High-titer convalescent plasma plus nirmatrelvir/ritonavir treatment for non-resolving COVID-19 in six immunocompromised patients

Objectives: Immunocompromised patients have an increased risk of severe or prolonged COVID-19. Currently available drugs are registered to treat COVID-19 during the first 5 to 7 days after symptom onset. Data on the effectivity in immunocompromised patients with chronic non-resolving COVID-19 are urgently needed. Here, we report the outcome of patients treated with nirmatrelvir/ritonavir together with high-titer convalescent plasma (CP) in six immunocompromised patients with non-resolving COVID-19. Methods: Immunocompromised patients with persisting COVID-19 (positive PCR with Ct values &lt;30 for ≥20 days) received off-label therapy with nirmatrelvir/ritonavir. It was combined with CP containing BA.5 neutralizing titers of ≥1/640 whenever available. Follow-up was done by PCR and sequencing on nasopharyngeal swabs on a weekly basis until viral genome was undetectable consecutively. Results: Five immunocompromised patients were treated with high-titer CP and 5 days of nirmatrelvir/ritonavir. One patient received nirmatrelvir/ritonavir monotherapy. Median duration of SARS-CoV-2 PCR positivity was 70 (range 20-231) days before nirmatrelvir/ritonavir treatment. In four patients receiving combination therapy, no viral genome of SARS-CoV-2 was detected on day 7 and 14 after treatment while the patient receiving nirmatrelvir/ritonavir monotherapy, the day 7 Ct value increased to 34 and viral genome was undetectable thereafter. Treatment was unsuccessful in one patient. In this patient, sequencing after nirmatrelvir/ritonavir treatment did not show protease gene mutations. Conclusions: In immunocompromised patients with non-resolving COVID-19, the combination of nirmatrelvir/ritonavir and CP may be an effective treatment. Larger prospective studies are needed to confirm these preliminary results and should compare different treatment durations.</p

Delay in Diagnostic Workup and Treatment of Esophageal Cancer

Introduction: Esophageal cancer should preferably be detected and treated at an early stage, but this may be prohibited by late onset of symptoms and delays in referral, diagnostic workup, and treatment. The aim of this study was to investigate the impact of these delays on outcome in patients with esophageal cancer. Methods: For 491 patients undergoing esophagectomy for cancer between 1991 and 2007, patients' short- and long-term outcome were analyzed according to different time intervals between onset of symptoms, diagnosis, and surgical treatment. Results: Length of prehospital delay (from onset of symptoms until endoscopic diagnosis) did not affect patient's short- or long-term outcome. A shorter hospital delay between establishing the diagnosis of esophageal cancer on endoscopy and surgery was associated with lower overall morbidity and in-hospital mortality. Patients of ASA classes I and II experienced a shorter hospital delay than patients of ASA classes III and IV. Length of hospital delay between endoscopic diagnosis and surgery did not affect pathological tumor-node-metastasis stage or R0-resection rate. Longer hospital delay did not result in worse survival: Overall survival after esophagectomy for cancer was not significantly different between patients with hospital delay 8 weeks (24. 7%, 21. 7%, and 32. 3%, respectively; p = 0. 12). Conclusion: A longer hospital delay (between endoscopic diagnosis and surgery) resulted in worse patient's short-term outcome (higher overall morbidity and mortality rates) but not in a worse long-term outcome (overall survival). This may be explained by a more time-consuming diagnostic workup in patients with a poorer physical status and not by tumor progression

Comparison of the 6th and 7th editions of the UICC-AJCC TNM classification for esophageal cancer

Background. The new 7th edition of the Union for International Cancer Control-American Joint Committee on Cancer (UICC-AJCC) tumor, node, metastasis (TNM) staging system is the ratification of data-driven recommendations from the Worldwide Esophageal Cancer Collaboration database. Generalizability remains questionable for single institutions. The present study serves as a validation of the 7th edition of the TNM system in a prospective cohort of patients with predominantly adenocarcinomas from a single institution. Methods

What Works When Treating Granulomatous Disease in Genetically Undefined CVID? A Systematic Review

