Structural Color from Cellulose Nanocrystals or Chitin Nanocrystals: Self-Assembly, Optics, and Applications.

Widespread concerns over the impact of human activity on the environment have resulted in a desire to replace artificial functional materials with naturally derived alternatives. As such, polysaccharides are drawing increasing attention due to offering a renewable, biodegradable, and biocompatible feedstock for functional nanomaterials. In particular, nanocrystals of cellulose and chitin have emerged as versatile and sustainable building blocks for diverse applications, ranging from mechanical reinforcement to structural coloration. Much of this interest arises from the tendency of these colloidally stable nanoparticles to self-organize in water into a lyotropic cholesteric liquid crystal, which can be readily manipulated in terms of its periodicity, structure, and geometry. Importantly, this helicoidal ordering can be retained into the solid-state, offering an accessible route to complex nanostructured films, coatings, and particles. In this review, the process of forming iridescent, structurally colored films from suspensions of cellulose nanocrystals (CNCs) is summarized and the mechanisms underlying the chemical and physical phenomena at each stage in the process explored. Analogy is then drawn with chitin nanocrystals (ChNCs), allowing for key differences to be critically assessed and strategies toward structural coloration to be presented. Importantly, the progress toward translating this technology from academia to industry is summarized, with unresolved scientific and technical questions put forward as challenges to the community.

Modeling Risk Factors for Intraindividual Variability: A Mixed-Effects Beta-Binomial Model Applied to Cognitive Function in Older People in the English Longitudinal Study of Ageing.

Cognitive functioning in older age profoundly impacts quality of life and health. While most research on cognition in older age has focused on mean levels, intraindividual variability (IIV) around this may have risk factors and outcomes independent of the mean value. Investigating risk factors associated with IIV has typically involved deriving a summary statistic for each person from residual error around a fitted mean. However, this ignores uncertainty in the estimates, prohibits exploring associations with time-varying factors, and is biased by floor/ceiling effects. To address this, we propose a mixed-effects location scale beta-binomial model for estimating average probability and IIV in a word recall test in the English Longitudinal Study of Ageing. After adjusting for mean performance, an analysis of 9,873 individuals across 7 (mean = 3.4) waves (2002-2015) found IIV to be greater at older ages, with lower education, in females, with more difficulties in activities of daily living, in later birth cohorts, and when interviewers recorded issues potentially affecting test performance. Our study introduces a novel method for identifying groups with greater IIV in bounded discrete outcomes. Our findings have implications for daily functioning and care, and further work is needed to identify the impact for future health outcomes.

Healthcare interactions prior to first hospital admission with alcohol-related liver disease.

BACKGROUND AND AIMS: To examine the healthcare contacts of patients in the year before an index admission to hospital with alcohol-related liver disease (ArLD) to identify where opportunities for earlier identification of alcohol use disorders (AUD) and ArLD and intervention may occur. METHODS: A retrospective cohort study using the regional database encompassing NHS organisations across North West London (344 general practitioner [GP] practices, 4 acute hospital trusts and 2 mental health and community health trusts). Patients who had an index admission with ArLD were identified through healthcare coding and compared with a control cohort. Healthcare contacts, blood tests and AUD testing in the year preceding admission were measured. RESULTS: The ArLD cohort had 1494 participants with an index hospital admission with ArLD. The control cohort included 4462 participants. In the year preceding an index admission with ArLD, 91% of participants had at least one contact with primary care with an average of 2.97 (SD 2.45) contacts; 80% (n = 1199/1494) attended ED, 68% attended an outpatient clinic, and 42% (n = 628/1494) had at least one inpatient admission. Only 9% of the ArLD (137/1494) had formal testing for AUD. Abnormal bilirubin and platelets were more common in the ArLD than the control cohort 25% (138/560) and 28% (231/837), respectively, v 1% (12/1228) and 1% (20/1784). CONCLUSIONS: Prior to an index admission with ArLD patients have numerous interactions with all healthcare settings, indicating missed opportunities for early identification and treatment.

Angle-resolved optical spectroscopy of photonic cellulose nanocrystal films reveals the influence of additives on the mechanism of kinetic arrest.

