Non-SARS-CoV-2 respiratory viral detection and whole genome sequencing from COVID-19 rapid antigen test devices: a laboratory evaluation study.

BACKGROUND: There has been high uptake of rapid antigen test device use for point-of-care COVID-19 diagnosis. Individuals who are symptomatic but test negative on COVID-19 rapid antigen test devices might have a different respiratory viral infection. We aimed to detect and sequence non-SARS-CoV-2 respiratory viruses from rapid antigen test devices, which could assist in the characterisation and surveillance of circulating respiratory viruses in the community. METHODS: We applied archival clinical nose and throat swabs collected between Jan 1, 2015, and Dec 31, 2022, that previously tested positive for a common respiratory virus (adenovirus, influenza, metapneumovirus, parainfluenza, rhinovirus, respiratory syncytial virus [RSV], or seasonal coronavirus; 132 swabs and 140 viral targets) on PCR to two commercially available COVID-19 rapid antigen test devices, the Panbio COVID-19 Ag Rapid Test Device and Roche SARS-CoV-2 Antigen Self-Test. In addition, we collected 31 COVID-19 rapid antigen test devices used to test patients who were symptomatic at The Royal Melbourne Hospital emergency department in Melbourne, Australia. We extracted total nucleic acid from the device paper test strips and assessed viral recovery using multiplex real-time PCR (rtPCR) and capture-based whole genome sequencing. Sequence and genome data were analysed through custom computational pipelines, including subtyping. FINDINGS: Of the 140 respiratory viral targets from archival samples, 89 (64%) and 88 (63%) were positive on rtPCR for the relevant taxa following extraction from Panbio or Roche rapid antigen test devices, respectively. Recovery was variable across taxa: we detected influenza A in nine of 18 samples from Panbio and seven of 18 from Roche devices; parainfluenza in 11 of 20 samples from Panbio and 12 of 20 from Roche devices; human metapneumovirus in 11 of 16 from Panbio and 14 of 16 from Roche devices; seasonal coronavirus in eight of 19 from Panbio and two of 19 from Roche devices; rhinovirus in 24 of 28 from Panbio and 27 of 28 from Roche devices; influenza B in four of 15 in both devices; and RSV in 16 of 18 in both devices. Of the 31 COVID-19 devices collected from The Royal Melbourne Hospital emergency department, 11 tested positive for a respiratory virus on rtPCR, including one device positive for influenza A virus, one positive for RSV, four positive for rhinovirus, and five positive for SARS-CoV-2. Sequences of target respiratory viruses from archival samples were detected in 55 (98·2%) of 56 samples from Panbio and 48 (85·7%) of 56 from Roche rapid antigen test devices. 98 (87·5%) of 112 viral genomes were completely assembled from these data, enabling subtyping for RSV and influenza viruses. All 11 samples collected from the emergency department had viral sequences detected, with near-complete genomes assembled for influenza A and RSV. INTERPRETATION: Non-SARS-CoV-2 respiratory viruses can be detected and sequenced from COVID-19 rapid antigen devices. Recovery of near full-length viral sequences from these devices provides a valuable opportunity to expand genomic surveillance programmes for public health monitoring of circulating respiratory viruses. FUNDING: Australian Government Medical Research Future Fund and Australian National Health and Medical Research Council.

Rapid antiretroviral therapy in primary HIV-1 infection enhances immune recovery.