Background: Granulomatous disease is reported in at least 8–20% of patients with common variable immunodeficiency (CVID). Granulomatous disease mainly affects the lungs, and is associated with significantly higher morbidity and mortality. In half of patients with granulomatous disease, extrapulmonary manifestations are found, affecting e.g. skin, liver, and lymph nodes. In literature various therapies have been reported, with varying effects on remission of granulomas and related clinical symptoms. However, consensus recommendations for optimal management of extrapulmonary granulomatous disease are lacking. Objective: To present a literature overview of the efficacy of currently described therapies for extrapulmonary granulomatous disease in CVID (CVID+EGD), compared to known treatment regimens for pulmonary granulomatous disease in CVID (CVID+PGD). Methods: The following databases were searched: Embase, Medline (Ovid), Web-of-Science Core Collection, Cochrane Central, and Google Scholar. Inclusion criteria were 1) CVID patients with granulomatous disease, 2) treatment for granulomatous disease reported, and 3) outcome of treatment reported. Patient characteristics, localization of granuloma, treatment, and association with remission of granulomatous disease were extracted from articles. Results: We identified 64 articles presenting 95 CVID patients with granulomatous disease, wherein 117 different treatment courses were described. Steroid monotherapy was most frequently described in CVID+EGD (21 out of 53 treatment courses) and resulted in remission in 85.7% of cases. In CVID+PGD steroid monotherapy was described in 15 out of 64 treatment courses, and was associated with remission in 66.7% of cases. Infliximab was reported in CVID+EGD in six out of 53 treatment courses and was mostly used in granulomatous disease affecting the skin (four out of six cases). All patients (n = 9) treated with anti-TNF-α therapies (infliximab and etanercept) showed remission of extrapulmonary granulomatous disease. Rituximab with or without azathioprine was rarely used for CVID+EGD, but frequently used in CVID+PGD where it was associated with remission of granulomatous disease in 94.4% (17 of 18 treatment courses). Conclusion: Although the number of CVID+EGD patients was limited, data indicate that steroid monotherapy often results in remission, and that anti-TNF-α treatment is effective for granulomatous disease affecting the skin. Also, rituximab with or without azathioprine was mainly described in CVID+PGD, and only in few cases of CVID+EGD

Effect of neoadjuvant chemoradiotherapy on health-Related quality of life in esophageal or junctional cancer: Results from the randomized CROSS trial

Purpose To compare pre-agreed health-related quality of life (HRQOL) domains in patients with esophageal or junctional cancer who received neoadjuvant chemoradiotherapy (nCRT) followed by surgery or surgery alone. Secondary aims were to examine the effect of nCRT on HRQOL before surgery and the effect of surgery on HRQOL. Patients and Methods Patients were randomly assigned to nCRT (carboplatin plus paclitaxel with concurrent 41.4-Gy radiotherapy) followed by surgery or surgery alone. HRQOL was measured using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire–Core 30 (QLQ-C30) and –Oesophageal Cancer Module (QLQ-OES24) questionnaires pretreatment and at 3, 6, 9, and 12 months postoperatively. The nCRT group also received preoperative questionnaires. Physical functioning (PF; QLQ-C30) and eating problems (EA; QLQ-OES24) were chosen as predefined primary end points. Predefined secondary end points were global QOL (GQOL; QLQ-C30), fatigue (FA; QLQ-C30), and emotional problems (EM; QLQ-OES24). Results A total of 363 patients were analyzed. No statistically significant differences in postoperative HRQOL were found between treatment groups. In the nCRT group, PF, EA, GQOL, FA, and EM scores deteriorated 1 week after nCRT (Cohen’s d: 20.93, P, .001; 0.47, P, .001; 20.84, P, .001; 1.45, P, .001; and 0.32, P = .001, respectively). In both treatment groups, all end points declined 3 months postoperatively compared with baseline (Cohen’s d: 21.00, 0.33, 20.47, 20.34, and 0.33, respectively; all P, .001), followed by a continuous gradual improvement. EA, GQOL, and EM were restored to baseline levels during follow-up, whereas PF and FA remained impaired 1 year postoperatively (Cohen’s d: 0.52 and 20.53, respectively; both P, .001). Conclusion Although HRQOL declined during nCRT, no effect of nCRT was apparent on postoperative HRQOL compared with surgery alone. In addition to the improvement in survival, these findings support the view that nCRT according to the Chemoradiotherapy for Esophageal Cancer Followed by Surgery Study–regimen can be regarded as a standard of care

The GATA-factor elt-2 is essential for formation of the Caenorhabditis elegans intestine

