Progesterone inactivation in decidual stromal cells: A mechanism for inflammation-induced parturition.

The process of human parturition involves inflammation at the interface where fetal chorion trophoblast cells interact with maternal decidual stromal (DS) cells and maternal immune cells in the decidua (endometrium of pregnancy). This study tested the hypothesis that inflammation at the chorion-decidua interface (CDI) induces labor by negating the capacity for progesterone (P4) to block labor and that this is mediated by inactivation of P4 in DS cells by aldo-keto reductase family 1 member C1 (AKR1C1). In human, Rhesus macaque, and mouse CDI, AKR1C1 expression increased in association with term and preterm labor. In a human DS cell line and in explant cultures of term human fetal membranes containing the CDI, the prolabor inflammatory cytokine, interleukin-1ß (IL-1ß), and media conditioned by LPS-stimulated macrophages increased AKR1C1 expression and coordinately reduced nuclear P4 levels and P4 responsiveness. Loss of P4 responsiveness was overcome by inhibition of AKR1C1 activity, inhibition of AKR1C1 expression, and bypassing AKR1C1 activity with a P4 analog that is not metabolized by AKR1C1. Increased P4 activity in response to AKR1C1 inhibition was prevented by the P4 receptor antagonist RU486. Pharmacologic inhibition of AKR1C1 activity prevented parturition in a mouse model of inflammation-induced preterm parturition. The data suggest that inflammatory stimuli at the CDI drive labor by inducing AKR1C1-mediated P4 inactivation in DS cells and that inhibiting and/or bypassing of AKR1C1-mediated P4 inactivation is a plausible therapeutic strategy to mitigate the risk of inflammation-associated preterm birth.

Cystic fibrosis pathogens persist in the upper respiratory tract following initiation of elexacaftor/tezacaftor/ivacaftor therapy.

Elexacaftor/tezacaftor/ivacaftor (ETI) therapy has revolutionized the treatment of cystic fibrosis (CF) for most affected individuals but the effects of treatment on sinus microbiota are still unknown. Changes to the airway microbiota in CF are associated with disease state and alterations to the bacterial community after ETI initiation may require changes to clinical management regimens. We collected sinus swab samples from the middle meatus in an observational study of 38 adults with CF and chronic rhinosinusitis (CRS) from 2017 to 2021 and captured the initiation of ETI therapy. We performed 16S and custom amplicon sequencing to characterize the sinus microbiota pre- and post-ETI. Real-time quantitative PCR (RT-qPCR) was performed to estimate total bacterial abundance. Sinus samples from people with CF (pwCF) clustered into three community types, dependent on the dominant bacterial organism: a Pseudomonas-dominant, Staphylococcus-dominant, and mixed dominance cluster. Shannon's diversity index was low and not significantly altered post-ETI. Total bacterial load was not significantly lowered post-ETI. Pseudomonas spp. abundance was significantly reduced post-ETI, but eradication was not observed. Staphylococcus spp. became the dominant organism in most individuals post-ETI and we showed the presence of methicillin-resistant Staphylococcus aureus (MRSA) in the sinus both pre- and post-ETI. We also demonstrated that the sinus microbiome is predictive of the presence of Pseudomonas spp., Staphylococcus spp., and Serratia spp. in the sputum. Pseudomonas spp. and Staphylococcus spp., including MRSA, persist in the sinuses of pwCF after ETI therapy, indicating that these pathogens will continue to be important in CF airway disease management in the era of highly effective modulator therapies (HEMT).IMPORTANCEHighly effective modulator therapies (HEMT), such as elexacaftor/tezacaftor/ivacaftor (ETI), for cystic fibrosis (CF) have revolutionized patient care and quality of life for most affected individuals. The effects of these therapies on the microbiota of the airways are still unclear, though work has already been published on changes to microbiota in the sputum. Our study presents evidence for reduced relative abundance of Pseudomonas spp. in the sinuses following ETI therapy. We also show that Staphylococcus spp. becomes the dominant organism in the sinus communities of most individuals in this cohort after ETI therapy. We identified methicillin-resistant Staphylococcus aureus (MRSA) in the sinus microbiota both pre- and post-therapy. These findings demonstrate that pathogen monitoring and treatment will remain a vital part of airway disease management for people with cystic fibrosis (pwCF) in the era of HEMT.