OBJECTIVE: We present findings from a large cohort of individuals treated during primary HIV infection (PHI) and examine the impact of time from HIV-1 acquisition to antiretroviral therapy (ART) initiation on clinical outcomes. We also examine the temporal changes in the demographics of individuals presenting with PHI to inform HIV-1 prevention strategies. METHODS: Individuals who fulfilled the criteria of PHI and started ART within 3 months of confirmed HIV-1 diagnosis were enrolled between 2009 and 2020. Baseline demographics of those diagnosed between 2009 and 2015 (before preexposure prophylaxis (PrEP) and universal ART availability) and 2015-2020 (post-PrEP and universal ART availability) were compared. We examined the factors associated with immune recovery and time to viral suppression. RESULTS: Two hundred four individuals enrolled, 144 from 2009 to 2015 and 90 from 2015 to 2020; median follow-up was 33 months. At PHI, the median age was 33 years; 4% were women, 39% were UK-born, and 84% were MSM. The proportion of UK-born individuals was 47% in 2009-2015, compared with 29% in 2015-2020. There was an association between earlier ART initiation after PHI diagnosis and increased immune recovery; each day that ART was delayed was associated with a lower likelihood of achieving a CD4 + cell count more than 900 cells/µl [hazard ratio 0.99 (95% confidence interval, 95% CI 0.98-0.99), P  = 0.02) and CD4/CD8 more than 1.0 (hazard ratio 0.98 (95% CI 0.97-0.99). CONCLUSION: Early initiation of ART at PHI diagnosis is associated with enhanced immune recovery, providing further evidence to support immediate ART in the context of PHI. Non-UK-born MSM accounts for an increasing proportion of those with primary infection; UK HIV-1 prevention strategies should better target this group.

Laboratory evaluation of ELISA and indirect immunofluorescence assay in response to emergence of Japanese encephalitis virus genotype IV in Australia.

The unexpected recent emergence of Japanese encephalitis virus (JEV) genotype IV in multiple southern states of Australia necessitated an evaluation of JEV serological tests suitable for diagnosing acute infection and for seroprevalence studies. This study examined the analytical and clinical performance of two high-throughput JEV assays, Euroimmun immunofluorescence assay (IFA) and Euroimmun enzyme-linked immunosorbent assay (ELISA), across four cohorts; (1) surveillance of piggery workers in outbreak areas, (2) surveillance of residents in outbreak areas, (3) acute JEV infection and (4) post-JEV vaccination. ELISA and IFA IgM demonstrated minimal cross-reactivity (0-1.8%) with other endemic flaviviruses, with high sensitivity (100%) for acute JEV infection in this low endemicity setting. Differences in IgG serodynamics between the two assays suggest convalescent and paired testing with IgM are critical in diagnosing acute infection. High assay concordance was observed between ELISA and IFA when used in serosurveillance (97.4% agreement, Cohen' κ 0.74 [95% CI 0.614-0.860]) and vaccination cohorts (91.1% agreement, Cohen's κ 0.806 [95% CI 0.672-0.941]). In conclusion, this study highlights the clinical & epidemiological applications and limitations of these two commercial JEV assays.

Adolescents' Self Perceptions: Connecting Psychosocial Competencies to the Sexual Self-Concept.

Adolescence is a crucial period for the development of the sexual self-concept. While existing research shows that adolescents' sexual self-concept varies, few studies have examined its relation with psychosocial competencies such as the general self-concept, interpersonal skills, and self-control capacities. The objective of this study was to examine the association between dimensions of the sexual self-concept (sexual self- and body esteem, self-efficacy, and anxiety) and psychosocial competencies among Canadian adolescents. Self-reported data from 1584 adolescents aged between 14 and 18 years (49.7% girls) were analyzed using path analysis. Results show that adolescents whose general self-concept was characterized by more internally consistent self-beliefs and greater self-worth, and who perceived their interpersonal skills as more developed, displayed higher sexual self- and body esteem, higher sexual self-efficacy, and lower sexual anxiety. Self-control capacities were positively correlated with sexual body-esteem and negatively correlated with sexual anxiety. These associations were, however, minimal and, when significant, exhibited a counterintuitive relationship with the sexual self-concept in the path model. Age, gender and sexual experience did not moderate these associations. Findings from the study highlight the need to pursue research on the interface between sexuality and psychosocial functioning to increase current understanding of adolescent development.

Japanese encephalitis clinical update: Changing diseases under a changing climate.

BACKGROUND: Japanese encephalitis virus (JEV) is a mosquito-borne arbovirus endemic to the Asia-Pacific that causes high morbidity and mortality in those who develop symptomatic disease. Prior to 2021, only five locally acquired cases had been detected in Australia, all in northern Australia. Following a sentinel case in 2021, widespread dissemination of JEV was detected in northern and south-eastern Australia, accompanied by an increase in locally acquired cases, which have been detected as far south as Victoria. This expansion has occurred in the setting of warmer and wetter conditions under the influence of climate change. OBJECTIVE: To provide Australian general practitioners (GPs) an overview of JEV, given its recent expansion, and the potential for sustained endemicity. DISCUSSION: As the distribution of JEV expands under the influence of climate change, Australian GPs need to be familiar with this condition, especially those practicing in rural areas and where detections have occurred.

