A randomized placebo-controlled trial of convalescent plasma for adults hospitalized with COVID-19 pneumonia.

Passive immunotherapy with convalescent plasma may be the only available agent during the early phases of a pandemic. Here, we report safety and efficacy of high-titer convalescent plasma for COVID-19 pneumonia. Double-blinded randomized multicenter placebo-controlled trial of adult patients hospitalized with COVID-19 pneumonia. The intervention was COVID-19 convalescent plasma and placebo was saline allocated 2:1. The primary outcome was clinical status 14 days after the intervention evaluated on a clinical ordinal scale. The trial was registered at ClinicalTrials.Gov, NCT04345289, 14/04/2020. The CCAP-2 trial was terminated prematurely due to futility. Of 147 patients randomized, we included 144 patients in the modified intention-to-treat population. The ordinal clinical status 14 days post-intervention was comparable between treatment groups (odds ratio (OR) 1.41, 95% confidence interval (CI) 0.72-2.09). Results were consistent when evaluating clinical progression on an individual level 14 days after intervention (OR 1.09; 95% CI 0.46-1.73). No significant differences in length of hospital stay, admission to ICU, frequency of severe adverse events or all-cause mortality during follow-up were found between the intervention and the placebo group. Infusion of convalescent plasma did not influence clinical progression, survival or length of hospitalization in patients with COVID-19 pneumonia.

Reduced prevalence of SARS-CoV-2 infection in ABO blood group O.

Identification of risk factors for contracting and developing serious illness following infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is of paramount interest. Here, we performed a retrospective cohort analysis of all Danish individuals tested for SARS-CoV-2 between 27 February 2020 and 30 July 2020, with a known ABO and RhD blood group, to determine the influence of common blood groups on virus susceptibility. Distribution of blood groups was compared with data from nontested individuals. Participants (29% of whom were male) included 473 654 individuals tested for SARS-CoV-2 using real-time polymerase chain reaction (7422 positive and 466 232 negative) and 2 204 742 nontested individuals, accounting for ∼38% of the total Danish population. Hospitalization and death from COVID-19, age, cardiovascular comorbidities, and job status were also collected for confirmed infected cases. ABO blood groups varied significantly between patients and the reference group, with only 38.41% (95% confidence interval [CI], 37.30-39.50) of the patients belonging to blood group O compared with 41.70% (95% CI, 41.60-41.80) in the controls, corresponding to a relative risk of 0.87 (95% CI, 0.83-0.91) for acquiring COVID-19. This study identifies ABO blood group as a risk factor for SARS-CoV-2 infection but not for hospitalization or death from COVID-19.

The value of circulating microRNAs for early diagnosis of B-cell lymphoma: A case-control study on historical samples.

MicroRNAs are small regulatory RNAs that are deregulated in a wide variety of human cancers, including different types of B-cell lymphoma. Nevertheless, the feasibility of circulating microRNA for early diagnosis of B-cell lymphoma has not been established. To address the possibility of detecting specific circulating microRNAs years before a B-cell lymphoma is diagnosed, we studied the plasma expression of microRNA first in pre-treatment samples from patients with diffuse large B-cell lymphoma and subsequently in repository samples from blood donors who later developed B-cell lymphomas. In addition, we studied the microRNA expression in the diagnostic lymphoma biopsy. The most strongly induced (miR-326) and suppressed (miR-375) plasma microRNA at diagnosis, when compared with healthy blood donors, were also substantially up- or down-regulated in plasma repository samples taken from several months to up to two years before the blood donors were diagnosed with B-cell lymphoma. Importantly, at these time points the donors had no signs of disease and felt healthy enough to donate blood. In conclusion, this first study of plasma microRNA profiles from apparently healthy individuals, taken several years before B-cell lymphoma diagnosis, suggests that plasma microRNA profiles may be predictive of lymphoma development.

HOXB4 Gene Expression Is Regulated by CDX2 in Intestinal Epithelial Cells.

The mammalian Caudal-related homeobox transcription factor 2 (CDX2) plays a key role in the homeobox regulatory network and is essential in regulating the expression of several homeobox (HOX) genes during embryonic development, particularly in the gut. Genome-wide CDX2 chromatin immunoprecipitation analysis and expression data from Caco2 cells also suggests a role for CDX2 in the regulation of HOXB4 gene expression in the intestinal epithelium. Thus, the aim of this study was to investigate whether HOXB4 gene expression is regulated by CDX2 in the intestinal epithelium. We demonstrated binding of CDX2 to four different CDX2 binding sites in an enhancer region located upstream of the HOXB4 transcription start site. Mutations in the CDX2 binding sites reduced HOXB4 gene activity, and knock down of endogenous CDX2 expression by shRNA reduced HOXB4 gene expression. This is the first report demonstrating the CDX2 regulation of HOXB4 gene expression in the developed intestinal epithelium, indicating a possible role for HOXB4 in intestinal homeostasis.

