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Background and Aims: Whereas cofermentation is a traditional practice in some Old‐World regions, its outcomes are largely unknown in New‐World wine regions. Herein we report the chemical and sensory effects of cofermentation of Syrah with selected Rhône white cultivars. Methods and Results: A Control wine comprising 100% Syrah (SY), and five SY blends [consisting of addition by mass of 10% pressed solids of Viognier (VG), Marsanne (MR), Roussanne (RS), Picpoul (PC), and Grenache Blanc (GB)] were produced. In addition, juice from each white cultivar was fermented separately and blended with finished SY wine at a rate of 10% after malolactic fermentation (MLF). Cofermentation had no effect on wine composition, but blending post‐MLF increased ethanol concentration. Cofermentation resulted in lower concentration of most anthocyanin pigments, whereas blending post‐MLF had the opposite effect. Tannins were higher in SY‐VG, SY‐RS and SY‐MR blends, whereas polymeric pigments increased in SY‐RS post‐MLF and SY‐PC post‐MLF. This was attributed to enhanced copigmentation due to comparatively higher concentration of anthocyanins and flavonols in post‐MLF blended wines, which resulted in a hyperchromic shift at 520 nm. Addition of VG, either as a coferment or as a blend post‐MLF increased the aromatic complexity of the resulting wines. Conclusions: Of the white cultivars studied, VG appeared to provide more aromatics both as a coferment or post‐MLF blending option. Post‐MLF blending gave increased aromatics and colour, while offering greater flexibility and fewer logistical issues than cofermentation. Significance of the Study: The use of VG as the preferred coferment of SY, and the practice of post‐MLF blending of SY with a small amount of white wine, were validated through chemical and sensory analysis. [ABSTRACT FROM AUTHOR]

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BACKGROUND The efficacy and safety of combination therapy with eflornithine and sulindac, as compared with either drug alone, in delaying disease progression in patients with familial adenomatous polyposis are unknown. METHODS We evaluated the efficacy and safety of the combination of eflornithine and sulindac, as compared with either drug alone, in adults with familial adenomatous polyposis. The patients were stratified on the basis of anatomical site with the highest polyp burden and surgical status; the strata were precolectomy (shortest projected time to disease progression), rectal or ileal pouch polyposis after colectomy (longest projected time), and duodenal polyposis (intermediate projected time). The patients were then randomly assigned in a 1:1:1 ratio to receive 750 mg of eflornithine, 150 mg of sulindac, or both once daily for up to 48 months. The primary end point, assessed in a time-to-event analysis, was disease progression, defined as a composite of major surgery, endoscopic excision of advanced adenomas, diagnosis of high-grade dysplasia in the rectum or pouch, or progression of duodenal disease. RESULTS A total of 171 patients underwent randomization. Disease progression occurred in 18 of 56 patients (32%) in the eflornithine-sulindac group, 22 of 58 (38%) in the sulindac group, and 23 of 57 (40%) in the eflornithine group, with a hazard ratio of 0.71 (95% confidence interval [CI], 0.39 to 1.32) for eflornithine-sulindac as compared with sulindac (P=0.29) and 0.66 (95% CI, 0.36 to 1.23) for eflornithine-sulindac as compared with eflornithine. Among 37 precolectomy patients, the corresponding values in the treatment groups were 2 of 12 patients (17%), 6 of 13 (46%), and 5 of 12 (42%) (hazard ratios, 0.30 [95% CI, 0.07 to 1.32] and 0.20 [95% CI, 0.03 to 1.32]); among 34 patients with rectal or ileal pouch polyposis, the values were 4 of 11 patients (36%), 2 of 11 (18%), and 5 of 12 (42%) (hazard ratios, 2.03 [95% CI, 0.43 to 9.62] and 0.84 [95% CI, 0.24 to 2.90]); and among 100 patients with duodenal polyposis, the values were 12 of 33 patients (36%), 14 of 34 (41%), and 13 of 33 (39%) (hazard ratios, 0.72 [95% CI, 0.34 to 1.52] and 0.76 [95% CI, 0.35 to 1.64]). Adverse and serious adverse events were similar across the treatment groups. CONCLUSIONS In this trial involving patients with familial adenomatous polyposis, the incidence of disease progression was not significantly lower with the combination of eflornithine and sulindac than with either drug alone. (Funded by Cancer Prevention Pharmaceuticals; ClinicalTrials.gov number, NCT01483144; EudraCT number, 2012-000427-41.) [ABSTRACT FROM AUTHOR]