Cellulose nanocrystals (CNCs) are rod-like nanoparticles whose chiral self-assembly into photonic films has been promoted as a sustainable source of colouration. Upon drying, an aqueous CNC suspension passes through two regimes: first, a liquid phase, where the CNCs self-organise into a cholesteric liquid crystal, followed by a kinetically-arrested phase, where the helicoidal structure compresses upon loss of solvent, resulting in a solid film with vibrant structural colour. The transition between these two regimes plays an important role in the visual appearance of photonic CNC films, but details on when and how kinetic arrest occurs have remained elusive. In this work, we combine angle-resolved optical spectroscopy of photonic films (approx. 100 vol% CNC) with a model for compressed helicoidal structures to retrieve the suspension conditions during kinetic arrest (approx. 10 vol% CNC). This analysis indicates a shift in the mechanism of kinetic arrest from a glass transition at lower ionic strength to gelation at higher ionic strength, explaining the trends in domain size and film colour. In contrast, neutral additives (glucose, poly(ethylene glycol)) appear to primarily reduce the compression upon drying without affecting cholesteric behaviour, as supported by a general analytical model. These findings deepen our understanding of CNC co-assembly with various commonly-used additives, enabling better control over the production of multifunctional structurally coloured materials.

An Inhaled Galectin-3 Inhibitor in COVID-19 Pneumonitis: A Phase Ib/IIa Randomized Controlled Clinical Trial (DEFINE).

Rationale: High circulating galectin-3 is associated with poor outcomes in patients with coronavirus disease (COVID-19). We hypothesized that GB0139, a potent inhaled thiodigalactoside galectin-3 inhibitor with antiinflammatory and antifibrotic actions, would be safely and effectively delivered in COVID-19 pneumonitis. Objectives: Primary outcomes were safety and tolerability of inhaled GB0139 as an add-on therapy for patients hospitalized with COVID-19 pneumonitis. Methods: We present the findings of two arms of a phase Ib/IIa randomized controlled platform trial in hospitalized patients with confirmed COVID-19 pneumonitis. Patients received standard of care (SoC) or SoC plus 10 mg inhaled GB0139 twice daily for 48 hours, then once daily for up to 14 days or discharge. Measurements and Main Results: Data are reported from 41 patients, 20 of which were assigned randomly to receive GB0139. Primary outcomes: the GB0139 group experienced no treatment-related serious adverse events. Incidences of adverse events were similar between treatment arms (40 with GB0139 + SoC vs. 35 with SoC). Secondary outcomes: plasma GB0139 was measurable in all patients after inhaled exposure and demonstrated target engagement with decreased circulating galectin (overall treatment effect post-hoc analysis of covariance [ANCOVA] over days 2-7; P = 0.0099 vs. SoC). Plasma biomarkers associated with inflammation, fibrosis, coagulopathy, and major organ function were evaluated. Conclusions: In COVID-19 pneumonitis, inhaled GB0139 was well-tolerated and achieved clinically relevant plasma concentrations with target engagement. The data support larger clinical trials to determine clinical efficacy. Clinical trial registered with ClinicalTrials.gov (NCT04473053) and EudraCT (2020-002230-32).

Diagnosis of Acute Aortic Syndrome in the Emergency Department (DAShED) study: an observational cohort study of people attending the emergency department with symptoms consistent with acute aortic syndrome.

BACKGROUND: The diagnosis of acute aortic syndrome (AAS) is commonly delayed or missed in the ED. We describe characteristics of ED attendances with symptoms potentially associated with AAS, diagnostic performance of clinical decision tools (CDTs) and physicians and yield of CT aorta angiogram (CTA). METHODS: This was a multicentre observational cohort study of adults attending 27 UK EDs between 26 September 2022 and 30 November 2022, with potential AAS symptoms: chest, back or abdominal pain, syncope or symptoms related to malperfusion. Patients were preferably identified prospectively, but retrospective recruitment was also permitted. Anonymised, routinely collected patient data including components of CDTs, was abstracted. Clinicians treating prospectively identified patients were asked to record their perceived likelihood of AAS, prior to any confirmatory testing. Reference standard was radiological or operative confirmation of AAS. 30-day electronic patient record follow-up evaluated whether a subsequent diagnosis of AAS had been made and mortality. RESULTS: 5548 patients presented, with a median age of 55 years (IQR 37-72; n=5539). 14 (0.3%; n=5353) had confirmed AAS. 10/1046 (1.0%) patients in whom the ED clinician thought AAS was possible had AAS. 5/147 (3.4%) patients in whom AAS was considered the most likely diagnosis had AAS. 2/3319 (0.06%) patients in whom AAS was considered not possible did have AAS. 540 (10%; n=5446) patients underwent CT, of which 407 were CTA (7%). 30-day follow-up did not reveal any missed AAS diagnoses. AUROC (area under the receiver operating characteristic) curve for ED clinician AAS likelihood rating was 0.958 (95% CI 0.933 to 0.983, n=4006) and for individual CDTs were: Aortic Dissection Detection Risk Score (ADD-RS) 0.674 (95% CI 0.508 to 0.839, n=4989), AORTAs 0.689 (95% CI 0.527 to 0.852, n=5132), Canadian 0.818 (95% CI 0.686 to 0.951, n=5180) and Sheffield 0.628 (95% CI 0.467 to 0.788, n=5092). CONCLUSION: Only 0.3% of patients presenting with potential AAS symptoms had AAS but 7% underwent CTA. CDTs incorporating clinician gestalt appear to be most promising, but further prospective work is needed, including evaluation of the role of D-dimer. TRIAL REGISTRATION NUMBER: NCT05582967; NCT05582967.

