Efficacy of the mRNA-1273 SARS-CoV-2 Vaccine at Completion of Blinded Phase.

BACKGROUND: At interim analysis in a phase 3, observer-blinded, placebo-controlled clinical trial, the mRNA-1273 vaccine showed 94.1% efficacy in preventing coronavirus disease 2019 (Covid-19). After emergency use of the vaccine was authorized, the protocol was amended to include an open-label phase. Final analyses of efficacy and safety data from the blinded phase of the trial are reported. METHODS: We enrolled volunteers who were at high risk for Covid-19 or its complications; participants were randomly assigned in a 1:1 ratio to receive two intramuscular injections of mRNA-1273 (100 µg) or placebo, 28 days apart, at 99 centers across the United States. The primary end point was prevention of Covid-19 illness with onset at least 14 days after the second injection in participants who had not previously been infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The data cutoff date was March 26, 2021. RESULTS: The trial enrolled 30,415 participants; 15,209 were assigned to receive the mRNA-1273 vaccine, and 15,206 to receive placebo. More than 96% of participants received both injections, 2.3% had evidence of SARS-CoV-2 infection at baseline, and the median follow-up was 5.3 months in the blinded phase. Vaccine efficacy in preventing Covid-19 illness was 93.2% (95% confidence interval [CI], 91.0 to 94.8), with 55 confirmed cases in the mRNA-1273 group (9.6 per 1000 person-years; 95% CI, 7.2 to 12.5) and 744 in the placebo group (136.6 per 1000 person-years; 95% CI, 127.0 to 146.8). The efficacy in preventing severe disease was 98.2% (95% CI, 92.8 to 99.6), with 2 cases in the mRNA-1273 group and 106 in the placebo group, and the efficacy in preventing asymptomatic infection starting 14 days after the second injection was 63.0% (95% CI, 56.6 to 68.5), with 214 cases in the mRNA-1273 group and 498 in the placebo group. Vaccine efficacy was consistent across ethnic and racial groups, age groups, and participants with coexisting conditions. No safety concerns were identified. CONCLUSIONS: The mRNA-1273 vaccine continued to be efficacious in preventing Covid-19 illness and severe disease at more than 5 months, with an acceptable safety profile, and protection against asymptomatic infection was observed. (Funded by the Biomedical Advanced Research and Development Authority and the National Institute of Allergy and Infectious Diseases; COVE ClinicalTrials.gov number, NCT04470427.).

Original SARS-CoV-2 monovalent and Omicron BA.4/BA.5 bivalent COVID-19 mRNA vaccines: phase 2/3 trial interim results.

This ongoing, open-label, phase 2/3 trial compared the safety and immunogenicity of the Omicron BA.4/BA.5-containing bivalent mRNA-1273.222 vaccine with the ancestral Wuhan-Hu-1 mRNA-1273 as booster doses. Two groups of adults who previously received mRNA-1273 as primary vaccination series and booster doses were enrolled in a sequential, nonrandomized manner and received single-second boosters of mRNA-1273 (n = 376) or bivalent mRNA-1273.222 (n = 511). Primary objectives were safety and the noninferiority or superiority of neutralizing antibody (nAb) responses against Omicron BA.4/BA.5 and ancestral SARS-CoV-2 with the D614G mutation (ancestral SARS-CoV-2 (D614G)), 28 days post boost. Superiority and noninferiority were based on prespecified success criteria (lower bounds of 95% CI > 1 and < 0.677, respectively) of the mRNA-1273.222:mRNA-1273 geometric mean ratios. Bivalent Omicron BA.4/BA.5-containing mRNA-1273.222 elicited superior nAb responses against BA.4/BA.5 versus mRNA-1273 and noninferior responses against ancestral SARS-CoV-2 (D614G) at day 29 post boost in participants without detectable prior SARS-CoV-2 infection. Day 29 seroresponses against Omicron BA.4/BA.5 were higher for mRNA-1273.222 than for mRNA-1273 and similar against ancestral SARS-CoV-2 (D614G), both meeting noninferiority criterion. The safety profile of mRNA-1273.222 was similar to that previously reported for mRNA-1273 with no new safety concerns identified. Continued monitoring of neutralization and real-world vaccine effectiveness are needed as additional divergent-virus variants emerge. ClinicalTrials.gov registration: NCT04927065.

