[Management of critically ill nontrauma patients in a nonuniversity emergency department]. / Nichttraumatologisches Schockraummanagement in einer nichtuniversitären Notaufnahme.

Purpose: Today there exists only limited knowledge regarding the care of critically ill nontrauma (CINT) patients in the resuscitation room (RR) in Germany. The goal of this observational study was to describe the management of CINT patients in the RR of a nonuniversity emergency department. Methods: Data of adult nontrauma patients in the RR were prospectively collected in this study from 26 January 2019 to 18 May 2021 using the OBSERvE­2 evaluation protocol. Results: In all, 213 patients were included in the study (age: 70 ± 15 years, 55% male; admission to the RR by emergency medical service 93%). 28% were brought in after out-of-hospital cardiac arrest. Leading admission causes were C (47%) and B problems (39%). Diagnoses at the end of RR treatment were 30% pulmonary and 26% cardiovascular diseases without myocardial infarction as well as pulmonary embolism (8% and 5%, respectively). Measures performed were airway protection (20%), invasive (46%) and noninvasive ventilation (25%), cardiopulmonary resuscitation (13%), catecholamine therapy (34%), emergency ultrasound (62%). The initial treatment lasted for 41 ± 22 min. Computed tomography was subsequently performed in 51%. On average 4-5 persons were involved in the treatment during the RR period. In total, 9% of the patients died during RR treatment and 40% in the hospital. Conclusion: Patients in a nonuniversity nontrauma RR are resource-intensive and have a high in-hospital lethality. RR care can be completed within 60 min. In order to achieve better comparability between patient populations of different locations, it is necessary to uniformly define admission criteria for the nontrauma resuscitation room.

Safety, immunogenicity and protection provided by unadjuvanted and adjuvanted formulations of recombinant plant-derived virus-like particle vaccine candidate for COVID-19 in non-human primates

Although antivirals are important tools to control the SARS-CoV-2 infection, effective vaccines are essential to control the current pandemic. Plant-derived virus-like particle (VLP) vaccine candidates have previously demonstrated immunogenicity and efficacy against influenza. Here we report the immunogenicity and protection induced in macaques by intramuscular injections of VLP bearing SARS-CoV-2 spike protein (CoVLP) vaccine candidate formulated with or without Adjuvant System 03 (AS03) or cytosine phosphoguanine (CpG) 1018. Although a single dose of unadjuvanted CoVLP vaccine candidate stimulated humoral and cell-mediated immune responses, booster immunization (at 28 days after prime) and adjuvants significantly improved both responses with a higher immunogenicity and protection provided by AS03 adjuvanted CoVLP. Fifteen microgram CoVLP adjuvanted with AS03 induced a balanced IL-2 driven response along with IL-4 expression in CD4 T cells and mobilization of CD4 follicular helper cells (Tfh). Animals were challenged by multiple routes (i.e. intratracheal, intranasal and ocular) with a total viral dose of 106 plaque forming units of SARS-CoV-2. Lower viral replication in nasal swabs and broncho-alveolar lavage (BAL) as well as fewer SARS-CoV-2 infected cells and immune cell infiltrates in the lungs concomitant with reduced levels of pro-inflammatory cytokines and chemotactic factors in BAL were observed in the animals immunized with CoVLP adjuvanted with AS03. No clinical, pathologic or virologic evidences of vaccine associated enhanced disease (VAED) were observed in vaccinated animals. CoVLP adjuvanted with AS03 was therefore selected for vaccine development and clinical trials.

Adjuvanting a subunit SARS-CoV-2 nanoparticle vaccine to induce protective immunity in non-human primates.