Alcohol-Related Liver Disease: Is There a Safe Alcohol Consumption Limit for Liver Disease?

This review is to evaluate how much alcohol is safe in the context of alcohol-related liver disease (ALD). In patients without an established diagnosis of ALD consuming alcohol at quantities below 12 to 20 g daily with alcohol-free days is associated with a very low risk of developing disease. This risk is mediated by the presence of cofactors such as sex, medical comorbidity, obesity, and genetic factors. A threshold effect below which liver disease will not occur is not seen, instead a dose-response relationship where risk ranges from low to high. Once ALD is present, natural history studies confirm that continued alcohol consumption is clearly associated with an increased risk of ill health and premature death. In conclusion, low-level alcohol consumption in the absence of liver disease is associated with a very small risk of developing ALD, but once ALD is present patients should be supported to achieve complete abstinence from alcohol.

The Natural History of Advanced Chronic Liver Disease Defined by Transient Elastography.

BACKGROUND & AIMS: The clinical course of cirrhosis does not follow a predictable trajectory. Transient elastography (TE) is commonly used in clinical practice to diagnose liver fibrosis and increasingly to risk stratify patients. The aim of this study was to assess the natural history of advanced chronic liver disease (ACLD) defined by TE using electronic health record (EHR) data in a multistate framework. METHODS: TE data were collected between 2008 and 2019. Patients with a liver stiffness measurement (LSM) >10 kPa were included. Disease and procedure code information held in EHR was analyzed. Clinical events including decompensation, hepatocellular carcinoma (HCC), and death were identified. Outcomes were described in a multistate model using flexible parametric survival methods including LSM and the albumin bilirubin (ALBI) score. RESULTS: Three thousand and twenty eight patients were included. Median follow up was 3.1 years. LSM and ALBI were associated with the development of varices and decompensation, and ALBI, age, sex, and viral liver disease were associated with the development of HCC from the compensated state. The cumulative incidence of HCC before decompensation was low for patients with alcohol-related liver disease (3.8%) and nonalcoholic fatty liver disease (1.3%) at 5 years after TE. Importantly, death was predicted to occur before decompensation or HCC in most cases. CONCLUSIONS: Liver stiffness, ALBI score, and disease etiology are each associated with outcomes in a large contemporary cohort with ACLD. EHR data can be used to define clinical progression in these patients, facilitating large clinical effectiveness trials and cost-effectiveness analyses.

Large-scale fabrication of structurally coloured cellulose nanocrystal films and effect pigments.

Cellulose nanocrystals are renewable plant-based colloidal particles capable of forming photonic films by solvent-evaporation-driven self-assembly. So far, the cellulose nanocrystal self-assembly process has been studied only at a small scale, neglecting the limitations and challenges posed by the continuous deposition processes that are required to exploit this sustainable material in an industrial context. Here, we addressed these limitations by using roll-to-roll deposition to produce large-area photonic films, which required optimization of the formulation of the cellulose nanocrystal suspension and the deposition and drying conditions. Furthermore, we showed how metre-long structurally coloured films can be processed into effect pigments and glitters that are dispersible, even in water-based formulations. These promising effect pigments are an industrially relevant cellulose-based alternative to current products that are either micro-polluting (for example, non-biodegradable microplastic glitters) or based on carcinogenic, unsustainable or unethically sourced compounds (for example, titania or mica).