Background: Sarcopenia is common in patients with cirrhosis and is a risk factor for increased mortality. Transjugular intrahepatic portosystemic shunt (TIPS) placement has been utilized in cirrhosis patients with decompensation . We investigated the role of sarcopenia in predicting mortality in patients undergoing TIPS., Methods: We conducted a single-center retrospective study of 232 patients with cirrhosis who underwent TIPS between January 2010 and December 2015. Sarcopenia was defined by the psoas muscle index (PMI) cutoff value, calculated based on dynamic time-dependent outcomes using X-tile software. Kaplan-Meier analysis demonstrated the difference in survival in the sarcopenia group versus the non-sarcopenia group. . Univariate and multivariate analyses were used to identify the relationship between sarcopenia and post-TIPS mortality during a follow-up period of 1 year., Results: For TIPS indications, 111 (47.84%) patients had refractory ascites, 69 (29.74%) patients had variceal bleeding, 12 (5.17%) patients had ascites, and 40 (17.24%) for other indications. The mean PMI was 4.40 ± 1.55. Sarcopenia was defined as a PMI value of <4.36 in males, and <3.23 in females. Sarcopenia was present in 96 (41.38%) of patients. . Kaplan-Meier analysis showed thatsarcopenia is associated with worse survival (log-rank P  < 0.01). Multivariate Cox regression analysis showed that sarcopenia is independently associated with worse survival during the 1-year follow-up period with an hazard ratio of 2.435 (95% CI 1.346-4.403) ( P  < 0.01), after adjusting for age, BMI, indications for TIPS, etiology for cirrhosis, and MELD score and stratified by sex., Conclusion: Sarcopenia is an independent risk factor for 1-year mortality in patients undergoing TIPS and should be considered when patients are evaluated as a candidate for TIPS., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Public health genomics prioritizes effective and ethical translation of genomic science into population health precision medicine. With the rapid development of cost-effective, next-generation genome sequencing, calls are growing for greater inclusion of Black people in genomic research, policy, and practice. Genetic testing is often the first step in precision medicine. This study explores racial differences in patient concerns about genetic testing for hereditary breast cancer. Employing a community-based participatory mixed methods research design, we developed a semi-structured survey that was shared broadly. There were 81 survey respondents, of which, forty-nine (60%) self-identified as Black, twenty-six (32%) indicated they had a history of a breast cancer diagnosis, or had received BRCA genetic testing. Black participants who expressed concerns about genetic testing were fairly equally distributed between concerns that could be addressed with genetic counseling (24%) and concerns about the subsequent use of their genetic data (27%). The concerns expressed by the participants in our study underscore a need for transparent disclosures and assurances regarding the use and handling of genetic data. These findings should be viewed in context with patient-led efforts to overcome systemic inequities in cancer care, as Black cancer patients have joined forces with advocates and researchers to develop protective health data initiatives and to improve their representation in genomic datasets. Future research should prioritize the information needs and concerns of Black cancer patients. Interventions should be developed to support their hidden work as a means to reduce barriers and improve representation in precision medicine.