The development of a portfolio of SARS-CoV-2 vaccines to vaccinate the global population remains an urgent public health imperative. Here, we demonstrate the capacity of a subunit vaccine under clinical development, comprising the SARS-CoV-2 Spike protein receptor-binding domain displayed on a two-component protein nanoparticle (RBD-NP), to stimulate robust and durable neutralizing antibody (nAb) responses and protection against SARS-CoV-2 in non-human primates. We evaluated five different adjuvants combined with RBD-NP including Essai O/W 1849101, a squalene-in-water emulsion; AS03, an alpha-tocopherol-containing squalene-based oil-in-water emulsion used in pandemic influenza vaccines; AS37, a TLR-7 agonist adsorbed to Alum; CpG 1018-Alum (CpG-Alum), a TLR-9 agonist formulated in Alum; or Alum, the most widely used adjuvant. All five adjuvants induced substantial nAb and CD4 T cell responses after two consecutive immunizations. Durable nAb responses were evaluated for RBD-NP/AS03 immunization and the live-virus nAb response was durably maintained up to 154 days post-vaccination. AS03, CpG-Alum, AS37 and Alum groups conferred significant protection against SARS-CoV-2 infection in the pharynges, nares and in the bronchoalveolar lavage. The nAb titers were highly correlated with protection against infection. Furthermore, RBD-NP when used in conjunction with AS03 was as potent as the prefusion stabilized Spike immunogen, HexaPro. Taken together, these data highlight the efficacy of the RBD-NP formulated with clinically relevant adjuvants in promoting robust immunity against SARS-CoV-2 in non-human primates.

Adjuvanting a subunit SARS-CoV-2 nanoparticle vaccine to induce protective immunity in non-human primates

The development of a portfolio of SARS-CoV-2 vaccines to vaccinate the global population remains an urgent public health imperative. Here, we demonstrate the capacity of a subunit vaccine under clinical development, comprising the SARS-CoV-2 Spike protein receptor binding domain displayed on a two-component protein nanoparticle (RBD-NP), to stimulate robust and durable neutralizing antibody (nAb) responses and protection against SARS-CoV-2 in non-human primates. We evaluated five different adjuvants combined with RBD-NP including Essai O/W 1849101, a squalene-in-water emulsion; AS03, an alpha-tocopherol-containing squalene-based oil-in-water emulsion used in pandemic influenza vaccines; AS37, a TLR-7 agonist adsorbed to Alum; CpG 1018-Alum (CpG-Alum), a TLR-9 agonist formulated in Alum; or Alum, the most widely used adjuvant. All five adjuvants induced substantial nAb and CD4 T cell responses after two consecutive immunizations. Durable nAb responses were evaluated for RBD-NP/AS03 immunization and the live-virus nAb response was durably maintained up to 154 days post-vaccination. AS03, CpG-Alum, AS37 and Alum groups conferred significant protection against SARS-CoV-2 infection in the pharynges, nares and in the bronchoalveolar lavage. The nAb titers were highly correlated with protection against infection. Furthermore, RBD-NP when used in conjunction with AS03 was as potent as the prefusion stabilized Spike immunogen, HexaPro. Taken together, these data highlight the efficacy of the RBD-NP formulated with clinically relevant adjuvants in promoting robust immunity against SARS-CoV-2 in non-human primates.

[Auricular chondritis as first symptom of ANCA-associated vasculitis]. / Aurikuläre Chondritis als Erstsymptom einer ANCA-assoziierten Vaskulitis.

Auricular chondritis frequently occurs in relapsing polychondritis. In addition to the primary form of the disease up to 30% of cases of chondritis can be secondary, e.g. due to autoimmune diseases. We describe the case of a 62-year-old male patient with auricular chondritis as the first symptom of granulomatosis with polyangiitis. Anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis should always be considered in the differential diagnostics of relapsing polychondritis and antibody testing should be performed accordingly.

Late Steroid Withdrawal Following AB0-Incompatible Renal Transplantation.