Case Report: The Conundrum of What to Pick? Antibiotic Susceptibility Variability in Burkholderia cenocepacia in Cystic Fibrosis: Implications for Antibiotic Susceptibility Testing and Treatment.

Within cystic fibrosis microbiology, there is often mismatch between the antibiotic susceptibility result of an isolated bacterial pathogen and the clinical outcome, when the patient is treated with the same antibiotic. The reasoning for this remains largely elusive. Antibiotic susceptibility to four antibiotics (ceftazidime, meropenem, minocycline and trimethoprim-sulfamethoxazole) was determined in consecutive isolates (n = 11) from an adult cystic fibrosis patient, over a 63 month period. Each isolate displayed its own unique resistotype. The first isolate was sensitive to all four antibiotics, in accordance with Clinical and Laboratory Standards Institute methodology and interpretative criteria. Resistance was first detected at four months, showing resistance to ceftazidime and meropenen and intermediate resistance to minocycline and trimethoprim-sulfamethoxazole. Pan resistance was first detected at 18 months (resistotype IV), with three resistotypes (I, II and III) preceding this complete resistotype. The bacterium continued to display further antibiotic susceptibility heterogeneity for the next 45 months, with the description of an additional seven resistotypes (resistotypes V-XI). The Relative Resistance Index of this bacterium over the 63 month period showed no relationship between the development of antibiotic resistance and time. Adoption of mathematical modelling employing multinomial distribution demonstrated that large numbers of individual colony picks (>40/sputum), would be required to be 78% confident of capturing all 11 resistotypes present. Such a requirement for large numbers of colony picks combined with antibiotic susceptibility-related methodological problems creates a conundrum in biomedical science practice, in providing a robust assay that will capture antibiotic susceptibility variation, be pragmatic and cost-effective to deliver as a pathology service, but have the reliability to help clinicians select appropriate antibiotics for their patients. This study represents an advance in biomedical science as it demonstrates potential variability in antibiotic susceptibility testing with Burkholderia cenocepacia. Respiratory physicians and paediatricians need to be made aware of such variation by biomedical scientists at the bench, so that clinicians can contextualise the significance of the reported susceptibility result, when selecting appropriate antibiotics for their cystic fibrosis patient. Furthermore, consideration needs to be given in providing additional guidance on the laboratory report to highlight this heterogeneity to emphasise the potential for misalignment between susceptibility result and clinical outcome.

Carriage of Neisseria meningitidis (meningococci) in the sputum of people with cystic fibrosis (CF): occupational health risks and mitigating interventions for physiotherapists.

OBJECTIVES: To estimate the carriage of Neisseira meningitidis (meningococci) in expectorated sputum from people with cystic fibrosis (CF) and to evaluate potential ramifications of such carriage for the health and (NM) wellbeing of physiotherapists performing airway clearance techniques. DESIGN: Descriptive observational study. MAIN OUTCOME MEASURES: Meningococcal carriage rate, CFTR mutation type and time to first meningococcal culture were determined. RESULTS: Microbiological data was examined from 100 patients from birth to present (31/12/2021), equating to 2455 patient years. NM was isolated from 6/100 (6%) adult CF patients who had F508del/F508del (homozygous), F508del/other (heterozygous) and other mutations. The median and mean time to first isolation of NM was 213 months and 230 months (standard deviation = 27.6 months), respectively, shortest time was 209 months, longest time 278 months. CONCLUSIONS: Physiotherapists should be aware of the risks to themselves of acquiring Neisseria meningtidis from CF patients' respiratory aerosols, whilst performing airway clearance techniques. Physiotherapists with underlying medical conditions or with specific concerns about meningococcal disease should discuss their circumstances with their occupational health team, to ensure optimal protection.

Feeding Tube Clinic Effect on Nutrition.

