Ceftobiprole for Treatment of Complicated Staphylococcus aureus Bacteremia.

BACKGROUND: Ceftobiprole is a cephalosporin that may be effective for treating complicated Staphylococcus aureus bacteremia, including methicillin-resistant S. aureus. METHODS: In this phase 3, double-blind, double-dummy, noninferiority trial, adults with complicated S. aureus bacteremia were randomly assigned in a 1:1 ratio to receive ceftobiprole at a dose of 500 mg intravenously every 6 hours for 8 days and every 8 hours thereafter, or daptomycin at a dose of 6 to 10 mg per kilogram of body weight intravenously every 24 hours plus optional aztreonam (at the discretion of the trial-site investigators). The primary outcome, overall treatment success 70 days after randomization (defined as survival, bacteremia clearance, symptom improvement, no new S. aureus bacteremia-related complications, and no receipt of other potentially effective antibiotics), with a noninferiority margin of 15%, was adjudicated by a data review committee whose members were unaware of the trial-group assignments. Safety was also assessed. RESULTS: Of 390 patients who underwent randomization, 387 (189 in the ceftobiprole group and 198 in the daptomycin group) had confirmed S. aureus bacteremia and received ceftobiprole or daptomycin (modified intention-to-treat population). A total of 132 of 189 patients (69.8%) in the ceftobiprole group and 136 of 198 patients (68.7%) in the daptomycin group had overall treatment success (adjusted difference, 2.0 percentage points; 95% confidence interval [CI], -7.1 to 11.1). Findings appeared to be consistent between the ceftobiprole and daptomycin groups in key subgroups and with respect to secondary outcomes, including mortality (9.0% and 9.1%, respectively; 95% CI, -6.2 to 5.2) and the percentage of patients with microbiologic eradication (82.0% and 77.3%; 95% CI, -2.9 to 13.0). Adverse events were reported in 121 of 191 patients (63.4%) who received ceftobiprole and 117 of 198 patients (59.1%) who received daptomycin; serious adverse events were reported in 36 patients (18.8%) and 45 patients (22.7%), respectively. Gastrointestinal adverse events (primarily mild nausea) were more frequent with ceftobiprole. CONCLUSIONS: Ceftobiprole was noninferior to daptomycin with respect to overall treatment success in patients with complicated S. aureus bacteremia. (Funded by Basilea Pharmaceutica International and the U.S. Department of Health and Human Services; ERADICATE ClinicalTrials.gov number, NCT03138733.).

Cardiovascular disease risk communication and prevention: a meta-analysis.

BACKGROUND AND AIMS: Knowledge of quantifiable cardiovascular disease (CVD) risk may improve health outcomes and trigger behavioural change in patients or clinicians. This review aimed to investigate the impact of CVD risk communication on patient-perceived CVD risk and changes in CVD risk factors. METHODS: PubMed, Embase, and PsycINFO databases were searched from inception to 6 June 2023, supplemented by citation analysis. Randomized trials that compared any CVD risk communication strategy versus usual care were included. Paired reviewers independently screened the identified records and extracted the data; disagreements were resolved by a third author. The primary outcome was the accuracy of risk perception. Secondary outcomes were clinician-reported changes in CVD risk, psychological responses, intention to modify lifestyle, and self-reported changes in risk factors and clinician prescribing of preventive medicines. RESULTS: Sixty-two trials were included. Accuracy of risk perception was higher among intervention participants (odds ratio = 2.31, 95% confidence interval = 1.63 to 3.27). A statistically significant improvement in overall CVD risk scores was found at 6-12 months (mean difference = -0.27, 95% confidence interval = -0.45 to -0.09). For primary prevention, risk communication significantly increased self-reported dietary modification (odds ratio = 1.50, 95% confidence interval = 1.21 to 1.86) with no increase in intention or actual changes in smoking cessation or physical activity. A significant impact on patients' intention to start preventive medication was found for primary and secondary prevention, with changes at follow-up for the primary prevention group. CONCLUSIONS: In this systematic review and meta-analysis, communicating CVD risk information, regardless of the method, reduced the overall risk factors and enhanced patients' self-perceived risk. Communication of CVD risk to patients should be considered in routine consultations.