Longitudinal Metabolite Changes in Progressive Multiple Sclerosis: A Study of 3 Potential Neuroprotective Treatments.

BACKGROUND: 1 H-magnetic resonance spectroscopy (1 H-MRS) may provide a direct index for the testing of medicines for neuroprotection and drug mechanisms in multiple sclerosis (MS) through measures of total N-acetyl-aspartate (tNAA), total creatine (tCr), myo-inositol (mIns), total-choline (tCho), and glutamate + glutamine (Glx). Neurometabolites may be associated with clinical disability with evidence that baseline neuroaxonal integrity is associated with upper limb function and processing speed in secondary progressive MS (SPMS). PURPOSE: To assess the effect on neurometabolites from three candidate drugs after 96-weeks as seen by 1 H-MRS and their association with clinical disability in SPMS. STUDY-TYPE: Longitudinal. POPULATION: 108 participants with SPMS randomized to receive neuroprotective drugs amiloride [mean age 55.4 (SD 7.4), 61% female], fluoxetine [55.6 (6.6), 71%], riluzole [54.6 (6.3), 68%], or placebo [54.8 (7.9), 67%]. FIELD STRENGTH/SEQUENCE: 3-Tesla. Chemical-shift-imaging 2D-point-resolved-spectroscopy (PRESS), 3DT1. ASSESSMENT: Brain metabolites in normal appearing white matter (NAWM) and gray matter (GM), brain volume, lesion load, nine-hole peg test (9HPT), and paced auditory serial addition test were measured at baseline and at 96-weeks. STATISTICAL TESTS: Paired t-test was used to analyze metabolite changes in the placebo arm over 96-weeks. Metabolite differences between treatment arms and placebo; and associations between baseline metabolites and upper limb function/information processing speed at 96-weeks assessed using multiple linear regression models. P-value<0.05 was considered statistically significant. RESULTS: In the placebo arm, tCho increased in GM (mean difference = -0.32 IU) but decreased in NAWM (mean difference = 0.13 IU). Compared to placebo, in the fluoxetine arm, mIns/tCr was lower (ß = -0.21); in the riluzole arm, GM Glx (ß = -0.25) and Glx/tCr (ß = -0.29) were reduced. Baseline tNAA(ß = 0.22) and tNAA/tCr (ß = 0.23) in NAWM were associated with 9HPT scores at 96-weeks. DATA CONCLUSION: 1 H-MRS demonstrated altered membrane turnover over 96-weeks in the placebo group. It also distinguished changes in neuro-metabolites related to gliosis and glutaminergic transmission, due to fluoxetine and riluzole, respectively. Data show tNAA is a potential marker for upper limb function. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY: Stage 4.

Extra-hepatic morbidity and mortality in alcohol-related liver disease: Systematic review and meta-analysis.

BACKGROUND: Alcohol use increases the risk of many conditions in addition to liver disease; patients with alcohol-related liver disease (ALD) are therefore at risk from both extra-hepatic and hepatic disease. AIMS: This review synthesises information about non-liver-related mortality in persons with ALD. METHODS: A systematic literature review was performed to identify studies describing non-liver outcomes in ALD. Information about overall non-liver mortality was extracted from included studies and sub-categorised into major causes: cardiovascular disease (CVD), non-liver cancer and infection. Single-proportion meta-analysis was done to calculate incidence rates (events/1000 patient-years) and relative risks (RR) compared with control populations. RESULTS: Thirty-seven studies describing 50 302 individuals with 155 820 patient-years of follow-up were included. Diabetes, CVD and obesity were highly prevalent amongst included patients (5.4%, 10.4% and 20.8% respectively). Outcomes varied across the spectrum of ALD: in alcohol-related fatty liver the rate of non-liver mortality was 43.4/1000 patient-years, whereas in alcoholic hepatitis the rate of non-liver mortality was 22.5/1000 patient-years. The risk of all studied outcomes was higher in ALD compared with control populations: The RR of death from CVD was 2.4 (1.6-3.8), from non-hepatic cancer 2.2 (1.6-2.9) and from infection 8.2 (4.7-14.3). CONCLUSION: Persons with ALD are at high risk of death from non-liver causes such as cardiovascular disease and non-hepatic cancer.

Preliminary results from the Australian Genetics of Bipolar Disorder Study: A nation-wide cohort.