Sentinel cluster of locally acquired Japanese encephalitis in southern Australia.

Prior to January 2022, only a single case of infection with Japanese encephalitis virus (JEV) had been reported on the Australian mainland, acquired in the northern extremity on Cape York. We report the clinical characteristics of the sentinel cluster of cases that confirmed the local acquisition of JEV in southern Australia along the Murray River bordering New South Wales and Victoria.

Sexual Misconduct: What Does a 20-Year Review of Cases in Quebec Reveal about the Characteristics of Professionals, Victims, and the Disciplinary Process?

While there is a considerable body of literature on sexual aggression, we know much less about the violation of sexual boundaries within professional relationships. To address this knowledge gap, the characteristics of cases of sexual misconduct in the province of Quebec were extracted, based on a search of published disciplinary decisions between 1998 and 2020, using the legal databases CANLII and SOQUIJ. The search yielded 296 decisions including 249 male and 47 female members from 22 professional orders, and involving 470 victims. Results indicate that male professionals approaching mid-career accounted for a greater proportion of cases of sexual misconduct. Moreover, physical and mental health professionals were overrepresented in cases, as were female adult victims. Acts of sexual misconduct concerned mostly sexual touching and intercourse and occurred during consultations. Female professionals were more inclined to establish romantic and sexual relationships with clients than their male counterparts. Of the 92.0% of professionals found guilty of at least one count of sexual misconduct, two thirds eventually returned to practice. Following the guilty verdict, few faced rehabilitative measures. Recommendations are provided for the prevention of sexual recidivism and the accompaniment of victims of sexual misconduct throughout the disciplinary process.

Sexual self-concept, functioning, and practices of women with binge eating episodes.

PURPOSE: Positive sexuality has received little empirical attention in relation to eating disorders. Two tendencies related to sexuality have been identified among women with anorexia nervosa (avoidance) and bulimia nervosa (disinhibition), but it is unclear if they also apply to women with binge eating episodes without compensatory behaviors. This study aimed at (1) exploring the sexual self-concept, functioning, and practices of women with binge eating episodes with or without comorbid restrictive and/or compensatory behaviors, considering past experiences of violence, and (2) verifying the presence of distinct profiles of sexual dispositions among this population. METHODS: In total, 253 women reporting recurrent episodes of loss of control related to food intake in the past 5 years, completed a web-based questionnaire. Descriptive and correlational analyses were conducted to outline participants' sexual self-concept, functioning, and practices and to examine the relationship between these factors. A two-step cluster analysis was also performed to determine whether participants presented distinct profiles of sexual dispositions. RESULTS: Participants were generally characterized by a negative sexual self-concept and poor sexual functioning. While a first subgroup of participants displayed a pattern of sexual difficulties and avoidance, a second subgroup had a positive sexual self-concept, better sexual functioning and a wider range of sexual practices. Subgroups did not differ relative to binge eating. CONCLUSIONS: Sexuality offers a platform for positive embodiment, which can lead to the improvement of body image and mind-body connection and may thus constitute an essential clinical target to improve treatment related to binge eating episodes. LEVEL OF EVIDENCE: Level II: The experimental study is a non-randomized controlled trial.

Soy and Gastrointestinal Health: A Review.