Importance: Patients with familial adenomatous polyposis (FAP) are at markedly increased risk for duodenal adenomas and cancer. Combination sulindac and erlotinib was previously shown to reduce duodenal polyp burden but was associated with a relatively high adverse event (AE) rate., Objective: To evaluate if a once weekly dosing schedule for erlotinib intervention improves the AE profile, while still providing efficacy with respect to reduced polyp burden, in participants with FAP., Design, Setting and Participants: Single-arm trial, enrolling 46 participants with FAP, conducted from October 2017 to September 2019 in eight academic cancer centres., Exposures: Participants self-administered 350 mg of erlotinib by mouth, one time per week for 6 months., Main Outcomes and Measures: Duodenal polyp burden (sum of polyp diameters) was assessed in the proximal duodenum by esophagogastroduodenoscopy performed at baseline and 6 months, with mean per cent change defined as the primary efficacy outcome of interest. Rate of grade 2-3 AEs was evaluated as a co-primary outcome. Secondary outcomes included changes in total duodenal polyp count, along with changes in lower gastrointestinal (GI) polyp burden and count (for participants examined by optional lower endoscopy)., Results: Forty-six participants (mean age, 44.1 years (range, 18-68); women, 22 (48%)) were enrolled; 42 participants completed 6 months of intervention and were included in the per-protocol analysis. Duodenal polyp burden was significantly reduced after 6 months of weekly erlotinib intervention, with a mean per cent change of -29.6% (95% CI, -39.6% to -19.7%; p<0.0001). Similar results were observed in subgroup analyses defined by participants with advanced duodenal polyposis (Spigelman 3) at baseline (mean, -27%; 95% CI, -38.7% to -15.2%; p<0.0001). Post-intervention Spigelman stage was downstaged in 12% of the participants. Lower GI polyp number was also decreased after 6 months of intervention (median, -30.8%; IQR, -47.4% to 0.0%; p=0.0256). Grade 2 or 3 AEs were reported in 71.7% of subjects, with only two experiencing grade 3 toxicity at least possibly related to intervention., Conclusion: In this single-arm, multi-centre trial of participants with FAP, erlotinib one time per week resulted in markedly lower duodenal polyp burden, and modestly reduced lower GI polyp burden, after 6 months of intervention. While AEs were still reported by nearly three-quarters of all participants, these events were generally lower grade and well-tolerated. These findings support further investigation of erlotinib as an effective, acceptable cancer preventive agent for FAP-associated GI polyposis., Trial Registration Number: NCT02961374., Competing Interests: Competing interests: PJL serves as Chief Medical Officer for Screening at Exact Sciences through a contracted services agreement with Mayo Clinic. PJL and Mayo Clinic have contractual rights to receive royalties through this agreement; Exact Sciences. JS is a consultant for Janssen Research and Development, Recursion Pharmaceuticals and Cancer Prevention Pharmaceuticals. CAB is a consultant for SLA pharma, Freenome, and has received research support from Janssen Pharmaceuticals, Cancer Prevention Pharmaceuticals, Ferring Pharmaceuticals and Emtora Biosciences. EV has a consulting or advisory role with Janssen Research and Development and Recursion Pharma and has received research support from Janssen Research and Development., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Germline variants in CDH1 are associated with elevated risks of diffuse gastric cancer and lobular breast cancer. It is uncertain whether there is an increased risk of colorectal neoplasia., Methods: This was a retrospective analysis of colonoscopy outcomes in patients with germline CDH1 pathogenic/likely pathogenic variants., Results: Eighty-five patients were included with a mean age of 46.9 years. Initial colonoscopy found adenomatous polyps in 30 patients (35.3%), including advanced adenomas in 9 (10.6%). No colorectal cancers were identified on index or subsequent colonoscopies (when available)., Discussion: CDH1 carriers have colorectal neoplasia identified at similar rates as in the general population. Despite potential difficulties after gastrectomy, colorectal cancer screening remains important in this population., (Copyright © 2022 by The American College of Gastroenterology.)

Genetic counselors (GCs) have traditionally been trained to adopt a position of equipoise or clinical neutrality. They provide information, answer questions, address barriers, and engage in shared decision-making, but generally, they do not prescribe a genetic test. Historically, GCs have generally been trained not to persuade the ambivalent or resistant patient. More recently, however, there has been discussion regarding when a greater degree of persuasion or directionality may be appropriate within genetic counseling (GC) and what role MI may play in this process. The role for "persuasive GC" is based on the premise that some genetic tests provide actionable information that would clearly benefit patients and families by impacting treatment or surveillance. For other tests, the benefits are less clear as they do not directly impact patient care or the benefits may be more subjective in nature, driven by patient values or psychological needs. For the former, we propose that GCs may adopt a more persuasive clinical approach while for the latter, a more traditional equipoise stance may be more appropriate. We suggest that motivational interviewing (MI) could serve as a unifying counseling model that allows GCs to handle both persuasive and equipoise encounters. For clearly beneficial tests, while directional, the MI encounter can still be non-directive, autonomy-supportive, and patient-centered. MI can also be adapted for equipoise situations, for example, placing less emphasis on eliciting and strengthening change talk as that is more a behavior change strategy than a shared decision-making strategy. The core principles and strategies of MI, such as autonomy support, evocation, open questions, reflective listening, and affirmation would apply to both persuasive and equipoise encounters. Key issues that merit discussion include how best to train GCs both during their initial and post-graduate education., (© 2022 The Authors. Journal of Genetic Counseling published by Wiley Periodicals LLC on behalf of National Society of Genetic Counselors.)