Safety, immunogenicity and antibody persistence of a bivalent Beta-containing booster vaccine against COVID-19: a phase 2/3 trial.

Updated immunization strategies are needed to address multiple severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants. Here we report interim results from an ongoing, open-label phase 2/3 trial evaluating the safety and immunogenicity of the bivalent Coronavirus Disease 2019 (COVID-19) vaccine candidate mRNA-1273.211, which contains equal mRNA amounts encoding the ancestral SARS-CoV-2 and Beta variant spike proteins, as 50-µg (n = 300) and 100-µg (n = 595) first booster doses administered approximately 8.7-9.7 months after the mRNA-1273 primary vaccine series ( NCT04927065 ). The primary objectives were to evaluate the safety and reactogenicity of mRNA-1273.211 and to demonstrate non-inferior antibody responses compared to the mRNA-1273 100-µg primary series. Additionally, a pre-specified immunogenicity objective was to demonstrate superior antibody responses compared to the previously authorized mRNA-1273 50-µg booster. The mRNA-1273.211 booster doses (50-µg or 100-µg) 28 days after immunization elicited higher neutralizing antibody responses against the ancestral SARS-CoV-2 and Beta variant than those elicited 28 days after the second mRNA­1273 dose of the primary series ( NCT04470427 ). Antibody responses 28 days and 180 days after the 50-µg mRNA-1273.211 booster dose were also higher than those after a 50-µg mRNA-1273 booster dose ( NCT04405076 ) against the ancestral SARS-CoV-2 and Beta, Omicron BA.1 and Delta variants, and all pre-specified immunogenicity objectives were met. The safety and reactogenicity profile of the bivalent mRNA-1273.211 booster (50-µg) was similar to the booster dose of mRNA-1273 (50-µg). Immunization with the primary series does not set a ceiling to the neutralizing antibody response, and a booster dose of the bivalent vaccine elicits a robust response with titers that are likely to be protective against COVID-19. These results indicate that bivalent booster vaccines can induce potent, durable and broad antibody responses against multiple variants, providing a new tool in response to emerging variants.

Vacuum-assisted closure (VAC) for postoperative secondary peritonitis: Effect on bacterial load as well as local and systemic cytokine response (initial results).

