Lynch syndrome (LS) is a common cause of hereditary colorectal cancer (CRC). Some CRC patients develop mismatch repair deficiency without germline pathogenic mutation, known as Lynch-like syndrome (LLS). We compared the risk of CRC in first-degree relatives (FDRs) in LLS and LS patients. LLS was diagnosed when tumors showed immunohistochemical loss of MSH2, MSH6, and PMS2; or loss of MLH1 with BRAF wild type; and/or no MLH1 methylation and absence of pathogenic mutation in these genes. CRC and other LS-related neoplasms were followed in patients diagnosed with LS and LLS and among their FDRs. Standardized incidence ratios (SIRs) were calculated for CRC and other neoplasms associated with LS among FDRs of LS and LLS patients. In total, 205 LS (1205 FDRs) and 131 LLS families (698 FDRs) had complete pedigrees. FDRs of patients with LLS had a high incidence of CRC (SIR, 2.08; 95% confidence interval (CI), 1.56–2.71), which was significantly lower than that in FDRs of patients with LS (SIR, 4.25; 95% CI, 3.67–4.90; p < 0.001). The risk of developing other neoplasms associated with LS also increased among FDR of LLS patients (SIR, 2.04; 95% CI, 1.44–2.80) but was lower than that among FDR of patients with LS (SIR, 5.01, 95% CI, 4.26–5.84; p < 0.001). FDRs with LLS have an increased risk of developing CRC as well as LS-related neoplasms, although this risk is lower than that of families with LS. Thus, their management should take into account this increased risk.
The prevalence of enterococcal isolation and factors associated with postoperative enterococcal infection remain ill defined.A prospective longitudinal observational study was conducted of consecutive patients with a first episode of intra-abdominal infection and a positive microbiological culture who did or did not develop a postoperative septic complication involving enterococci. The prevalence of initial enterococcal isolation was determined for each focus of infection. Postoperative enterococcal infections were related to whether appropriate (piperacillin--tazobactam), suboptimal (carbapenems) or inappropriate (cefotaxime plus metronidazole) antienterococcal therapy had been administered empirically.Enterococci were isolated in 42 (21 per cent) of the 200 patients investigated. The isolation rates were 11 per cent for community-acquired peritonitis, 50 per cent for postoperative peritonitis and 23 per cent for intra-abdominal abscesses of both origins. No enterococci were isolated from 49 patients with perforated appendicitis. Independent factors for postoperative enterococcal infection were type of intra-abdominal infection (P = 0.006), Acute Physiology And Chronic Health Evaluation (APACHE) II score greater than 12 (P = 0.04) and inappropriate empirical antibiotic cover (P = 0.05). Postoperative enterococcal infections were associated with a high mortality rate (21 versus 4 per cent; P < 0.0007).Enterococci are frequently isolated from intra-abdominal infections of non-appendiceal origin and are often involved in postoperative infectious complications, particularly peritonitis. Empirical antibiotic therapy covering Enterococcus faecalis should be contemplated in some circumstances.
Abstract Background Phase IIb HIPRA-HH-2 study results showed that PHH-1V as first booster dose elicited a strong and sustained neutralising antibody response against various SARS-CoV-2 variants. Here, we report the safety and immunogenicity of a fourth booster dose of PHH-1V against the most prevalent Omicron SARS-CoV-2 variants in Spain. Methods The HIPRA-HH-2 open-label extension study ( NCT05142553 ) evaluated the safety and immunogenicity of PHH-1V as a fourth booster dose in subjects aged ≥18 years and followed for 6 months. Subjects received a fourth dose of PHH-1V 6–12 months after a previous regime of either two doses of BNT162b2 plus a third dose of PHH-1V (Cohort 1) or three doses of BNT162b2 (Cohort 2). Primary regulatory endpoint evaluated the neutralisation titres (GMT) against Omicron BA.1 on Day 14 of PHH-1V used as fourth dose in Cohort 2 vs the BNT162b2 used as third dose in initial HIPRA-HH-2 study. The immunogenicity of PHH-1V as fourth dose was also investigated by GMTs against Beta, Delta, and Omicron BA.1, BA.4/5 and XBB.1.5 on Days 14, 98 and 182 post-immunisation in the overall study population and in Cohorts 1 and 2 versus baseline. Safety of the fourth dose was also assessed. Findings From September 2022, 288 subjects received PHH-1V as a fourth dose (Cohort 1 n=106; Cohort 2 n=182). A significant increase in neutralising antibodies against Omicron BA.1 subvariant at Day 14 was observed from the third homologous booster with mRNA vaccine compared to the fourth heterologous booster with PHH-1V (1739.02 vs 4049.01; GMT ratio 0.43 (95% CI: 0.28; 0.65; p-value < 0.0001). PHH-1V used as fourth booster induced a statistically significant increase in neutralising antibody titres 14 days after immunisation for all variants compared