OBJECTIVE: The Australian Genetics of Bipolar Disorder Study is a nation-wide cohort of adults living with bipolar disorder. The study aims to detect the relationships between genetic risk, symptom severity, and the lifetime prevalence of bipolar disorder, treatment response and medication side effects, and patterns and costs of health care usage. METHODS: A total of 6682 participants (68.3% female; aged 44.8 ± 13.6 years [range = 18-90]) were recruited in three waves: a nation-wide media campaign, a mail-out based on prescriptions for lithium carbonate and through the Australian Genetics of Depression Study. Participants completed a self-report questionnaire. A total of 4706 (70%) participants provided a saliva sample and were genotyped and 5506 (82%) consented to record linkage of their Pharmaceutical and Medicare Benefits Schedule data. RESULTS: Most participants were living with bipolar I disorder (n = 4068) while 1622 participants were living with bipolar II disorder and 992 with sub-threshold bipolar disorder. The mean age of bipolar disorder diagnosis was 32.7 ± 11.6 years but was younger in bipolar I (p = 2.0E-26) and females (p = 5.7E-23). Excluding depression with onset prior to bipolar disorder diagnosis, 64.5% of participants reported one or more co-occurring psychiatric disorders: most commonly generalised anxiety disorder (43.5%) and posttraumatic stress disorder (20.7%). Adverse drug reactions were common and resulted in discontinuation rates ranging from 33.4% for lithium to 63.0% for carbamazepine. CONCLUSION: Our findings highlight the high rate of comorbidities and adverse drug reactions among adults living with bipolar disorder in the general Australian population. Future genomic analyses focus on identifying genetic variants influencing pharmacotherapy treatment response and side effects.

High-Sensitivity Cardiac Troponin on Presentation to Rule Out Myocardial Infarction: A Stepped-Wedge Cluster Randomized Controlled Trial.

BACKGROUND: High-sensitivity cardiac troponin assays enable myocardial infarction to be ruled out earlier, but the safety and efficacy of this approach is uncertain. We investigated whether an early rule-out pathway is safe and effective for patients with suspected acute coronary syndrome. METHODS: We performed a stepped-wedge cluster randomized controlled trial in the emergency departments of 7 acute care hospitals in Scotland. Consecutive patients presenting with suspected acute coronary syndrome between December 2014 and December 2016 were included. Sites were randomized to implement an early rule-out pathway where myocardial infarction was excluded if high-sensitivity cardiac troponin I concentrations were <5 ng/L at presentation. During a previous validation phase, myocardial infarction was ruled out when troponin concentrations were <99th percentile at 6 to 12 hours after symptom onset. The coprimary outcome was length of stay (efficacy) and myocardial infarction or cardiac death after discharge at 30 days (safety). Patients were followed for 1 year to evaluate safety and other secondary outcomes. RESULTS: We enrolled 31 492 patients (59±17 years of age [mean±SD]; 45% women) with troponin concentrations <99th percentile at presentation. Length of stay was reduced from 10.1±4.1 to 6.8±3.9 hours (adjusted geometric mean ratio, 0.78 [95% CI, 0.73-0.83]; P<0.001) after implementation and the proportion of patients discharged increased from 50% to 71% (adjusted odds ratio, 1.59 [95% CI, 1.45-1.75]). Noninferiority was not demonstrated for the 30-day safety outcome (upper limit of 1-sided 95% CI for adjusted risk difference, 0.70% [noninferiority margin 0.50%]; P=0.068), but the observed differences favored the early rule-out pathway (0.4% [57/14 700] versus 0.3% [56/16 792]). At 1 year, the safety outcome occurred in 2.7% (396/14 700) and 1.8% (307/16 792) of patients before and after implementation (adjusted odds ratio, 1.02 [95% CI, 0.74-1.40]; P=0.894), and there were no differences in hospital reattendance or all-cause mortality. CONCLUSIONS: Implementation of an early rule-out pathway for myocardial infarction reduced length of stay and hospital admission. Although noninferiority for the safety outcome was not demonstrated at 30 days, there was no increase in cardiac events at 1 year. Adoption of this pathway would have major benefits for patients and health care providers. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03005158.

The Placebo Response in Randomized Trials in Nonalcoholic Steatohepatitis Simply Explained.