Objective: To compare colorectal cancer (CRC) incidences in carriers of pathogenic variants of the MMR genes in the PLSD and IMRC cohorts, of which only the former included mandatory colonoscopy surveillance for all participants., Methods: CRC incidences were calculated in an intervention group comprising a cohort of confirmed carriers of pathogenic or likely pathogenic variants in mismatch repair genes (path&#95;MMR) followed prospectively by the Prospective Lynch Syndrome Database (PLSD). All had colonoscopy surveillance, with polypectomy when polyps were identified. Comparison was made with a retrospective cohort reported by the International Mismatch Repair Consortium (IMRC). This comprised confirmed and inferred path&#95;MMR carriers who were first- or second-degree relatives of Lynch syndrome probands., Results: In the PLSD, 8,153 subjects had follow-up colonoscopy surveillance for a total of 67,604 years and 578 carriers had CRC diagnosed. Average cumulative incidences of CRC in path&#95;MLH1 carriers at 70 years of age were 52% in males and 41% in females; for path&#95;MSH2 50% and 39%; for path&#95;MSH6 13% and 17% and for path&#95;PMS2 11% and 8%. In contrast, in the IMRC cohort, corresponding cumulative incidences were 40% and 27%; 34% and 23%; 16% and 8% and 7% and 6%. Comparing just the European carriers in the two series gave similar findings. Numbers in the PLSD series did not allow comparisons of carriers from other continents separately. Cumulative incidences at 25 years were < 1% in all retrospective groups., Conclusions: Prospectively observed CRC incidences (PLSD) in path&#95;MLH1 and path&#95;MSH2 carriers undergoing colonoscopy surveillance and polypectomy were higher than in the retrospective (IMRC) series, and were not reduced in path&#95;MSH6 carriers. These findings were the opposite to those expected. CRC point incidence before 50 years of age was reduced in path&#95;PMS2 carriers subjected to colonoscopy, but not significantly so., (© 2022. The Author(s).)

HIV-1 infection remains a public health problem with no cure. Anti-retroviral therapy (ART) is effective but requires lifelong drug administration owing to a stable reservoir of latent proviruses integrated into the genome of CD4 + T cells 1 . Immunotherapy with anti-HIV-1 antibodies has the potential to suppress infection and increase the rate of clearance of infected cells 2,3 . Here we report on a clinical study in which people living with HIV received seven doses of a combination of two broadly neutralizing antibodies over 20 weeks in the presence or absence of ART. Without pre-screening for antibody sensitivity, 76% (13 out of 17) of the volunteers maintained virologic suppression for at least 20 weeks off ART. Post hoc sensitivity analyses were not predictive of the time to viral rebound. Individuals in whom virus remained suppressed for more than 20 weeks showed rebound viraemia after one of the antibodies reached serum concentrations below 10 µg ml -1 . Two of the individuals who received all seven antibody doses maintained suppression after one year. Reservoir analysis performed after six months of antibody therapy revealed changes in the size and composition of the intact proviral reservoir. By contrast, there was no measurable decrease in the defective reservoir in the same individuals. These data suggest that antibody administration affects the HIV-1 reservoir, but additional larger and longer studies will be required to define the precise effect of antibody immunotherapy on the reservoir., (© 2022. The Author(s).)

Background: Mismatch repair (MMR) deficiency is the hallmark of tumours from Lynch syndrome (LS), sporadic MLH1 hypermethylated and Lynch-like syndrome (LLS), but there is a lack of understanding of the variability in their mutational profiles based on clinical phenotypes. The aim of this study was to perform a molecular characterisation to identify novel features that can impact tumour behaviour and clinical management., Methods: We tested 105 MMR-deficient colorectal cancer tumours (25 LS, 35 LLS and 45 sporadic) for global exome microsatellite instability, cancer mutational signatures, mutational spectrum and neoepitope load., Results: Fifty-three percent of tumours showed high contribution of MMR-deficient mutational signatures, high level of global exome microsatellite instability, loss of MLH1/PMS2 protein expression and included sporadic tumours. Thirty-one percent of tumours showed weaker features of MMR deficiency, 62% lost MSH2/MSH6 expression and included 60% of LS and 44% of LLS tumours. Remarkably, 9% of all tumours lacked global exome microsatellite instability. Lastly, HLA-B07:02 could be triggering the neoantigen presentation in tumours that show the strongest contribution of MMR-deficient tumours., Conclusions: Next-generation sequencing approaches allow for a granular molecular characterisation of MMR-deficient tumours, which can be essential to properly diagnose and treat patients with these tumours in the setting of personalised medicine., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Lynch syndrome (LS) is an autosomal dominant hereditary cancer syndrome caused by pathogenic germline variants (PGV) in any of the 4 DNA mismatch repair (MMR) genes, MLH1, MSH2, MSH6, and PMS2, or deletions in EPCAM. LS leads to an increased risk of intestinal and extraintestinal cancers, of which colorectal and endometrial cancers are the most common. Individuals at risk for LS can be identified by using clinical criteria, prediction models, and universal tumor testing. Understanding each of these tools, including limitations and mimics of LS, is essential to the early identification of at-risk individuals., Competing Interests: Disclosure Dr. Maratt receives support from Grant Number UL1TR002529 from the National Institutes of Health (NIH), National Center for Advancing Translational Sciences, Clinical and Translational Sciences Award. The views expressed in this manuscript do not reflect views of the NIH., (Published by Elsevier Inc.)