BACKGROUND: Current evidence on steroid withdrawal following AB0-incompatible (AB0i) renal transplantation is low. We compared clinical outcomes of patients who agreed to late steroid withdrawal and patients who remained on steroid treatment. METHODS: Steroid withdrawal was carried out in 11 patients at ≥12 months after transplantation (group W). For comparison, we analyzed 19 patients who remained on triple immunosuppression including steroids (group M). Minimum follow-up was 24 months following transplantation and 12 months after steroid withdrawal. RESULTS: Baseline characteristics, including observation times, were not different between groups W and M. Graft survival was 100% in group W compared with 84% (16/19) in group M (P = .15). In group M, 1 patient experienced graft failure because of suspected antibody-mediated rejection (ABMR) following temporary cessation of mycophenolate treatment after a diagnosis of cryptococcal pneumonia. Two patients died with functioning graft because of sepsis. In group W, we observed 1 episode of ABMR following steroid withdrawal. At the end of follow-up, estimated glomerular filtration rates (eGFR) were 54 (19-91) versus 60 (15-85) mL/min/1.73 m2 in group W versus M, respectively (P = .67). CONCLUSIONS: Late steroid withdrawal following AB0i transplantation is feasible at a moderate risk of rejection. We recommend close monitoring of renal function and HLA antibodies during and after steroid withdrawal. On the other hand, the occurrence of severe infections causing death and graft loss in patients on triple maintenance immunosuppression including steroids should remind us to consider the overall immunosuppressive burden.

Oncotype DX(®) colon cancer assay for prediction of recurrence risk in patients with stage II and III colon cancer: A review of the evidence.

Advances in molecular biology have enabled identification of tumor biomarkers that allow for individualized risk assessment for patients with cancer. Molecular predictors of clinical outcome can help inform discussion regarding the role of adjuvant chemotherapy in patients with resected colon cancer, such as those with stage II colon cancer in which the benefit of adjuvant therapy is controversial or those with stage III colon cancer who may have a lower risk of recurrence and less absolute benefit from oxaliplatin therapy. This article summarizes the data surrounding the development, validation, and clinical and economic utility of the Oncotype DX(®) colon cancer assay, a multigene expression assay validated to independently predict recurrence risk in patients with stage II and III colon cancer beyond traditional factors.

The "global surgeon": is it time for modifications in the American surgical training paradigm?

OBJECTIVE: "Global surgery" is becoming an increasingly popular concept not only for new trainees, but also for established surgeons. The need to provide surgical care in low-resource settings is laudable, but the American surgical training system currently does not impart the breadth of skills required to provide quality care. We propose one possible model for a surgical fellowship program that provides those trainees who desire to practice in these settings a comprehensive experience that encompasses not only broad technical skills but also the opportunity to engage in policy and programmatic development and implementation. METHODS: This is a descriptive commentary based on personal experience and a review of the literature. RESULTS: The proposed model is 2 years long, and can either be done after general surgery training as an additional "global surgery" fellowship or as part of a 3 + 2 general surgery + global surgery system. It would incorporate training in general surgery as well as orthopedics, urology, obstetrics & gynecology, neurosurgery, plastics & reconstructive surgery, as well as dedicated time for health systems training. Incorporating such training in a low-resource setting would be a requirement of such a program, in order to obtain field experience. CONCLUSIONS: Global surgery is a key word these days in attracting young trainees to academic surgical residency programs, yet they are subsequently inadequately trained to provide the required surgical services in these low-resource settings. Dedicated programmatic changes are required to allow those who choose to practice in these settings to obtain the full breadth of training needed to become safe, competent surgeons in such environments.

Acute cellular rejection with isolated v-lesions is not associated with more favorable outcomes than vascular rejection with more tubulointerstitial inflammations.