Soybean is the most economically important legume globally, providing a major source of plant protein for millions of people; it offers a high-quality, cost-competitive and versatile base-protein ingredient for plant-based meat alternatives. The health benefits of soybean and its constituents have largely been attributed to the actions of phytoestrogens, which are present at high levels. Additionally, consumption of soy-based foods may also modulate gastrointestinal (GI) health, in particular colorectal cancer risk, via effects on the composition and metabolic activity of the GI microbiome. The aim of this narrative review was to critically evaluate the emerging evidence from clinical trials, observational studies and animal trials relating to the effects of consuming soybeans, soy-based products and the key constituents of soybeans (isoflavones, soy proteins and oligosaccharides) on measures of GI health. Our review suggests that there are consistent favourable changes in measures of GI health for some soy foods, such as fermented rather than unfermented soy milk, and for those individuals with a microbiome that can metabolise equol. However, as consumption of foods containing soy protein isolates and textured soy proteins increases, further clinical evidence is needed to understand whether these foods elicit similar or additional functional effects on GI health.

Real-time analysis of hospital length of stay in a mixed SARS-CoV-2 Omicron and Delta epidemic in New South Wales, Australia.

BACKGROUND: The distribution of the duration that clinical cases of COVID-19 occupy hospital beds (the 'length of stay') is a key factor in determining how incident caseloads translate into health system burden. Robust estimation of length of stay in real-time requires the use of survival methods that can account for right-censoring induced by yet unobserved events in patient progression (e.g. discharge, death). In this study, we estimate in real-time the length of stay distributions of hospitalised COVID-19 cases in New South Wales, Australia, comparing estimates between a period where Delta was the dominant variant and a subsequent period where Omicron was dominant. METHODS: Using data on the hospital stays of 19,574 individuals who tested positive to COVID-19 prior to admission, we performed a competing-risk survival analysis of COVID-19 clinical progression. RESULTS: During the mixed Omicron-Delta epidemic, we found that the mean length of stay for individuals who were discharged directly from ward without an ICU stay was, for age groups 0-39, 40-69 and 70 +, respectively, 2.16 (95% CI: 2.12-2.21), 3.93 (95% CI: 3.78-4.07) and 7.61 days (95% CI: 7.31-8.01), compared to 3.60 (95% CI: 3.48-3.81), 5.78 (95% CI: 5.59-5.99) and 12.31 days (95% CI: 11.75-12.95) across the preceding Delta epidemic (1 July 2021-15 December 2021). We also considered data on the stays of individuals within the Hunter New England Local Health District, where it was reported that Omicron was the only circulating variant, and found mean ward-to-discharge length of stays of 2.05 (95% CI: 1.80-2.30), 2.92 (95% CI: 2.50-3.67) and 6.02 days (95% CI: 4.91-7.01) for the same age groups. CONCLUSIONS: Hospital length of stay was substantially reduced across all clinical pathways during a mixed Omicron-Delta epidemic compared to a prior Delta epidemic, contributing to a lessened health system burden despite a greatly increased infection burden. Our results demonstrate the utility of survival analysis in producing real-time estimates of hospital length of stay for assisting in situational assessment and planning of the COVID-19 response.

Avocado Consumption and Cardiometabolic Health: A Systematic Review and Meta-Analysis.

