years of age were predominantly involved. A total of 94.5% of the assessed injuries were caused by dogs. Wound infections occurred in 8.1%. Lackmann type II was the most common type of injury (36.9%). The perioral area was affected most frequently (40.5%). Primary wound closure was carried out in 74.8% of the cases. In 91.9% of the cases, antibiotic prophylaxis was prescribed. The most often administered type of antibiotic was amoxicillin with clavulanic acid (62.1%). Patients without antibiotics showed an increased infection rate without significance. Wound infections occurred significantly more frequently in wounds to the cheeks (p = 0.003) and when local flap reconstruction was necessary (p = 0.048). Compared to the other surgical treatment options, primary closure showed the lowest infection rates (4.8%, p = 0.029). We recommend antibiotic prophylaxis using amoxicillin with clavulanic acid and wound drains for wounds of Lackmann class II or higher. Primary closure seems to be the treatment of choice whenever possible

Loss of MMP-27 Predicts Mandibular Bone Invasion in Oral Squamous Cell Carcinoma

Invasion of the mandibular bone is frequent in oral squamous cell carcinoma (OSCC), which often results in extensive ablative and reconstructive procedures for the patient. The purpose of this single-center, retrospective study was to identify and evaluate potential biomarkers and risk factors for bone invasion in OSCC. Initially, in silico gene expression analysis was performed for different HNSCC tumor T-stages to find factors associated with invasive (T4a) tumor growth. Afterwards, the protein expression of bone-metabolizing MMP-27, TNFRSF11B (Osteoprotegerin, OPG), and TNFSF11 (RANKL) was investigated via Tissue Microarrays (TMAs) for their impact on mandibular bone invasion. TMAs were assembled from the bone–tumor interface of primary OSCCs of the floor of the mouth and gingiva from 119 patients. Sixty-four carcinomas with patho-histological jaw invasion (pT4a) were compared to 55 carcinomas growing along the mandible without invasion (pT2, pT3). Tissue samples were additionally evaluated for patterns of invasion using the WPOI grading system. Statistical analysis of in silico data revealed decreased MMP-27 mRNA expression to be strongly associated with the pT4a-stage in OSCC, indicating invasive tumor growth with infiltration of adjacent anatomical structures. Our own clinico-pathological data on OSCCs presented a significant decrease of MMP-27 in tumors invading the nearby mandible (pT4a), compared to pT2 and pT3 tumors without bone invasion. Loss of MMP27 evolved as the strongest predictor of mandibular bone invasion in binary logistic regression analysis. To our knowledge, this is the first study investigating the role of MMP-27 expression in OSCC and demonstrating the importance of the loss of MMP-27 in mandibular bone invasion