AbstractThe Caenorhabditis elegans elt-2 gene encodes a single-finger GATA factor, previously cloned by virtue of its binding to a tandem pair of GATA sites that control the gut-specific ges-1 esterase gene. In the present paper, we show that elt-2 expression is completely gut specific, beginning when the embryonic gut has only two cells (one cell cycle prior to ges-1 expression) and continuing in every cell of the gut throughout the life of the worm. When elt-2 is expressed ectopically using a transgenic heat-shock construct, the endogenous ges-1 gene is now expressed in most if not all cells of the embryo; several other gut markers (including a transgenic elt-2-promoter: lacZ reporter construct designed to test for elt-2 autoregulation) are also expressed ectopically in the same experiment. These effects are specific in that two other C. elegans GATA factors (elt-1 and elt-3) do not cause ectopic gut gene expression. An imprecise transposon excision was identified that removes the entire elt-2 coding region. Homozygous elt-2 null mutants die at the L1 larval stage with an apparent malformation or degeneration of gut cells. Although the loss of elt-2 function has major consequences for later gut morphogenesis and function, mutant embryos still express ges-1. We suggest that elt-2 is part of a redundant network of genes that controls embryonic gut development; other factors may be able to compensate for elt-2 loss in the earlier stages of gut development but not in later stages. We discuss whether elements of this regulatory network may be conserved in all metazoa

Ten-Year Outcome of Neoadjuvant Chemoradiotherapy Plus Surgery for Esophageal Cancer:The Randomized Controlled CROSS Trial

PURPOSE: Preoperative chemoradiotherapy according to the chemoradiotherapy for esophageal cancer followed by surgery study (CROSS) has become a standard of care for patients with locally advanced resectable esophageal or junctional cancer. We aimed to assess long-term outcome of this regimen. METHODS: From 2004 through 2008, we randomly assigned 366 patients to either five weekly cycles of carboplatin and paclitaxel with concurrent radiotherapy (41.4 Gy in 23 fractions, 5 days per week) followed by surgery, or surgery alone. Follow-up data were collected through 2018. Cox regression analyses were performed to compare overall survival, cause-specific survival, and risks of locoregional and distant relapse. The effect of neoadjuvant chemoradiotherapy beyond 5 years of follow-up was tested with time-dependent Cox regression and landmark analyses. RESULTS: The median follow-up was 147 months (interquartile range, 134-157). Patients receiving neoadjuvant chemoradiotherapy had better overall survival (hazard ratio [HR], 0.70; 95% CI, 0.55 to 0.89). The effect of neoadjuvant chemoradiotherapy on overall survival was not time-dependent (P value for interaction, P = .73), and landmark analyses suggested a stable effect on overall survival up to 10 years of follow-up. The absolute 10-year overall survival benefit was 13% (38% v 25%). Neoadjuvant chemoradiotherapy reduced risk of death from esophageal cancer (HR, 0.60; 95% CI, 0.46 to 0.80). Death from other causes was similar between study arms (HR, 1.17; 95% CI, 0.68 to 1.99). Although a clear effect on isolated locoregional (HR, 0.40; 95% CI, 0.21 to 0.72) and synchronous locoregional plus distant relapse (HR, 0.43; 95% CI, 0.26 to 0.72) persisted, isolated distant relapse was comparable (HR, 0.76; 95% CI, 0.52 to 1.13). CONCLUSION: The overall survival benefit of patients with locally advanced resectable esophageal or junctional cancer who receive preoperative chemoradiotherapy according to CROSS persists for at least 10 years

Detailed dimethylacetal and fatty acid composition of rumen content from lambs fed lucerne or concentrate supplemented with soybean oil

Articles in International JournalsLipid metabolism in the rumen is responsible for the complex fatty acid profile of rumen outflow compared with the dietary fatty acid composition, contributing to the lipid profile of ruminant products. A method for the detailed dimethylacetal and fatty acid analysis of rumen contents was developed and applied to rumen content collected from lambs fed lucerne or concentrate based diets supplemented with soybean oil. The methodological approach developed consisted on a basic/ acid direct transesterification followed by thin-layer chromatography to isolate fatty acid methyl esters from dimethylacetal, oxo- fatty acid and fatty acid dimethylesters. The dimethylacetal composition was quite similar to the fatty acid composition, presenting even-, odd- and branched-chain structures. Total and individual odd- and branched-chain dimethylacetals were mostly affected by basal diet. The presence of 18:1 dimethylacetals indicates that biohydrogenation intermediates might be incorporated in structural microbial lipids. Moreover, medium-chain fatty acid dimethylesters were identified for the first time in the rumen content despite their concentration being relatively low. The fatty acids containing 18 carbon-chain lengths comprise the majority of the fatty acids present in the rumen content, most of them being biohydrogenation intermediates of 18:2n26 and 18:3n23. Additionally, three oxo- fatty acids were identified in rumen samples, and 16-O-18:0 might be produced during biohydrogenation of the 18:3n23