BACKGROUND: It is still a matter of debate what the best management of peritonitis is following eliminating the source of infection. This particularly concerns the amplitude of local and systemic inflammatory response as well as bacterial clearence at the infectious site. AIM: To investigate the effects of vacuum-assisted closure (VAC) vs. relaparotomy on demand (ROD) onto the i) severity and course of disease, ii) surgical outcome, iii) intraperitoneal bacterial load as well as iv) local and systemic inflammatory and immune response in postoperative secondary peritonitis. METHODS: Over a defined time period, all consecutive patients of the reporting surgical department with a secondary peritonitis (assessed by Mannheim's Peritonitis Index [MPI] and APPACHE II score) were enrolled in this systematic unicenter clinical prospective observational pilot study reflecting daily surgical practice and as a contribution to internal quality assurance. Patients were subclassified into VAC or ROD group according to surgeon's individual decision at the time point of primary surgical intervention with the intent to sanitize the source of infection. Early postoperative result was assessed by 30-d and in-hospital mortality. Bacterial load was characterized by microbiological culture of intraperitoneal fluid collection obtained on postoperative days (POD) 0 (primary surgical intervention), 1, 4, 7, 10, 13 and following description of the microbial spectrum including semiquantitative assessment of bacterial load. Local and systemic inflammatory and immune response was determined by ELISA-based analysis of CrP, PCT and the representative cytokines such as TNF-α, IL-1ß, IL-6, IL-8, and IL-10 of serum and peritoneal fluid samples. RESULTS: Over a 26-months investigation period, 18 patients (sex ratio, male:female=9:9) were eligible for study criteria: n=8 were enrolled in the VAC (m:f=4:4) and n=10 in the ROD group (m:f=5:5). With regard to early postoperative results represented by mortality, there is no significant difference between both patients groups. Despite the relatively low number of cases enrolled in this study, a trend for more severe findings associated with the VAC group could be detected based on MPI score. There was also a trend of higher APACHE II scores in the VAC group from the 7th POD on and, in addition, patients of this group had a longer hospital stay. For patients with persisting infection, there were no relevant differences comparing VAC therapy and ROD. Cytokines released, in particular, at the beginning of the inflammation cascade with proinflammatory characteristics, showed higher values within the peritoneal fluid whereas CrP and PCT were found to be higher within the serum samples. Summary & Conclusion: Comparing data of various local and systemic inflammatory and immune parameters, there were only a few correlations. This may indicate a compartimentation of the inflammatory process within the abdominal cavity. Based on the observed inter-individual variation of this pilot study data, the clinically applicable benefit appears questionable. In this context, a reliable effect of VAC therapy onto reduction of bacterial burden within the abdominal cavity could not clearly be detected.

Solid-pseudopapillary tumor of the pancreatic tail.

We report a case of the rare solid-pseudopapillary tumor of the pancreas. In contrast to other pancreatic tumors, the solid-pseudopapillary tumor has a favorable prognosis. The 60-year-old female patient we report on here was treated by left pancreatic resection combined with splenectomy for a non-metastasizing tumor of the pancreas. A solid-pseudopapillary tumor was found on histology. The patient had no signs of metastases at present. Since a microscopically invasive tumor growth is assumed, oncologically curative resection should be preferred vs the less radical enucleation. The rare solid-pseudopapillary tumor of the pancreas has a good prognosis after successful oncological resection.

Sealing of the hepatic resection area using fibrin glue reduces significant amount of postoperative drain fluid.

AIM: To investigate whether the routine use of fibrin glue applied onto the hepatic resection area can diminish postoperative volume of bloody or biliary fluids drained via intraoperatively placed perihepatic tubes and can thus lower the complication rate. METHODS: Two groups of consecutive patients with a comparable spectrum of recent hepatic resections were compared: (1) 13 patients who underwent application of fibrin glue immediately after resection of liver parenchyma; (2) 12 patients who did not. Volumes of postoperative drainage fluid were determined in 4-h intervals through 24 h indicating the intervention caused bloody and biliary segregation. RESULTS: Through the first 8 h postoperatively, there was a tendency of higher amounts of fluids in patients with no additional application of fibrin glue while through the following intervals, a significant increase of drainage volumes was documented in comparison with the first two 4-h intervals, e.g., after 12 h, 149.6 mL +/-110 mL vs 63.2 mL +/-78 mL. Using fibrin glue, postoperative fluid amounts were significantly lower through the postoperative observation period of 24 h (851 mL +/-715 mL vs 315 mL +/-305 mL). CONCLUSION: For hepatic resections, the use of fibrin glue appears to be advantageous in terms of a significant decrease of surgically associated segregation of blood or bile out of the resection area. This might result in a better outcome.

Randomized trial to compare the safety and immunogenicity of CSL Limited's 2009 trivalent inactivated influenza vaccine to an established vaccine in United States children.