BACKGROUND: Optimizing nutrition is essential for recovery after major surgery or severe illness. Feeding tubes (FT) can be placed in patients limited by oral enteral nutrition. Given the myriad of locations in which these procedures are performed (radiology, intensive care unit, and endoscopy suite), routine follow-up is challenging. The purpose of this study was to evaluate the impact of an FT clinic on nutrition. We hypothesized that enrollment in the FT clinic would result in improved nutritional outcomes. METHODS: Retrospective review of Veteran Affairs Medical Center patients with FTs placed from January 2010 to January 2020. Demographics and body mass index (BMI) were recorded. Serum albumin recorded within 1 month of tube placement was compared to within 1 month of tube removal, death, or at the end of the study period. FT clinic participation required at least 2 visits. Indications for FT placement and duration were recorded. Patients were excluded when both BMI and albumin values were incomplete, and if FTs were placed for decompression. RESULTS: Ninety-three patients underwent FT placement during the study period; 5 (5%) were excluded. The average age was 64.8±9.7 years, with the majority being male, 85 patients (97%). Eighteen (20%) patients were seen in the FT clinic (FTC) and 70 (80%) were managed outside of FTC (nFTC). There were no differences in age, gender, or indication for FT. Mean albumin increased 0.42±0.85 g/dL in the FTC group versus -0.07±0.72 g/dL in the nFTC group (P=0.037). The FTC group BMI increased, 0.38 kg/m2 vs. -1.48 kg/m2 in nFTC patients, P=0.041. The FTC patients maintained their tubes longer (36.5 vs. 7.0 mo, P=0.0014). CONCLUSIONS: Patients managed in a dedicated FT clinic experienced an improvement in their serum albumin values and increases in their BMI. In addition, they also maintained their FTs longer. To optimize nutrition and reduce weight loss, patients who require FTs should be enrolled in a dedicated FT clinic.

Australian rheumatologists' perception of autologous haemopoietic stem cell transplantation for the treatment of systemic sclerosis: a cross-sectional survey.

BACKGROUND: Autologous haemopoietic stem cell transplantation (AHSCT) is an effective treatment for systemic sclerosis (SSc); however, treatment-related toxicity remains a key issue. AIMS: To investigate the perceptions of rheumatologists on the use of AHSCT for SSc. METHODS: Australian rheumatologists were asked for their opinion on the role of AHSCT, the indications for treatment and the barriers to the use of AHSCT for SSc. A secondary analysis assessed what factors influenced the perception of AHSCT. RESULTS: A total of 77.8% rheumatologists agreed or strongly agreed with the statement that AHSCT is an accepted treatment for SSc. While 65.1% agreed or strongly agreed that treatment-associated mortality was a significant barrier to referral for AHSCT, only 15.2% agreed or strongly agreed that this risk was unacceptable. Progressive lung or skin disease, or lack of response to other therapies, were considered the main referral criteria. A total of 92.0% of respondents agreed or strongly agreed that reduction of treatment toxicity would increase their likelihood to refer patients for AHSCT. Rheumatologists who were aware of the correct evidence base were more likely to consider AHSCT an acceptable treatment for SSc (4.21 ± 0.7 vs 3.64 ± 0.9, P = 0.007). Rheumatologists desire improved patient selection criteria and access to treatment. CONCLUSION: In this national survey of rheumatologists, AHSCT is considered an accepted therapy. However, concern about toxicity remains a potential barrier to patient referral. Access, studies to refine patient selection and development of AHSCT protocols that improve safety were identified as key areas of need.

HIV BG505 SOSIP.664 trimer with 3M-052-AF/alum induces human autologous tier-2 neutralizing antibodies.

Stabilized trimers preserving the native-like HIV envelope structure may be key components of a preventive HIV vaccine regimen to induce broadly neutralizing antibodies (bnAbs). We evaluated trimeric BG505 SOSIP.664 gp140, formulated with a novel TLR7/8 signaling adjuvant, 3M-052-AF/Alum, for safety, adjuvant dose-finding and immunogenicity in a first-in-healthy adult (n=17), randomized, placebo-controlled trial (HVTN 137A). The vaccine regimen appeared safe. Robust, trimer-specific antibody, B-cell and CD4+ T-cell responses emerged post-vaccination. Five vaccinees developed serum autologous tier-2 nAbs (ID50 titer, 1:28-1:8647) after 2-3 doses targeting C3/V5 and/or V1/V2/V3 Env regions by electron microscopy and mutated pseudovirus-based neutralization analyses. Trimer-specific, B-cell-derived monoclonal antibody activities confirmed these results and showed weak heterologous neutralization in the strongest responder. Our findings demonstrate the clinical utility of the 3M-052-AF/alum adjuvant and support further improvements of trimer-based Env immunogens to focus responses on multiple broad nAb epitopes. KEY TAKEAWAY/TAKE-HOME MESSAGES: HIV BG505 SOSIP.664 trimer with novel 3M-052-AF/alum adjuvant in humans appears safe and induces serum neutralizing antibodies to matched clade A, tier 2 virus, that map to diverse Env epitopes with relatively high titers. The novel adjuvant may be an important mediator of vaccine response.