with baseline [GMFR on Day 14 (95%CI) was 6.96 (5.23, 9.25) for Beta variant; 6.27 (4.79, 8.22) for Delta variant; 9.21 (5.57, 15.21) for Omicron BA.1 variant; 11.80 (8.29, 16.80) for Omicron BA.4/5 variant and 5.22 (3.97, 6.87) for Omicron XBB.1.5 variant]. Titres remained significantly higher compared with baseline at 3 and 6 months post-vaccination. Cohort comparison revealed no significant differences at 14, 98 and 182 days post-vaccination. The most frequent adverse events were injection site pain (Cohort 1: 84.0%; Cohort 2: 77.5%) and fatigue (Cohort 1: 17.9%; Cohort 2: 29.1%). No subjects experienced severe COVID-19 infection. Interpretation The PHH-1V vaccine as a booster induced a potent and sustained neutralising antibody response against previous circulating Beta, Delta variants and Omicron BA.1, BA.4/5, and XBB.1.5 subvariants in subjects previously vaccinated with three doses regardless of previous regimen. These findings suggest that PHH-1V could be an appropriate strategy for upcoming heterologous vaccination campaigns. Funding HIPRA SCIENTIFIC, S.L.U (HIPRA), Spain. Research in context Unmet needs Immunity against SARS-CoV-2 will continue to increase in the community through widespread vaccination and infection. Despite this, at the individual level, the humoral response against new variants is diminished in both vaccinated and infected individuals. Booster strategies have demonstrated a reduction in the risk of not only COVID-19 infection but also of long COVID-19 or persistent post-COVID manifestations. Furthermore, heterologous booster strategies for vaccination regimens offer broad neutralising responses. However, available evidence regarding new platforms beyond mRNA-based vaccines is currently limited. Evidence before this study The PHH-1V vaccine elicits high and long-lasting levels of neutralising antibodies against all COVID-19 variants studied, as well as a strong cellular immunity response, when used as a heterologous booster in previously vaccinated individuals receiving mRNA and viral vector vaccines. However, safety and immunogenicity data on a fourth booster dose of PHH-1V against the most prevalent Omicron variants in Spain were not available at the time of the study period. Added value of this study The PHH-1V dimeric adjuvanted vaccine delivered as a fourth booster dose can induce a potent and significant neutralising antibody response against previous circulating Beta, Delta variants and Omicron BA.1, BA.4/5, and also against XBB.1.5 subvariants from Day 14 through Day 182 compared with baseline regardless of the primary vaccination received (two doses of BNT162b2 plus a third dose of PHH-1V (Cohort 1) or three doses of BNT162b2 (Cohort 2)) and confirm the higher response of PHH-1V when used as a heterologous fourth-dose booster. This open-label extension study also demonstrated that PHH-1V is well tolerated and safe irrespective of the prior booster vaccination received. Implications of all the available evidence These data confirm the advantages of heterologous booster vaccination with PHH-1V and the broad-spectrum response of the PHH-1V vaccine against the different emerging variants of COVID-19, suggesting that PHH-1V could be an appropriate booster for upcoming heterologous vaccination campaigns.
Objectives: This study focuses on the different surgical and endoscopic treatment alternatives when dealing with severe complications after slide tracheoplasty. Methods: We undertook a retrospective study of patients with symptomatic congenital tracheal stenosis (CTS), admitted into a single institution between January 1997 and January 2013, surgically treated by means of a slide tracheoplasty. The following variables were evaluated: demographics, preoperative CTS characteristics, and outcome measures. Results: The cohort included 14 patients (8 boys and 6 girls) with a mean age when treated of 8.7 (range 1-43) months. Eleven patients (78%) showed a long segment CTS (more than 30% of total tracheal length) and nine (64%) had associated cardiac or great vessel anomalies (left pulmonary artery sling). Three patients (21%) showed severe postoperative complications that required significant airway reintervention: tracheal resection of a re-stenotic segment, laser division with balloon dilation of a residual stenosis, and placement of a biodegradable endotracheal stent in an extensive tracheal narrowing. All patients are in good clinical condition with a mean follow-up of 6.3 years (range 2 months-16 years). Conclusions: Slide tracheoplasty has become the procedure of choice when dealing with CTS. Although it shows clear advantages compared to other surgical techniques, severe and difficult to manage complications may occur. Surgeons involved in the treatment of CTS should be familiar with diverse surgical and endoscopic procedures. Absorbable airway stenting is a new and promising technique when long and severe post-surgical tracheal stenosis is present.