BACKGROUND: The impact of isolated v-lesions on clinical outcome in biopsies with acute cellular rejection (ACR) is unclear. METHODS: Two hundred and sixty-five biopsies showing the highest ACR severity for each patient were recruited and classified into four groups: (i) acute interstitial rejection (AIR) I with minimal tubulointerstitial inflammation (TI), (ii) AIR II with intensive TI, (iii) acute vascular rejection (AVR) I with minimal TI, and (iv) AVR II with intensive TI. RESULTS: The complete reversal rates of AIR I and AIR II groups were marginally higher than AVR I and AVR II groups (p = 0.16). At eight yr of transplantation, the death-censored graft survival (DCGS) rate of AIR I group (93.3%) was significantly higher compared with the AVR I (72.7%) or AVR II (72.9%) group. AVR I group had a similar DCGS rate with AVR II group (72.7% vs. 74.1%), whereas AVR with v1-lesion showed significantly higher graft survival (GS) rate than those with v2-lesion (70.2% vs. 45.5%). The t-lesion of AIR and v-lesion of AVR group were associated with graft loss. CONCLUSION: The extent of TI is non-specifically associated with graft loss in biopsies with AVR; the higher grade v-lesion predicts the lower complete reversal rate and poorer long-term graft survival.

[Fingertip necroses of unknown origin]. / Unklare akrale Nekrosen an den Fingern.

A 63-year old woman presented with dry necrotic areas on the distal and medial phalanges of her right index and middle finger caused by burns while smoking. Differential diagnostic considerations included occlusive arterial disease, vasculitis, endangiitis obliterans, peripheral embolisms and exposure to chemicals. The patient had the habit of smoking her cigarettes until the last possible drag, putting her skin in direct contact with the burning tobacco.

[Systemic therapy for malignant melanoma]. / Medikamentöse Therapie des malignen Melanoms.

For decades dacarbazine was the standard in the therapy for metastatic melanoma even though response rates were low. In recent years multiple pharmacological approaches have led to new therapy options including immune modulators like anti-CTLA4 antibodies and kinase inhibitors of the MAPK signaling pathway that showed better response rates and increased overall survival. However, since immune modulators lead only in a small subgroup of patients to long-term responses and kinase inhibitors lose their function due to development of resistance after several months, continuation of clinical studies is strongly required. Classical chemotherapeutic drugs will remain a basic part of the therapy especially as combinations of different treatment options have to be focused on in order to achieve better long-term survival rates.

Donor-specific HLA antibodies in a cohort comparing everolimus with cyclosporine after kidney transplantation.

Donor-specific HLA antibodies (DSA) have a negative impact on kidney graft survival. Therefore, we analyzed the occurrence of DSA and antibody-mediated rejection (AMR) in patients from two prospective randomized trials in our center. At 3-4.5 months posttransplant 127 patients were randomized to continue cyclosporine or converted to everolimus therapy. The presence of DSA was prospectively assessed using Luminex assays. AMR was defined according to the Banff 2009 classification. Antibody screening was available in 126 patients with a median follow-up of 1059 days. Seven out of 65 (10.8%) patients on cyclosporine developed DSA after a median of 991 days. In comparison, 14/61 patients (23.0%) randomized to everolimus developed DSA after 551 days (log-rank: p = 0.048). Eight patients on everolimus compared to two patients on cyclosporine developed AMR (log-rank: p = 0.036). Four of 10 patients with AMR-all in the everolimus group-lost their graft. A multivariate regression model revealed everolimus, >3 mismatches and living donor as significant risk factors for DSA. Acute rejection within the first year, >3 mismatches, everolimus and living donor were independent risk factors for AMR. This single center analysis demonstrates for the first time that everolimus-based immunosuppression is associated with an increased risk for the development of DSA and AMR.

[Documentation of ophthalmological findings in contact lens wearers: software-based symbol library of the Efron grading scale]. / Ophthalmologische Befunddokumentation bei Kontaktlinsenträgern: Softwarebasierte Symbolbibliothek nach Efron-Standard.

BACKGROUND: To prevent complications through the use of contact lenses the efforts spent on documentation will have to be increased to meet the demands of quality management. How can ophthalmologists benefit from the use of software-based graphical documentation? METHODS: To make a standardized documentation of contact lens complications possible a software module with a graphically intuitive visualization scheme of the Efron grading scale was developed. The Efron grading scale defines 16 different classes of findings scaled to 5 grades. RESULTS: The software module shows a schematic view of the eye which allows an easy sectoral assignment of all 16 Efron findings. The designated sector can simply be marked with a mouse click. A subsequently appearing context menu offers all 16 Efron findings together with the corresponding 5 grades. Finally the chosen Efron grade is graphically visualized in the corresponding sector. CONCLUSION: The software module supplies a feasible way for high quality documentation in the clinical routine with illustrative visualization. The practical application of software tools to assist clinical documentation can help to meet the challenges of quality management in contact lens utilization.