Report of the first nationally implemented clinical routine screening for fetal RHD in D- pregnant women to ascertain the requirement for antenatal RhD prophylaxis.

BACKGROUND: A combination of antenatal and postnatal RhD prophylaxis is more effective in reducing D immunization in pregnancy than postnatal RhD prophylaxis alone. Based on the result from antenatal screening for the fetal RHD gene, antenatal RhD prophylaxis in Denmark is given only to those D- women who carry a D+ fetus. We present an evaluation of the first national clinical application of antenatal RHD screening. STUDY DESIGN AND METHODS: In each of the five Danish health care regions, blood samples were drawn from D- women in Gestational Week 25. DNA was extracted from the maternal plasma and analyzed for the presence of the RHD gene by real-time polymerase chain reaction targeting two RHD exons. Prediction of the fetal RhD type was compared with serologic typing of the newborn in 2312 pregnancies, which represented the first 6 months of routine analysis. RESULTS: For the detection of fetal RHD, the sensitivity was 99.9%. The accuracy was 96.5%. The recommendation for unnecessary antenatal RhD prophylaxis for women carrying a D- fetus was correctly avoided in 862 cases (37.3%), while 39 women (1.7%) were recommended for antenatal RhD prophylaxis unnecessarily. Two RHD+ fetuses (0.087%) were not detected, and antenatal RhIG was not given. CONCLUSION: These data represent the first demonstration of the reliability of routine antenatal fetal RHD screening in D-, pregnant women to ascertain the requirement for antenatal RhD prophylaxis. Our findings should encourage the implementation of such screening programs worldwide, to reduce the unnecessary use of RhIG.

Increased mortality among persons infected with hepatitis C virus.

BACKGROUND & AIMS: The long-term mortality of patients infected with hepatitis C virus (HCV) is not known; few studies have controlled for potential confounders, investigated how mortality changes with age at diagnosis and length of follow-up period, provided absolute risk estimates of death, or analyzed specific causes of death. METHODS: Using a Danish population, we compared mortality of a cohort of 10,991 HCV-infected patients with that of an age- and sex-matched cohort. Using regression analysis, we adjusted for municipality of residence, history of psychiatric illness, comorbidities, alcohol and drug abuse, and income. We analyzed causes of death and effects of HCV with age and length of follow-up period. RESULTS: HCV-infected patients had lower income levels and more comorbidities, psychiatric illnesses, and substance and alcohol abuse than the comparison cohort. The 10-year survival rate decreased from 84.1% among HCV-infected patients aged 20 to 29 years to 21.1% among those aged 70 years or older. The increased risk of death among HCV-infected patients was more pronounced in the first year of follow-up period than in subsequent years and in the unadjusted than in the adjusted analysis. Starting in the second year of the follow-up period, HCV-infected patients aged 20 to 29 years had an 18.2-fold increased risk of death, whereas those that were 70 years or older had a 1.6-fold increased risk. Most deaths among younger patients were from unnatural causes, and most deaths among patients 70 years or older were from non-liver-related natural causes. CONCLUSIONS: HCV infection is associated with increased mortality; younger patients (age, 20-29 y) have an increased risk of unnatural death.

Time trend of the prevalence of hepatitis E antibodies among farmers and blood donors: a potential zoonosis in Denmark.

BACKGROUND: Antibody to hepatitis E virus (anti-HEV) is prevalent in Western countries, where clinical hepatitis E is rarely reported. The aim of this study was to determine the prevalence of anti-HEV among Danish blood donors and Danish farmers. In addition, we compared the prevalence among 2 sets of serum samples obtained from blood donors 20 years apart. METHODS: Samples from 291 Danish farmers and 169 blood donors that were collected in 1983 and samples from 461 blood donors that were collected in 2003 were tested for anti-HEV. Relevant information on HEV exposure was collected by self-administered questionnaire. RESULTS: Anti-HEV testing was performed on samples after 20 years of storage at -20 degrees C. The prevalence of anti-HEV was 50.4% among farmers and 32.9% among donors in 1983 and 20.6% among donors in 2003 (P < .05). Presence of anti-HEV was significantly correlated with increasing age in all 3 groups (P < .05). Among donors who had serum samples obtained in 2003, age, contact with horses, and the presence of antibody to hepatitis A virus were associated with the presence of anti-HEV in multivariate analysis. Among farmers, only age was independently associated with the presence of anti-HEV. CONCLUSION: Anti-HEV was highly prevalent among Danes but has decreased in prevalence over the past 50 years. Our study supports the hypothesis that HEV infection in Denmark may be an asymptomatic zoonotic infection.