BACKGROUND: Avocados are a rich source of unsaturated fats and bioactives, however, their role in altering cardiometabolic risk factors is unclear. OBJECTIVE: The aim was to review the effects of consuming diets containing avocado compared with control diets containing no or low amounts of avocado on cardiometabolic risk factors in adults who were healthy, had clinical cardiovascular disease, or were at increased risk of cardiovascular disease. METHODS: Five electronic databases were searched (PubMed, Web of Science, Scopus, ProQuest, and a Clinical Trials Registry) along with Google Scholar to identify studies published between January 1990 and November 10, 2021. Randomized controlled trials ≥3 weeks and prospective cohort studies were included. Ten studies-9 randomized controlled trials (n = 503 participants) and 1 prospective observational study (n = 55,407)-met the inclusion criteria. Outcomes assessed by means of meta-analysis were low-density lipoprotein cholesterol (LDL-C) (primary), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and triglycerides. Outcomes assessed by narrative review were TC to HDL-C ratio, non-HDL-C, apolipoprotein B, blood pressure, body weight, body mass index (calculated as kg/m2), waist circumference, waist-to-hip ratio, body composition, and blood glucose and insulin concentrations. Risk of bias was assessed using the Cochrane Risk of Bias tool, version 2.0 and Newcastle-Ottawa Scale; quality of evidence was examined using the Grading of Recommendations, Assessment, Development and Evaluation method. Random-effects models meta-analyses were performed when there were ≥3 studies of the same design (ie, randomized controlled trial) and reporting the same outcome. Statistical heterogeneity was assessed by calculating χ2 and I2 statistics and publication bias was assessed by funnel plots. RESULTS: Overall, there was a small, significant reduction in TC (-5.08 mg/dL [to convert to mmol/L, divide by 38.67]; 95% CI -9.29 to -0.87 mg/dL; P = .02) in avocado vs the control groups and no significant difference in LDL-C, HDL-C, or triglycerides. Subgroup analysis demonstrated significant reductions in LDL-C (-9.4 mg/dL [to convert to mmol/L, divide by 38.67]; 95% CI -10.84 to -7.95 mg/dL; P < .00001) and TC (-7.54 mg/dL; 95% CI -9.40 to -5.68 mg/dL; P < .00001) in avocado vs control groups in hypercholesterolemic populations, and no differences were seen in normocholesterolemic populations. However, the certainty in the findings was graded as low to very low. Body weight and composition were not negatively affected by avocado consumption. CONCLUSIONS: Avocado consumption may reduce TC and LDL-C in people with hypercholesterolemia. Avocado consumption does not negatively impact body weight. Larger, well-conducted studies are needed to have greater confidence in the role of avocado consumption on cardiovascular disease risk factors.

Environmental sustainability in national food-based dietary guidelines: a global review.

Food-based dietary guidelines (FBDGs) provide country-specific guidance on what constitutes a healthy diet. With increasing evidence for the synergy between human and planetary health, FBDGs have started to consider the environmental sustainability of food choices. However, the number of countries that discuss environmental sustainability in their guidelines is unknown. The purpose of this Review was to identify countries with government-endorsed FBDGs that made explicit mention of environmental sustainability and to examine the breadth and depth of the inclusion of sustainability in FBDGs. The Food and Agriculture Organization of the UN identified 95 countries with FBDGs. We assessed 83 countries against our inclusion criteria, of which 37 mentioned environmental sustainability. Relevant content was assessed against a set of criteria based on the Food and Agriculture Organization's guiding principles for sustainable healthy diets. The depth to which environmental sustainability was discussed varied and it was often restricted to general explanations of what a sustainable diet is. Few FBDGs addressed why sustainability is important, how dietary changes can be made, or provided quantified advice for implementing sustainable diets.

Towards healthier and more sustainable diets in the Australian context: comparison of current diets with the Australian Dietary Guidelines and the EAT-Lancet Planetary Health Diet.

BACKGROUND: There is increasing focus on moving populations towards healthier and more environmentally sustainable dietary patterns. The Australian Dietary Guidelines provide dietary patterns that promote health and wellbeing. It is unclear how these guidelines align with the more recently published global recommendations of the EAT-Lancet Planetary Health Reference Diet, and how Australian diets compare to both sets of recommendations. METHODS: Data from one 24-h recall collected for the 2011-13 National Nutrition and Physical Activity Survey were analysed for 5,920 adults aged 19-50 years. Subgroups of this population were identified by diet quality and lower or higher consumption of foods often considered to be environmentally intensive (higher animal meat and dairy foods) or associated with healthiness (higher vegetables and lower discretionary choices). Food group and nutrient composition of Australian diets were compared to diets modelled on the Australian Dietary Guidelines and Planetary Health Reference Diet. The environmental impacts of diets were estimated using an index of combined metrics. RESULTS: Compared with the Planetary Health Reference Diet, the Australian Dietary Guidelines contained more servings of the vegetable, dairy and alternatives, fruit, and discretionary choices. The amount of meat and alternatives was higher in the Planetary Health Reference Diet than Australian Dietary Guidelines due to the inclusion of more plant-based meat alternatives. The average Australian diet contained two to almost four times the Australian Dietary Guidelines and Planetary Health Reference Diet maximum recommended intake of discretionary choices, and provided inadequate amounts of the vegetables, cereals, unsaturated fats and meats and alternatives food groups, primarily due to lower intakes of plant-based alternatives. The average Australian diet also contained less dairy and alternatives than the Australian Dietary Guidelines. In the average Australian diet, red meat and poultry contributed 73% to the total servings of meat and alternatives compared to 33% and 10% for the Australian Dietary Guidelines and Planetary Health Reference Diet respectively. The modelled Australian Dietary Guidelines diet met the relevant nutrient reference value for all 22 nutrients examined, whereas the Planetary Health Reference Diet contained an inadequate amount of calcium. The environmental impact scores of the Planetary Health Reference Diet and Australian Dietary Guidelines were 31% and 46% lower than the average Australian diet. CONCLUSIONS: Significant changes are required for Australians' dietary intake to align more closely with national and global dietary recommendations for health and environmental sustainability.