Abstract Study question Is there a common transcriptomic signature in the endometrial early/mid secretory phase of healthy women in natural cycles? Summary answer We observed a conserved transcriptomic regulation of the endometrium around the window of implantation (WOI), consistent across donors, and not influenced by the biopsy procedure. What is known already Extensive research has been conducted on the gene expression changes that characterize the WOI, aiming to identify signals that indicate its onset. However, much of this work has utilized whole-transcriptome techniques and has involved IVF patients, who require luteal phase support. The few studies performed in natural cycles often relied on restricted methods, such as qPCR that examines only a few targets simultaneously. As such, an extensive transcriptomics study in volunteer donors in true natural cycles is lacking. This may provide deeper insights into the physiological changes during the WOI in young women driven by the endogenous effects of progesterone. Study design, size, duration 34 healthy donors were enrolled. Each donor provided one endometrial sample, on a day between LH + 2 and LH + 9 during their natural cycle. A minimum of two and a maximum of five donors were allocated to each day. Ovulation was detected via ecographic inspection and hormonal determination of LH/E2/P4. LH + 0 was established when the LH peak was detected (>2.8 times basal levels), together with a subsequenc decrease in E2 (-30%) and increase in P4 (>1.6ng/ml) Participants/materials, setting, methods When the biopsy was of sufficient size, we separated it in two parts and extracted RNA separately to assess concordance between different areas of the same biopsy. RNAseq libraries were prepared with NEBNextUltraII Directional RNA LibraryPrep and sequenced on a NovaSeq6000. Fastq files were aligned with STAR to GRCh38. Principal component analyses (PCA) were created with plotPCA, gene expression time course analysis was performed with DEseq2, and pseudotime analysis was performed using the slingshot package. Main results and the role of chance Of the 34 donors, we obtained good quality RNAseq data (minimum 20 million reads) from 41 samples, with 27 donors having one sample sequenced, while 2 independent samples from the same biopsy were obtained from 7 volunteers. Analysing same-biopsy concordance via PCA revealed a great degree of similarity between all the pairs, which clustered close to each other. Samples from different donors collected on the same day also showed a good clustering, apart from a single day LH + 4 sample. Pseudotime analysis revealed a distinct trajectory in transcriptomic profiles changing progressively from day LH + 2 to LH + 9. This analysis clearly delineated three phases: LH + 2 to LH + 5, LH + 6 to LH + 7, and LH + 8 to LH + 9. Accordingly, we categorized these into pre-receptive, receptive and post receptive groups, and conducted a time course experiment. We identified a total of 3,311 genes with varying expression across these three timepoints, primarily associated with progesterone signalling, metabolism and cell-to-cell communication. Based on their expression patterns, we isolated a subset of 538 genes which increased their expression during the receptive phase only. These genes could represent novel markers for a more in-depth characterization of the WOI. Limitations, reasons for caution The samples analysed are in bulk, and the genes identified could be expressed either in the stroma or in the epithelial compartment. These findings are not applicable to artificial cycles, as the absence of the corpus luteum and varying levels of exogenous progesterone administered may change the transcriptomic signatures. Wider implications of the findings Our study revealed good concordance of whole transcriptome profiles of donor’s endometria according to cycle progression. This may lead to the identification of novel markers involved in the regulation of the WOI that may not have been found in previous studies performed on artificial cycles. Trial registration number not applicable
Purpose:The TOSCANA study aimed to determine the relationship between CD4 cell counts and liver toxicity in patients undergoing treatment simplification or substitution with nevirapine due to the toxicity or poor tolerability of a previous regimen.Methods: A retrospective analysis was conducted of patients with prior viral suppression who were switched to nevirapine.Results: Overall, 221 patients were included, representing 1134.83 patient-years. The median baseline CD4 cell count at the switch was 464 cells/µL, with 75.6% showing high CD4 cell counts (≥250 cells/µL in women or ≥400 cells/µL in men). Hepatotoxicity, defined as liver aminotransferase levels 5 times above the upper limit of normal, was detected in 6.7% of the participants with high CD4 cell counts and 13.0% in those with low counts. The relative risk was 0.51 (95% CI 0.21–1.25), and the incidence rates were 2.63 and 1.26 per 100 patient-years for the low- and high-count subpopulations, respectively. Liver toxicity was mild, reversible upon discontinuation, and more likely to appear after 6 months of nevirapine therapy.Conclusions: Switching to nevirapine was associated with a low incidence of liver toxicity that was unrelated to high CD4 cell counts in patients on prior antiretroviral therapy undergoing simplification or substitution therapy.
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