The HIV proviral reservoir is the major barrier to cure. The predominantly replication-defective proviral landscape makes the measurement of virus that is likely to cause rebound upon antiretroviral therapy (ART)-cessation challenging. To address this issue, novel assays to measure intact HIV proviruses have been developed. The intact proviral DNA assay (IPDA) is a high-throughput assay that uses two probes to exclude the majority of defective proviruses and determine the frequency of intact proviruses, albeit without sequence confirmation. Quadruplex PCR with four probes (Q4PCR) is a lower-throughput assay that uses limiting dilution long-distance PCR amplification followed by quantitative PCR (qPCR) and near-full-length genome sequencing (nFGS) to estimate the frequency of sequence-confirmed intact proviruses and provide insight into their clonal composition. To explore the advantages and limitations of these assays, we compared IPDA and Q4PCR measurements from 39 ART-suppressed people living with HIV. We found that IPDA and Q4PCR measurements correlated with one another, but frequencies of intact proviral DNA differed by approximately 19-fold. This difference may be in part due to inefficiencies in long-distance PCR amplification of proviruses in Q4PCR, leading to underestimates of intact proviral frequencies. In addition, nFGS analysis within Q4PCR explained that some of this difference is explained by proviruses that are classified as intact by IPDA but carry defects elsewhere in the genome. Taken together, this head-to-head comparison of novel intact proviral DNA assays provides important context for their interpretation in studies to deplete the HIV reservoir and shows that together the assays bracket true reservoir size. IMPORTANCE The intact proviral DNA assay (IPDA) and quadruplex PCR (Q4PCR) represent major advances in accurately quantifying and characterizing the replication-competent HIV reservoir. This study compares the two novel approaches for measuring intact HIV proviral DNA in samples from 39 antiretroviral therapy (ART)-suppressed people living with HIV, thereby informing ongoing efforts to deplete the HIV reservoir in cure-related trials., (Copyright © 2021 Gaebler et al.)

Background: Lynch syndrome (LS) is the most common hereditary colorectal cancer (CRC) syndrome, yet is grossly under-recognized. Multiple professional societies recommend screening all CRCs for LS by performing tumor testing. The veterans affairs system has not adopted universal tumor testing as a national performance metric and leaves screening for LS to clinical care at individual sites., Aims: Describe adherence to LS screening in the VA system., Methods: Dual-center, retrospective review of all CRCs diagnosed between 2010 and 2016. Rates of tumor testing, personal and family history of cancer were extracted from the medical record. Univariate and multivariate regression analysis was performed to determine predictors of tumor-based screening for LS., Results: A total of 421 cancers were reviewed. 15.1% of all cancers underwent either MSI and/or IHC for LS screening over the study period. There was improvement in LS screening from 3% of all CRCs in 2010 to 45% of all CRCs in 2016. 34% and 70% of patients did not have documentation of CRC in first- and second-degree relatives, respectively. Of the 73 patients who met one of the Revised Bethesda Criteria or had a PREMM1,2,6 score of ≥ 5, 34% and 56% underwent tumor testing, respectively. Younger age, non-Caucasian race, meeting Bethesda or PREMM1,2,6 criteria and right-sided tumor location were predictors of undergoing tumor testing., Conclusions: CRC tumor screening for LS is grossly inadequate when left to routine clinical care. Our results lend support to implementation of reflexive universal tumor testing within the VA system.