Progress on priming HIV-1 immunity.

Four new studies inform on the multistep path to generate broadly active HIV-1 antibodies.

The role of hydraulic conductivity in the Pine Island Glacier's subglacial water distribution.

Global climate warming leads to ever-increasing glacier mass loss. Pine Island Glacier in Antarctica is one of the largest contributors to global sea level rise (SLR). One of the biggest uncertainties in the assessment of glacier contribution to SLR at present are subglacial hydrology processes which are less well known than other ice dynamical processes. We use the Glacier Drainage System (GlaDS) model which couples both distributed and channelized components to simulate the basal hydrology of Pine Island Glacier with basal sliding and meltwater production taken from a full-Stokes Elmer/Ice model fitting observed surface velocities. We find ≈100 km long Rothlisberger channels up to 26 m in diameter extending up glacier from the grounding line along the main trunk of Pine Island Glacier delivering 51 m3 s-1 of fresh water to the grounding line. Channelization occurs at high water pressure because of high basal melt rates (maximum of 1 m a-1) caused by high rates of shear heating in regions with fast ice flow (>1000 m a-1). We simulate a shallow "swamp" of 0.8 m water depth where flow transitions from a distributed system into the channels. We performed a set of 38 sensitivity experiments varying sheet and channel conductivity over 4 orders of magnitude. We find a threshold behavior in distributed sheet conductivity above which basal water pressures are unaffected by changing channel conductivities. Our findings suggest a strong need to better understand controls on basal water conductivity through the distributed system. This issue is critical to improve model-based predictive capability for the Pine Island Glacier and, more generally, the Antarctic Ice Sheet.

Persistence and evolution of Pseudomonas aeruginosa following initiation of highly effective modulator therapy in cystic fibrosis.

Today, more than 90% of people with cystic fibrosis (pwCF) are eligible for the highly effective cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy called elexacaftor/tezacaftor/ivacaftor (ETI) and its use is widespread. Given the drastic respiratory symptom improvement experienced by many post-ETI, clinical studies are already underway to reduce the number of respiratory therapies, including antibiotic regimens, that pwCF historically relied on to combat lung disease progression. Early studies suggest that bacterial burden in the lungs is reduced post-ETI, yet it is unknown how chronic Pseudomonas aeruginosa populations are impacted by ETI. We found that pwCF remain infected throughout their upper and lower respiratory tract with their same strain of P. aeruginosa post-ETI, and these strains continue to evolve in response to the newly CFTR-corrected airway. Our work underscores the continued importance of CF airway microbiology in the new era of highly effective CFTR modulator therapy. IMPORTANCE: The highly effective cystic fibrosis transmembrane conductance regulator modulator therapy Elexakaftor/Tezacaftor/Ivacaftor (ETI) has changed cystic fibrosis (CF) disease for many people with cystic fibrosis. While respiratory symptoms are improved by ETI, we found that people with CF remain infected with Pseudomonas aeruginosa. How these persistent and evolving bacterial populations will impact the clinical manifestations of CF in the coming years remains to be seen, but the role and potentially changing face of infection in CF should not be discounted in the era of highly effective modulator therapy.

Outcomes of Patients With Diffuse Systemic Sclerosis Eligible for Autologous Stem Cell Transplantation Treated With Conventional Therapy.