CXCR3+CD4+ T cells are enriched in inflamed kidneys and urine and provide a new biomarker for acute nephritis flares in systemic lupus erythematosus patients.

OBJECTIVE: The high frequency of CD4+ T cells in interstitial infiltrates of patients with lupus nephritis suggests a contribution of these cells to local pathogenesis. The aim of this study was to examine the role of CXCR3 and the chemokine CXCL10 in recruiting these cells into the kidney and to determine whether the infiltrating T cells could be monitored in the urine to provide a reliable biomarker for acute lupus nephritis. METHODS: The frequencies of CD3+ T cells, CXCR3+ cells, and CXCL10+ cells were determined by immunohistochemical and immunofluorescence analyses of kidney sections from 18 patients with lupus nephritis. The frequency of CXCR3+CD4+ T cells was determined by flow cytometry of peripheral blood and urine from 38 patients with systemic lupus erythematosus (SLE), and the values were compared with disease activity as determined by the Systemic Lupus Erythematosus Disease Activity Index. RESULTS: In renal biopsy tissues from patients with lupus nephritis, a mean of 63% of the infiltrating cells expressed CXCR3, approximately 60% of them were T cells, and the CXCR3+ cells colocalized with CXCL10-producing cells. In biopsy tissues from SLE patients with acute nephritis, approximately 50% of the urinary CD4+ T cells were CXCR3+, as compared with 22% in the peripheral blood, and the frequency of urinary CXCR3+CD4+ T cells correlated with disease activity. Moreover, the number of urinary CD4+ T cells reflected nephritis activity, and elevation above 800 CD4+ T cells per 100 ml of urine sharply delineated active from inactive nephritis. CONCLUSION: CXCR3+ T cells are recruited into the inflamed kidneys, are enriched in the urine, and are a valuable marker of nephritis activity in SLE. They also present a potential target for future therapies.

The electrochemical detection of droplets in microfluidic devices.

This paper presents a new electrochemical method for the detection and characterisation of aqueous droplets in an organic carrier fluid (1,2-dichloroethane) formed in flow-focusing microfluidic devices. The devices consist of a conventional flow-focusing channel 250 microm wide and 250 microm deep cast out of poly(dimethylsiloxane) (PDMS) which is sealed onto a glass substrate containing a set of microelectrodes 100 microm long. Chronoamperometric analysis of a suitable electrolyte contained in the organic phase is presented for characterising the droplet frequency and size. This chronoamperometric method is then extended to a dual working electrode approach in order to determine the velocity of the droplet. Good agreement between experimental measurements and theory was observed.

Liver resection for metastatic gastric cancer.

AIMS: Liver resection represents a curative treatment approach in patients suffering from liver metastases from gastric cancer. However, its value in the treatment of these patients remains controversial. This study was conducted to evaluate the safety and effectiveness of liver resection in these conditions and to identify criteria for the selection of suitable patients. METHODS: From January 1988 to December 2002, 24 patients underwent liver resection for metastatic gastric cancer. The outcome of these 24 patients was retrospectively reviewed using a prospective database. Patient, tumour and operative parameters were analyzed for their influence on long-term survival. RESULTS: One patient died and four patients (17%) developed complications during the postoperative course. The overall one-, three- and five-year survival was 38%, 16% and 10%, respectively. After curative resection (n=17), the one-, three- and five-year survival rate was 53%, 22% and 15%, respectively, and patients with metachronous metastases restricted to the liver (n=5) had a one-, three- and five-year survival of 80%, 40% and 40%, respectively. In the univariate analysis, extrahepatic manifestation showed in tendency (p=0.069) and resection margins statistically significant (p=0.005) influence on survival. The multivariate analysis revealed only resection margins as an independent prognostic factor for survival. CONCLUSIONS: Long-term survival can be achieved by liver resection in well selected patients and may be considered in the multidisciplinary treatment approach of metastatic gastric cancer. Patients with metastatic disease restricted to the liver in whom a curative resection can be achieved seem to be most suitable for liver resection.