A trivalent inactivated influenza vaccine (CSL's TIV, CSL Limited) was licensed under USA accelerated approval regulations for use in persons≥18 years. We performed a randomized, observer-blind study to assess the safety and immunogenicity of CSL's TIV versus an established US-licensed vaccine in a population≥6 months to <18 years of age. Subjects were stratified as follows: Cohort A (≥6 months to <3 years); Cohort B (≥3 years to <9 years); and Cohort C (≥9 years to <18 years). The subject's age and influenza vaccination history determined the dosing regimen (one or two vaccinations). Subjects received CSL's TIV (n=739) or the established vaccine (n=735) in the autumn of 2009. Serum hemagglutination-inhibition titers were determined pre-vaccination and 30 days after the last vaccination. No febrile seizures or other vaccine-related SAEs were reported. After the first vaccination for Cohorts A and B, respectively, the relative risks of fever were 2.73 and 2.32 times higher for CSL's TIV compared to the established vaccine. Irritability and loss of appetite (for Cohort A) and malaise (for Cohort B) were also significantly higher for CSL's TIV compared to the established vaccine. Post-vaccination geometric mean titers (GMTs) for CSL's TIV versus the established vaccine were 385.49 vs. 382.45 for H1N1; 669.13 vs. 705.61 for H3N2; and 100.65 vs. 93.72 for B. CSL's TIV demonstrated immunological non-inferiority to the established vaccine in all cohorts.

Penetrating abdomino-thoracic injuries: report of four impressive, spectacular and representative cases as well as their challenging surgical management.

UNLABELLED: Gunshot wounds are rare events in European countries, but stab and impalement injuries occur more frequently and are often spectacular. The aim of the study was to describe several types of penetrating abdomino-thoracic injuries as well as the appropriate surgical interventions, including complex wound management. MATERIAL AND METHODS: The representative case series includes four patients with abdomino-thoracic penetrating trauma (two impalements and two stabbings), who were treated in a surgical university hospital (tertiary) centre during a 12-month period. RESULTS: 1. A man was impaled on a steel pipe, which entered the body above the right kidney and behind the liver through the mediastinum via the right thorax, passing the heart and aortic arch up to the left clavicle. The rod was removed via sternotomy and median laparotomy. Only the left subclavian vein required repair. Postoperatively, a residual lesion of the left brachial plexus caused temporary pneumonia. 2. A leg of a collapsing chair drilled into a woman's left foramen obturatorium and exited the body at the right anterior iliac spine. At a regional hospital, the chair leg was removed and the canal caused by gluteal penetration was excised. Exploratory laparotomy revealed peritonitis resulting from a perforated ileum. The injury was repaired with segmental resection and anastomosis. Postoperative right inguinal wound necrosis necessitated excision and vacuum-assisted closure sealing. The patient has residual paresthesia in her left leg resulting from a sacral plexus lesion. 3. During an altercation, a man was stabbed twice in the right thorax. The right pulmonary lobe, the diaphragm, and the liver dome between segment VIII and V were injured. The patient also had a large scalp avulsion at the left and right parietooccipital site and transection of the biceps muscle at the middle third of the right humerus. The chest injuries, approached via right subcostal incision and right anterior thoracotomy were managed with liver packing (two towels, removed after 2 days), suture of the diaphragm, and pleural drainage. 4. A man was stabbed in the left thorax, resulting in pneumothorax and lesions of the diaphragm and left third of the transversal colon, and the neck, resulting in lesions of the pharynx and internal jugular vein. These injuries were approached with left thoracic drainage and suture of the colon and diaphragm lesions. Subsequent right thoracotomy was required to treat right pleural empyema caused by bronchopneumonia as a consequence of blunt thoracic trauma. In addition, the patient required relaparotomy to drain an abscess within the Douglas space and Billroth II gastric resection to control recurrent Forrest-Ia bleeding. CONCLUSIONS: Penetrating abdomino-thoracic injuries demand immediate life-saving measures, transfer to a trauma centre, appropriate resuscitative care, prompt diagnosis, and surgical intervention by an interdisciplinary team of abdominal, vascular, and cardiac surgeons. If these measures are provided, outcomes are maximized, mortality is minimized, and permanent damage can be avoided.