Hepatitis A infection and vaccination among Danish blood donors.

When testing 466 Danish blood donors, of whom 60 reported to be vaccinated against hepatitis A, 55 (11.8%, 95% CI: 9.0-15.1) had detectable levels of anti-hepatitis A virus IgG (> 10 m IU/ml). Among unvaccinated donors, the prevalence rate was 23/376 (6.1%, 95% CI: 3.9-9.0) with age above 50 y and use of private water supply being independently associated with seropositivity.

Acute and Late Toxicity Following Adjuvant High-Dose Chemotherapy for High-Risk Primary Operable Breast Cancer A Quality Assessment Study.

From 1996 to 2000, high-dose chemotherapy with haematopoietic stem-cell support was used as an adjuvant treatment strategy for management of primary high-risk breast cancer patients with more than five positive nodes. This single institution study included 52 women aged h 56 years with primary operable breast cancer and S 6 tumour-positive axillary lymph nodes. The treatment regimen consisted of at least three initial courses of FEC (5-fluorouracil, epirubicin, cyclophosphamide) followed by high-dose chemotherapy (cyclophosphamide, thiotepa, carboplatin) supported by autologous peripheral blood stem-cell reinfusion. This study focuses on quality control including evaluation of toxicity, supportive therapy and assessment of the stem-cell products. Cytokeratin 19 positive cells were found in the stem-cell product from 3/37 patients. Data regarding organ toxicity were used for evaluation of short- and long-term side effects. Substantial acute toxicity and frequent catheter-related infections were found. Long-term toxicities included reduced lung diffusion capacity (n=36), fatigue (n=14), arthralgia/myalgia (n=10), neurotoxicity (n=9) and memory loss (n=4). However, most toxicities were grade 1-2 and reversible within two years. No treatment-related death occurred. Within a median follow-up of 30 months (range, 11-57), 25% of the patients had relapsed. Recurrence-free survival was 75% and overall survival was 88% three years after the start of treatment. Overall, high-dose chemotherapy was relatively well tolerated, with manageable toxicity and an acceptable requirement of supportive therapy. Until now, high-dose chemotherapy has not proven superior to conventional-dose adjuvant chemotherapy, therefore it is necessary in the future to focus on well-designed randomized studies.

Acute and late toxicity following adjuvant high-dose chemotherapy for high-risk primary operable breast cancer--a quality assessment study.

From 1996 to 2000, high-dose chemotherapy with haematopoietic stem-cell support was used as an adjuvant treatment strategy for management of primary high-risk breast cancer patients with more than five positive nodes. This single institution study included 52 women aged < or = 56 years with primary operable breast cancer and > or = 6 tumour-positive axillary lymph nodes. The treatment regimen consisted of at least three initial courses of FEC (5-fluorouracil, epirubicin, cyclophosphamide) followed by high-dose chemotherapy (cyclophosphamide, thiotepa, carboplatin) supported by autologous peripheral blood stem-cell reinfusion. This study focuses on quality control including evaluation of toxicity, supportive therapy and assessment of the stem-cell products. Cytokeratin 19 positive cells were found in the stem-cell product from 3/37 patients. Data regarding organ toxicity were used for evaluation of short- and long-term side effects. Substantial acute toxicity and frequent catheter-related infections were found. Long-term toxicities included reduced lung diffusion capacity (n = 36), fatigue (n = 14), arthralgia/myalgia (n = 10), neurotoxicity (n = 9) and memory loss (n = 4). However, most toxicities were grade 1-2 and reversible within two years. No treatment-related death occurred. Within a median follow-up of 30 months (range, 11-57), 25% of the patients had relapsed. Recurrence-free survival was 75% and overall survival was 88% three years after the start of treatment. Overall, high-dose chemotherapy was relatively well tolerated, with manageable toxicity and an acceptable requirement of supportive therapy. Until now, high-dose chemotherapy has not proven superior to conventional-dose adjuvant chemotherapy, therefore it is necessary in the future to focus on well-designed randomized studies.