BACKGROUND & AIMS: Liver histology is the primary endpoint in phase III trials in nonalcoholic steatohepatitis (NASH). There is an appreciable response to placebo that confounds endpoint assessment. The aim of this study was to quantify contributors to the placebo response and its impact on liver fibrosis improvement. METHODS: Estimates of fibrosis improvement in placebo-treated participants were made using probabilistic simulation. Each simulated trial included 120 participants. Parameters considered in the model included sampling and observer variability, regression to the mean, and net fibrosis progression calibrated to reported trial outcomes. RESULTS: In large phase IIb and III trials, 22% of placebo-treated participants with fibrosis stage 2 or 3 NASH at baseline improved by at least 1 fibrosis stage with minimal net disease progression. Estimates of sampling and observer variability in simultaneous biopsy studies highlighted an imbalance where apparent fibrosis improvement was more likely than worsening. Using these estimates and known trial outcomes, net fibrosis progression was estimated at 0.05 stages per year. Simulations of the placebo response rate showed a rate of 22% with 80% of trials falling between 15 and 30%, in keeping with trials reported to date. Additional increases in observer variability further increased the placebo response. CONCLUSIONS: The analyses presented simply define the placebo response in liver fibrosis in trials in NASH in terms of sampling and observer variability, regression to the mean, and fibrosis progression. Factors relating to liver biopsy are largely unmodifiable, and the variation in placebo response rates, both simulated and observed, challenges the role of biopsy in trial endpoint assessment.

Trajectory of Serum Bilirubin Predicts Spontaneous Recovery in a Real-World Cohort of Patients With Alcoholic Hepatitis.

BACKGROUND AND AIMS: Alcoholic hepatitis (AH) is a severe condition with poor short-term prognosis. Specific treatment with corticosteroids slightly improves short-term survival but is associated with infection and is not used in many centers. A reliable method to identify patients who will recover spontaneously will minimise the numbers of patients who experience side effects of available treatments. METHODS: We analysed the trajectory of serum bilirubin concentration over the course of hospital admissions in patients with AH to predict spontaneous survival and the need for treatment. RESULTS: data from 426 patients were analysed. Based on bilirubin trajectory, patients were categorized into three groups: 'fast fallers' (bilirubin <0.8 x admission value at day 7), 'static' (bilirubin of >0.9 - <1.2 x admission value) and 'rapid risers' (bilirubin of ≥1.2 x admission bilirubin). Fast fallers had significantly better 90-day survival compared to other groups (log rank p < .001), and showed no benefit of corticosteroid therapy (OR for survival at 28 days of treatment, 0.94, 95% CI 0.06 - 8.41). These findings remained even amongst patients with severe disease based on initial DF, GAHS or MELD scores. CONCLUSIONS: We present an intuitive method of classifying patients with AH based on the trajectory of bilirubin over the first week of admission. It is complimentary to existing scores that identify candidates for corticosteroid treatment or assess response to treatment. This method identifies a group of patients with AH who recover spontaneously and can avoid corticosteroid therapy.

Outcomes After Liver Transplantation With Incidental Cholangiocarcinoma.

Cholangiocarcinoma (CCA) is currently a contraindication to liver transplantation (LT) in the United Kingdom (UK). Incidental CCA occurs rarely in some patients undergoing LT. We report on retrospective outcomes of patients with incidental CCA from six UK LT centres. Cases were identified from pathology records. Data regarding tumour characteristics and post-transplant survival were collected. CCA was classified by TNM staging and anatomical location. 95 patients who underwent LT between 1988-2020 were identified. Median follow-up after LT was 2.1 years (14 days-18.6 years). Most patients were male (68.4%), median age at LT was 53 (IQR 46-62), and the majority had underlying PSC (61%). Overall median survival after LT was 4.4 years. Survival differed by tumour site: 1-, 3-, and 5-year estimated survival was 82.1%, 68.7%, and 57.1%, respectively, in intrahepatic CCA (n = 40) and 58.5%, 42.6%, and 30.2% in perihilar CCA (n = 42; p = 0.06). 1-, 3-, and 5-year estimated survival was 95.8%, 86.5%, and 80.6%, respectively, in pT1 tumours (28.2% of cohort), and 65.8%, 44.7%, and 31.1%, respectively, in pT2-4 (p = 0.018). Survival after LT for recipients with incidental CCA is inferior compared to usual outcomes for LT in the United Kingdom. LT for earlier stage CCA has similar survival to LT for hepatocellular cancer, and intrahepatic CCAs have better survival compared to perihilar CCAs. These observations may support LT for CCA in selected cases.