OBJECTIVE: The study objective was to determine the event-free survival (EFS) of Australian patients with diffuse cutaneous systemic sclerosis (dcSSc) who met eligibility criteria for autologous stem cell transplant (ASCT) in previously published randomized controlled trials but were not treated with ASCT. METHODS: Patients who met inclusion criteria for the Autologous Stem Cell Transplantation International Scleroderma (ASTIS) and Scleroderma: Cyclophosphamide Or Transplantation (SCOT) trials were identified from the multicenter Australian Scleroderma Cohort Study (ASCS). EFS (survival without cardiac, renal, or pulmonary failure or death) at 4 years was assessed. ASCS patients who had already undergone transplantation were excluded from analysis. RESULTS: Of the 492 patients with dcSSc in the ASCS, 56 met ASTIS inclusion criteria for ASCT (56 of 492 [11.4%]) and 30 met SCOT inclusion criteria (30 of 492 [6.1%]). An additional 11 patients met ASTIS or SCOT inclusion criteria, but they were excluded due to severe organ manifestations. EFS at 4 years in ASCS patients meeting ASTIS inclusion criteria was 83.3% and in ASCS patients meeting SCOT inclusion criteria was 81.2%. EFS at 4 years in ASCS patients who met ASTIS and SCOT inclusion but also exclusion criteria was 46.7% and 45.7%, respectively. CONCLUSION: ASCS patients meeting ASTIS and/or SCOT inclusion criteria who were not treated with ASCT have similar EFS at 4 years as patients receiving ASCT and better EFS than those receiving cyclophosphamide in the ASTIS and SCOT trials. This may reflect confounders unable to be controlled for, including survivor bias, but may also reflect improved standard of care for dcSSc over time.

Attitudes to cross infection, nebuliser hygiene and antimicrobial resistance in people with cystic fibrosis: Results of an international survey.

BACKGROUND: Respiratory infection is a major cause of disease severity in people with cystic fibrosis (PwCF). This project aimed to establish the CF community's opinion regarding cross infection (CI), nebuliser hygiene, antimicrobial resistance, personal impact of microbiological findings and the role of the microbiology laboratory. METHODS: A questionnaire was completed anonymously (n = 280; PwCF (n = 128), parents (n = 123); friends/family/carers/charity personnel (n = 29)) from 13 countries. Readability scores (Flesch Reading Ease (FRE), Flesch Kincaid Grade Level (FKGL)) were determined for CI/IP&C information from six national CF charities and 21 scientific abstracts. RESULTS: Respondents (72.5%) indicated knowledge of laboratory aspects of CF microbiology was important, however implications of microbiological findings on personal health/well-being were of higher importance (p < 0.0001). Cross infection/infection prevention & control (CI/IP&C) was of highest importance (95.6% respondents) with 27.3% indicating they were not given adequate information, particularly in older respondents (50 y+) (p = 0.006) versus young adults (16-29 y) and respondents from the Middle East versus N. America (p = 0.022) and Europe (p = 0.045). Responses highlighted how CI/IP&C health literacy could be enhanced. Respondents (77.3%), particularly females (p < 0.0001), indicated they would increase the frequency of nebuliser disinfection following guidance on infection risks/best practice, therefore an educational video was prepared. CI/IP&C readability scores (mean ± sd) from CF charities (FRE 52.5 ± 10.8; FKGL 9.7 ± 2.3) were more readable (p < 0.0001) than scientific abstracts (FRE 13.3 ± 11.1; FKGL 16.9 ± 2.3), however not meeting the targets (FRE≥60 and FKGL≤8). CONCLUSION: There is a requirement for further CI/IP&C evidence-based guidance, policies/guidelines, education awareness, best practice in the home environment and multi-modal communication, enabling the CF community to make informed choices on lifestyle behaviours.

Outcomes reported in randomised trials of surgical prehabilitation: a scoping review.

BACKGROUND: Heterogeneity of reported outcomes can impact the certainty of evidence for prehabilitation. The objective of this scoping review was to systematically map outcomes and assessment tools used in trials of surgical prehabilitation. METHODS: MEDLINE, EMBASE, PsychInfo, Web of Science, CINAHL, and Cochrane were searched in February 2023. Randomised controlled trials of unimodal or multimodal prehabilitation interventions (nutrition, exercise, psychological support) lasting at least 7 days in adults undergoing elective surgery were included. Reported outcomes were classified according to the International Society for Pharmacoeconomics and Outcomes Research framework. RESULTS: We included 76 trials, mostly focused on abdominal or orthopaedic surgeries. A total of 50 different outcomes were identified, measured using 184 outcome assessment tools. Observer-reported outcomes were collected in 86% of trials (n=65), with hospital length of stay being most common. Performance outcomes were reported in 80% of trials (n=61), most commonly as exercise capacity assessed by cardiopulmonary exercise testing. Clinician-reported outcomes were included in 78% (n=59) of trials and most frequently included postoperative complications with Clavien-Dindo classification. Patient-reported outcomes were reported in 76% (n=58) of trials, with health-related quality of life using the 36- or 12-Item Short Form Survey being most prevalent. Biomarker outcomes were reported in 16% of trials (n=12) most commonly using inflammatory markers assessed with C-reactive protein. CONCLUSIONS: There is substantial heterogeneity in the reporting of outcomes and assessment tools across surgical prehabilitation trials. Identification of meaningful outcomes, and agreement on appropriate assessment tools, could inform the development of a prehabilitation core outcomes set to harmonise outcome reporting and facilitate meta-analyses.