Impact of antiretroviral therapy in primary HIV infection on natural killer cell function and the association with viral rebound and HIV DNA following treatment interruption.

Natural Killer (NK) cells play a key role in controlling HIV replication, with potential downstream impact on the size of the HIV reservoir and likelihood of viral rebound after antiretroviral therapy (ART) cessation. It is therefore important to understand how primary HIV infection (PHI) disrupts NK cell function, and how these functions are restored by early ART. We examined the impact of commencing ART during PHI on phenotypic and functional NK cell markers at treatment initiation (baseline), 3 months, 1 year, and 2 years in seven well-characterised participants in comparison to HIV seronegative volunteers. We then examined how those NK cell properties differentially impacted by ART related to time to viral rebound and HIV DNA levels in 44 individuals from the SPARTAC trial who stopped ART after 48 weeks treatment, started during PHI. NK cell markers that were significantly different between the seven people with HIV (PWH) treated for 2 years and HIV uninfected individuals included NKG2C levels in CD56dim NK cells, Tim-3 expression in CD56bright NK cells, IFN-γ expressed by CD56dim NK cells after IL-12/IL-18 stimulation and the fraction of Eomes-/T-bet+ in CD56dim and CD56bright NK cells. When exploring time to viral rebound after stopping ART among the 44 SPARTAC participants, no single NK phenotypic marker correlated with control. Higher levels of IL-12/IL-18 mediated NK cell degranulation at baseline were associated with longer times to viral rebound after treatment interruption (P=0.028). Additionally, we found higher fractions of CD56dim NK cells in individuals with lower levels of HIV DNA (P=0.048). NKG2A and NKp30 levels in CD56neg NK cells were higher in patients with lower HIV DNA levels (p=0.00174, r=-0.49 and p=0.03, r= -0.327, respectively) while CD27 levels were higher in those with higher levels of HIV DNA (p=0.026). These data show NK cell functions are heterogeneously impacted by HIV infection with a mixed picture of resolution on ART, and that while NK cells may affect HIV DNA levels and time to viral rebound, no single NK cell marker defined delayed viral rebound.

Adolescents' Perception of Their Sexual Self, Relational Capacities, Attitudes Towards Sexual Pleasure and Sexual Practices: a Descriptive Analysis.

Positive psychosexual development in adolescence is crucial to sexual health. Evidence suggests that adolescent's psychosexual development is influenced by the sexual self-concept, relational skills, attitudes toward sexual pleasure, and sexual practices. To date, however, understanding of normative dispositions and experiences that positively shape adolescents' psychosexual development remains limited. The goal of the study was to provide a descriptive analysis of adolescents' perceptions of their sexual self, relational skills, and attitudes towards sexual pleasure as well as their sexual practices while considering age and gender differences. A Canadian sample of 1584 adolescents (49.7% girls, 49.4% boys and 0.9% gender diverse) aged 14 to 18 years old (M = 15.53, SD = 0.93) completed a self-reported questionnaire evaluating various aspects of sexuality and sexual practices. Results indicated that most youth are sexually active through autoerotic or partnered sexual practices, and that positive perceptions towards the sexual self, relational capacities and pleasure increase with age. Moreover, compared to girls, boys presented a more positive sexual self-concept, less positive perceptions of their relational skills and they were more likely to report autoerotic sexual practices. Cluster analysis supported classifying adolescents into the following profiles: positive, mildly positive, mildly negative and negative perception of the sexual self and sexuality. These profiles varied according to sexual practices, gender and age. This study provides further insight into general patterns and heterogeneity of adolescents' sexuality that are relevant for adapting sexuality education and sexual health intervention.