Self-reported impact of developmental stuttering across the lifespan.

AIM: To examine the phenomenology of stuttering across the lifespan in the largest prospective cohort to date. METHOD: Participants aged 7 years and older with a history of developmental stuttering were recruited. Self-reported phenotypic data were collected online including stuttering symptomatology, co-occurring phenotypes, genetic predisposition, factors associated with stuttering severity, and impact on anxiety, education, and employment. RESULTS: A total of 987 participants (852 adults: 590 males, 262 females, mean age 49 years [SD = 17 years 10 months; range = 18-93 years] and 135 children: 97 males, 38 females, mean age 11 years 4 months [SD = 3 years; range = 7-17 years]) were recruited. Stuttering onset occurred at age 3 to 6 years in 64.0%. Blocking (73.2%) was the most frequent phenotype; 75.9% had sought stuttering therapy and 15.5% identified as having recovered. Half (49.9%) reported a family history. There was a significant negative correlation with age for both stuttering frequency and severity in adults. Most were anxious due to stuttering (90.4%) and perceived stuttering as a barrier to education and employment outcomes (80.7%). INTERPRETATION: The frequent persistence of stuttering and the high proportion with a family history suggest that stuttering is a complex trait that does not often resolve, even with therapy. These data provide new insights into the phenotype and prognosis of stuttering, information that is critically needed to encourage the development of more effective speech therapies. WHAT THIS PAPER ADDS: Half of the study cohort had a family history of stuttering. While 75.9% of participants had sought stuttering therapy, only 15.5% identified as having recovered. There was a significant negative correlation between age and stuttering frequency and severity in adults.

Framing HIV and AIDS: how leaders of black religious institutions in New York City interpret and address sex and sexuality in their HIV interventions.

This study explored how leaders of Black churches active in the fight against HIV conceptualised sex and sexuality when describing HIV interventions within their institutions. We analysed interviews with pastors and identified three frames through which leaders understood and communicated about sex and sexuality: (1) an evasive frame, in which participants avoided discussing behaviours and populations that have historically been disparaged within the church by emphasising involuntary risk exposure; (2) an agentic frame, which recognised sexual behaviour that differed from heteronormative conduct; and, (3) a pluralist frame, which allowed individuals to maintain their own beliefs about appropriate sexual conduct. Participants used frames to engage in a range of HIV interventions while upholding stigmatising beliefs about sexual behaviour and identity.

Improving menstrual equity in the USA: perspectives from trans and non-binary people assigned female at birth and health care providers.

Menstruation research has largely focused on addressing menstrual management barriers facing cisgender women and girls in low and middle-income countries. Scant literature has assessed the menstrual management needs of trans and non-binary people assigned female at birth. To better understand these frequently invisibilised menstruation-related needs, we conducted a multi-method qualitative study in New York City which included: 17 in-depth interviews across trans and non-binary people (n = 10) and health care providers who serve them (n = 7); and seven anonymous post-interview participatory writing responses with trans and non-binary participants to further elucidate their lived experiences with menstrual management. Lack of health care provider transgender competency, public toilet design (i.e. gaps in cubicle doors and lack of in-cubicle menstrual product disposal bins), and the social dynamics of public toilets (i.e. work and school) were identified as significant barriers to managing menstruation safely and accessibly for trans and non-binary people. These findings have important implications for healthcare policy, public toilet legislation and advancing menstrual equity in the USA.

HIV prevention among gay and other men who have sex with men: public policy and social movements in Brazil, 1983-2019.

This article revisits the history of HIV prevention for gay and other men who have sex with men in relation to public health policy and the role of LGBT and AIDS-related social movements in Brazil. An interpretive study was undertaken informed by philosophical and phenomenological hermeneutics. It included interviews with policymakers, researchers and activists involved in HIV and AIDS, especially HIV prevention among gay and other men who have sex with men. Prevention initiatives were analysed with a focus on the social and programmatic aspects of vulnerability to HIV, and advances and setbacks in the Brazilian response to the epidemic. The recent crisis in HIV prevention triggered by a growing conservatism in Brazilian politics and the current government's LGBT-phobia pose barriers that compromise issues of profound importance with regards to policy on HIV and AIDS: namely, engagement with human rights and social participation.