Towards a common definition of surgical prehabilitation: a scoping review of randomised trials.

BACKGROUND: There is no universally accepted definition for surgical prehabilitation. The objectives of this scoping review were to (1) identify how surgical prehabilitation is defined across randomised controlled trials and (2) propose a common definition. METHODS: The final search was conducted in February 2023 using MEDLINE, Embase, PsycINFO, Web of Science, CINAHL, and Cochrane. We included randomised controlled trials (RCTs) of unimodal or multimodal prehabilitation interventions (nutrition, exercise, and psychological support) lasting at least 7 days in adults undergoing elective surgery. Qualitative data were analysed using summative content analysis. RESULTS: We identified 76 prehabilitation trials of patients undergoing abdominal (n=26, 34%), orthopaedic (n=20, 26%), thoracic (n=14, 18%), cardiac (n=7, 9%), spinal (n=4, 5%), and other (n=5, 7%) surgeries. Surgical prehabilitation was explicitly defined in more than half of these RCTs (n=42, 55%). Our findings consolidated the following definition: 'Prehabilitation is a process from diagnosis to surgery, consisting of one or more preoperative interventions of exercise, nutrition, psychological strategies and respiratory training, that aims to enhance functional capacity and physiological reserve to allow patients to withstand surgical stressors, improve postoperative outcomes, and facilitate recovery.' CONCLUSIONS: A common definition is the first step towards standardisation, which is needed to guide future high-quality research and advance the field of prehabilitation. The proposed definition should be further evaluated by international stakeholders to ensure that it is comprehensive and globally accepted.

International consensus is needed on a core outcome set to advance the evidence of best practice in cancer prehabilitation services and research.

Prehabilitation aims to optimise patients' physical and psychological status before treatment. The types of outcomes measured to assess the impact of prehabilitation interventions vary across clinical research and service evaluation, limiting the ability to compare between studies and services and to pool data. An international workshop involving academic and clinical experts in cancer prehabilitation was convened in May 2022 at Sheffield Hallam University's Advanced Wellbeing Research Centre, England. The workshop substantiated calls for a core outcome set to advance knowledge and understanding of best practice in cancer prehabilitation and to develop national and international databases to assess outcomes at a population level.

How comparable are patient outcomes in the "real-world" with populations studied in pivotal AML trials?

Despite an increasing desire to use historical cohorts as "synthetic" controls for new drug evaluation, limited data exist regarding the comparability of real-world outcomes to those in clinical trials. Governmental cancer data often lacks details on treatment, response, and molecular characterization of disease sub-groups. The Australasian Leukaemia and Lymphoma Group National Blood Cancer Registry (ALLG NBCR) includes source information on morphology, cytogenetics, flow cytometry, and molecular features linked to treatment received (including transplantation), response to treatment, relapse, and survival outcome. Using data from 942 AML patients enrolled between 2012-2018, we assessed age and disease-matched control and interventional populations from published randomized trials that led to the registration of midostaurin, gemtuzumab ozogamicin, CPX-351, oral azacitidine, and venetoclax. Our analyses highlight important differences in real-world outcomes compared to clinical trial populations, including variations in anthracycline type, cytarabine intensity and scheduling during consolidation, and the frequency of allogeneic hematopoietic cell transplantation in first remission. Although real-world outcomes were comparable to some published studies, notable differences were apparent in others. If historical datasets were used to assess the impact of novel therapies, this work underscores the need to assess diverse datasets to enable geographic differences in treatment outcomes to be accounted for.

Sociodemographic and treatment-related determinants of recent substance use among adults with comorbid substance misuse and psychotic disorders discharged from substance use treatment.