Severe upper airway obstruction due to delayed retropharyngeal hematoma formation following blunt cervical trauma.

BACKGROUND: We report a case of severe upper airway obstruction due to a retropharyngeal hematoma that presented nearly one day after a precipitating traumatic injury. Retropharyngeal hematomas are rare, but may cause life-threatening airway compromise. CASE PRESENTATION: A 50 year-old man developed severe dyspnea with oropharyngeal airway compression due to retropharyngeal hematoma 20 hours after presenting to the emergency department. The patient also had a fractured first cervical vertebra and was diagnosed with a left brachial plexopathy. The patient underwent emergent awake fiberoptic endotracheal intubation to provide a definitive airway. CONCLUSION: Retropharyngeal hematoma with life-threatening airway compromise can develop hours or days after a precipitating injury. Clinicians should be alert to the potential for this delayed airway collapse, and should also be prepared to rapidly secure the airway in this patient population likely to have concomitant cervical spinal or head injuries.

Liver resection for metastases from renal cell carcinoma.

BACKGROUND: This study was conducted to evaluate the safety and efficacy of liver resection in patients with hepatic metastases from renal cell carcinoma and to identify selection criteria for patients suitable for resection. METHODS: Between January 1988 and March 2006, 31 patients underwent liver resection for metastases from renal cell carcinoma. Patients were identified from a prospective database and retrospectively reviewed. Patient, tumor, and operative parameters were analyzed for their influence on long-term survival. RESULTS: The overall 1-, 3- and 5-year survival rates were 82.2%, 54.3%, and 38.9%, respectively. One patient was deceased and 4 developed complications during the postoperative course. In the univariate analysis, site of the primary tumor (P = 0.013), disease-free interval (P = 0.012), and resection margins (P = 0.008) showed significant influence on long-term survival. In the multivariate analysis, only the resection margins were identified as an independent prognostic factor after liver resection. CONCLUSIONS: Liver resection is effective and safe in the treatment of patients with hepatic metastases from renal cell carcinoma and offers the chance of long-term survival and cure. Achieving a margin-negative resection is the most important criterion in the selection of suitable patients for liver resection. However, the number of patients in the present study was small, and investigations of larger series may provide further prognostic parameters in these patients.

Extended resections of liver metastases from colorectal cancer.

BACKGROUND: Indications for resection of liver metastases from colorectal cancer and surgical strategies are still under debate. METHODS: We have retrospectively reviewed the outcome of 660 patients after 685 liver resections for metastases of colorectal cancer in our institution from 1988 to 2004. All surviving patients have a minimum follow-up period of 1 year. The longest follow-up in these patients is 16 years. Three different time periods of 5 to 6 years each were analyzed. RESULTS: The 30- and 60-day mortality rates were 1.5% (n = 10) and 2.2 % (n = 15), respectively. The rate of formally curative (R0) resections was 84%. Five-year survival rates in all patients and in patients after R0 resection were 37% and 42%, respectively. If only resections from 1999 to 2004 were considered, 5-year survival in patients after R0 resection was 50%. In a multivariate analysis, surgical radicality, ligamental lymph node involvement, number of liver metastases, and time period, in which the liver resection had been performed, were independent prognostic parameters. CONCLUSIONS: Outcome after liver resection for metastases from colorectal cancer has constantly improved. A formally curative resection is the most relevant prognostic parameter. Number of liver metastases and, in the few patients concerned, lymph node infiltration of the hepatoduodenal ligament, were further prognostic parameters.