Integrating Tumor Sequencing Into Clinical Practice for Patients With Mismatch Repair-Deficient Lynch Syndrome Spectrum Cancers.

INTRODUCTION: Uninformative germline genetic testing presents a challenge to clinical management for patients suspected to have Lynch syndrome, a cancer predisposition syndrome caused by germline variants in the mismatch repair (MMR) genes or EPCAM. METHODS: Among a consecutive series of MMR-deficient Lynch syndrome spectrum cancers identified through immunohistochemistry-based tumor screening, we investigated the clinical utility of tumor sequencing for the molecular diagnosis and management of suspected Lynch syndrome families. MLH1-deficient colorectal cancers were prescreened for BRAF V600E before referral for genetic counseling. Microsatellite instability, MLH1 promoter hypermethylation, and somatic and germline genetic variants in the MMR genes were assessed according to an established clinical protocol. RESULTS: Eighty-four individuals with primarily colorectal (62%) and endometrial (31%) cancers received tumor-normal sequencing as part of routine clinical genetic assessment. Overall, 27% received a molecular diagnosis of Lynch syndrome. Most of the MLH1-deficient tumors were more likely of sporadic origin, mediated by MLH1 promoter hypermethylation in 54% and double somatic genetic alterations in MLH1 (17%). MSH2-deficient, MSH6-deficient, and/or PMS2-deficient tumors could be attributed to pathogenic germline variants in 37% and double somatic events in 28%. Notably, tumor sequencing could explain 49% of cases without causal germline variants, somatic MLH1 promoter hypermethylation, or somatic variants in BRAF. DISCUSSION: Our findings support the integration of tumor sequencing into current Lynch syndrome screening programs to improve clinical management for individuals whose germline testing is uninformative.

Epigenetic scars of CD8+ T cell exhaustion persist after cure of chronic infection in humans.

T cell exhaustion is an induced state of dysfunction that arises in response to chronic infection and cancer. Exhausted CD8+ T cells acquire a distinct epigenetic state, but it is not known whether that chromatin landscape is fixed or plastic following the resolution of a chronic infection. Here we show that the epigenetic state of exhaustion is largely irreversible, even after curative therapy. Analysis of chromatin accessibility in HCV- and HIV-specific responses identifies a core epigenetic program of exhaustion in CD8+ T cells, which undergoes only limited remodeling before and after resolution of infection. Moreover, canonical features of exhaustion, including super-enhancers near the genes TOX and HIF1A, remain 'epigenetically scarred.' T cell exhaustion is therefore a conserved epigenetic state that becomes fixed and persists independent of chronic antigen stimulation and inflammation. Therapeutic efforts to reverse T cell exhaustion may require new approaches that increase the epigenetic plasticity of exhausted T cells.

Epigenetic Features of HIV-Induced T-Cell Exhaustion Persist Despite Early Antiretroviral Therapy.

T cell dysfunction occurs early following HIV infection, impacting the emergence of non-AIDS morbidities and limiting curative efforts. ART initiated during primary HIV infection (PHI) can reverse this dysfunction, but the extent of recovery is unknown. We studied 66 HIV-infected individuals treated from early PHI with up to three years of ART. Compared with HIV-uninfected controls, CD4 and CD8 T cells from early HIV infection were characterised by T cell activation and increased expression of the immune checkpoint receptors (ICRs) PD1, Tim-3 and TIGIT. Three years of ART lead to partial - but not complete - normalisation of ICR expression, the dynamics of which varied for individual ICRs. For HIV-specific cells, epigenetic profiling of tetramer-sorted CD8 T cells revealed that epigenetic features of exhaustion typically seen in chronic HIV infection were already present early in PHI, and that ART initiation during PHI resulted in only a partial shift of the epigenome to one with more favourable memory characteristics. These findings suggest that although ART initiation during PHI results in significant immune reconstitution, there may be only partial resolution of HIV-related phenotypic and epigenetic changes.