Endoscopic treatment of thoracic esophageal anastomotic leaks by using silicone-covered, self-expanding polyester stents.

BACKGROUND: Surgery, as well as conservative treatment, in patients with clinically apparent intrathoracic esophageal anastomotic leaks often is associated with poor results and carries a high morbidity and mortality. The successful treatment of esophageal anastomotic insufficiencies and perforations when using covered, self-expanding metallic stents is described. METHODS: The feasibility and the outcome of endoscopic treatment of intrathoracic anastomotic leakages when using silicone-covered self-expanding polyester stents were investigated. Twelve consecutive patients presented with clinically apparent intrathoracic esophageal anastomotic leak caused by resection of an epiphrenic diverticulum (n = 1), esophagectomy for esophageal cancer (n = 9), or gastrectomy for gastric cancer (n = 2), were endoscopically treated in our department. The extent of the dehiscences ranged from about 20% to 70% of the anastomotic circumference. After endoscopic lavage and debridement of the leakage at 2-day intervals (mean duration, 8.6 days), a large-diameter polyester stent (Polyflex; proximal/distal diameters 25/21 mm) was placed to seal the leakage. Simultaneously, the periesophageal mediastinum was drained by chest drains. OBSERVATIONS: All 12 patients were successfully treated endoscopically without the need for reoperation. A complete closure of the leakage was obtained in 11 of 12 patients after stent removal (median time to stent retrieval, 4 weeks, range 2-8 weeks). In one patient, a persistent leak was sealed endoscopically after stent removal by using 3 clips. Distal stent migration was obtained in two patients. CONCLUSIONS: The placement of silicone-covered self-expanding polyester stents seems to be a successful minimally invasive treatment option for clinically apparent intrathoracic esophageal anastomotic leaks.

Ethical and regulatory issues arising from proteomic research and technology.

Over the last two decades, medical research has begun to make extensive use of products of human origin in therapeutics, oncology, and most recently, in genetic diseases. This has raised many ethical issues involving patient rights, including issues of consent. Besides informed consent, researchers should address several topics when designing studies using human tissues. Reward for the patient should be kept minimal. Sample transfer should be organized along non-profit lines, at least in Europe. Sampling procedures should be at no risk for human volunteers, and at minimal risk for patients. Biosafety aspects should be addressed, in particular when international collaborations are intended or when collaboration is existing between academia and industry. Regulations on importation and exportation of human tissues should be observed. Data acquisition and storage should be addressed in accordance with national data protection regulations, in particular when using computerized databases. If follow-up information is to be taken, the authorization for such information should be requested. The right for patient's information (or for no information) on the research results should also be addressed. The issues of validation and patenting should be also solved, usually by informing the patient that he/she will have no commercial rights on potential research results. The patient should be told if the samples are transferred to another research laboratory or private company. Samples and related data should be destroyed on request at any time point during the course of the study. If possible, traceability of the donor should be ensured.

Informed consent for molecular-based diagnostic and prognostic studies in the cancer patient.

The consent of the subject who is donating cells, tissues, organs or body fluid for research purposes is a precondition for biomedical research on human samples. Before such consent can be obtained, comprehensive information should be provided to the subject by the investigators. This information includes the scope of research, the intended use of subject's body parts and associated data, the risks and benefits associated with the research project, and the right to withdraw their consent at any time without prejudice. Consent is free and must not be obtained under any kind of pressure. The traditional practice of obtaining consent for unspecified future use of biological samples and data generated from clinical trials is no longer adequate for genetic research. However, the investigator has still interest to keep the definition of the field of research as broad as possible. Privacy is an issue of importance for the patient, who is the primary supplier of human samples, and for his relatives. Benefit sharing is another field of contradictory discussion. Normal volunteers are a special case among gene expression studies. An example of informed consent form is provided.