INTRODUCTION: Rates of alcohol and illicit substance use are higher among persons with psychotic disorders relative to the general population. The adverse health and psychological effects of substance use behaviors disproportionately impact persons with psychotic disorders. Prior research has shown that persons with psychotic disorders experience increased difficulty in reducing substance use behaviors, and interventions targeting substance use behavior change among this population have demonstrated limited effectiveness. One reason for this is that little is known about the factors that influence substance use and behavior change among this population. To address these disparities, the present study investigated sociodemographic and treatment-related factors of substance use recurrence among persons with psychotic disorders who received substance use treatment services. METHODS: Data came from the 2015-2018 Treatment Episode Dataset-Discharges (TEDS-D). TEDS-D collects annual data on adolescent and adult discharges from state-certified substance use treatment centers in the United States. The study conducted all analyses with a subsample of 1956 adult discharges with a psychotic disorder who received services from an outpatient substance use treatment center for at least one month. χ2 tests of independence and multivariable logistic regression analyses were used to examine associations of sociodemographic and treatment-related characteristics with substance use recurrence while in treatment (α < 0.05 analyses). The study presents results from multivariable logistic regression models as adjusted odds ratios (AORs) with 95 % confidence intervals (CI). RESULTS: Those who were age 50 or older, were referred to treatment by the criminal justice system, and attended substance use self-help groups had lower odds of substance use recurrence while in treatment. Sex, educational attainment, employment status, living situation, type of substance use, and treatment history were not significantly associated with substance use recurrence. CONCLUSIONS: In designing treatment services, providers should consider whether focusing on sociodemographic, including cultural, factors can affect more positive substance use behavior change and other desired treatment outcomes among those with psychotic disorders and comorbid substance misuse. Further study is needed to identify these factors among specific subpopulations of those with psychotic disorders and substance misuse.

Effects of highly effective modulator therapy on the dynamics of the respiratory mucosal environment and inflammatory response in cystic fibrosis.

BACKGROUND: While the widespread initiation of elexacaftor/tezacaftor/ivacaftor (ETI) has led to dramatic clinical improvements among persons with cystic fibrosis (pwCF), little is known about how ETI affects the respiratory mucosal inflammatory and physiochemical environment, or how these changes relate to lung function. METHODS: We performed a prospective, longitudinal study of adults with CF and chronic rhinosinusitis (CF-CRS) followed at our CF center (n = 18). Endoscopic upper respiratory tract (paranasal sinus) aspirates from multiple visit dates, both pre- and post-ETI initiation, were collected and tested for cytokines, metals, pH, and lactate levels. Generalized estimating equations were used to identify relationships between ETI and upper respiratory tract (URT) biomarker levels, and between URT biomarkers and lung function or clinical sinus parameters. RESULTS: ETI was associated with decreased upper respiratory mucosal cytokines B-cell activating factor (BAFF), IL-12p40, IL-32, IL-8, IL-22 and soluble tumor necrosis factor-1 (sTNFR1), and an increase in a proliferation-inducing ligand (APRIL) and IL-19. ETI was also associated with decreased URT levels of copper, manganese, and zinc. In turn, lower URT levels of BAFF, IL-8, lactate, and potassium were each associated with ~1.5% to 4.3% improved forced expiratory volume in 1 s (FEV1), while higher levels of IFNγ, iron, and selenium were associated with ~2% to 10% higher FEV1. CONCLUSIONS: Our observations suggest a dampening of inflammatory signals and restriction in microbial nutrients in the upper respiratory tract with ETI. These findings improve our understanding of how ETI impacts the mucosal environment in the respiratory tract, and may give insight into the improved infectious and inflammatory status and the resulting clinical improvements seen in pwCF.

Improving health literacy of passengers of cruise ships: readability of passenger-facing COVID-19 information provided by commercial cruise lines-an infodemiology study.

Readability of COVID-19 information from 35 cruise lines was examined. Mean Flesch Reading Ease and Flesch-Kincaid Grade Level scores (±standard error of mean) were 46.6 ± 1.3 (target ≥60) and 10.9 ± 0.3 (target ≤ 8.0), respectively. Two (6%) cruise lines met readability reference targets. Readability tools may aid in preparing more easily read passenger-facing health-related information on existing infections, including COVID-19, other respiratory infections, as well as gastroenteritis (e.g. norovirus), as well as providing a methodology for improving the readability of information prepared for newly emerging infectious diseases.