Immunogenicity, reactogenicity, and IgE-mediated immune responses of a mixed whole-cell and acellular pertussis vaccine schedule in Australian infants: A randomised, double-blind, noninferiority trial.

BACKGROUND: In many countries, infant vaccination with acellular pertussis (aP) vaccines has replaced use of more reactogenic whole-cell pertussis (wP) vaccines. Based on immunological and epidemiological evidence, we hypothesised that substituting the first aP dose in the routine vaccination schedule with wP vaccine might protect against IgE-mediated food allergy. We aimed to compare reactogenicity, immunogenicity, and IgE-mediated responses of a mixed wP/aP primary schedule versus the standard aP-only schedule. METHODS AND FINDINGS: OPTIMUM is a Bayesian, 2-stage, double-blind, randomised trial. In stage one, infants were assigned (1:1) to either a first dose of a pentavalent wP combination vaccine (DTwP-Hib-HepB, Pentabio PT Bio Farma, Indonesia) or a hexavalent aP vaccine (DTaP-Hib-HepB-IPV, Infanrix hexa, GlaxoSmithKline, Australia) at approximately 6 weeks old. Subsequently, all infants received the hexavalent aP vaccine at 4 and 6 months old as well as an aP vaccine at 18 months old (DTaP-IPV, Infanrix-IPV, GlaxoSmithKline, Australia). Stage two is ongoing and follows the above randomisation strategy and vaccination schedule. Ahead of ascertainment of the primary clinical outcome of allergist-confirmed IgE-mediated food allergy by 12 months old, here we present the results of secondary immunogenicity, reactogenicity, tetanus toxoid IgE-mediated immune responses, and parental acceptability endpoints. Serum IgG responses to diphtheria, tetanus, and pertussis antigens were measured using a multiplex fluorescent bead-based immunoassay; total and specific IgE were measured in plasma by means of the ImmunoCAP assay (Thermo Fisher Scientific). The immunogenicity of the mixed schedule was defined as being noninferior to that of the aP-only schedule using a noninferiority margin of 2/3 on the ratio of the geometric mean concentrations (GMR) of pertussis toxin (PT)-IgG 1 month after the 6-month aP. Solicited adverse reactions were summarised by study arm and included all children who received the first dose of either wP or aP. Parental acceptance was assessed using a 5-point Likert scale. The primary analyses were based on intention-to-treat (ITT); secondary per-protocol (PP) analyses were also performed. The trial is registered with ANZCTR (ACTRN12617000065392p). Between March 7, 2018 and January 13, 2020, 150 infants were randomised (75 per arm). PT-IgG responses of the mixed schedule were noninferior to the aP-only schedule at approximately 1 month after the 6-month aP dose [GMR = 0·98, 95% credible interval (0·77 to 1·26); probability (GMR > 2/3) > 0·99; ITT analysis]. At 7 months old, the posterior median probability of quantitation for tetanus toxoid IgE was 0·22 (95% credible interval 0·12 to 0·34) in both the mixed schedule group and in the aP-only group. Despite exclusions, the results were consistent in the PP analysis. At 6 weeks old, irritability was the most common systemic solicited reaction reported in wP (65 [88%] of 74) versus aP (59 [82%] of 72) vaccinees. At the same age, severe systemic reactions were reported among 14 (19%) of 74 infants after wP and 8 (11%) of 72 infants after aP. There were 7 SAEs among 5 participants within the first 6 months of follow-up; on blinded assessment, none were deemed to be related to the study vaccines. Parental acceptance of mixed and aP-only schedules was high (71 [97%] of 73 versus 69 [96%] of 72 would agree to have the same schedule again). CONCLUSIONS: Compared to the aP-only schedule, the mixed schedule evoked noninferior PT-IgG responses, was associated with more severe reactions, but was well accepted by parents. Tetanus toxoid IgE responses did not differ across the study groups. TRIAL REGISTRATION: Trial registered at the Australian and New Zealand Clinical 207 Trial Registry (ACTRN12617000065392p).

Mortality surrogates in combined pulmonary fibrosis and emphysema.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) with coexistent emphysema, termed combined pulmonary fibrosis and emphysema (CPFE) may associate with reduced forced vital capacity (FVC) declines compared to non-CPFE IPF patients. We examined associations between mortality and functional measures of disease progression in two IPF cohorts. METHODS: Visual emphysema presence (>0% emphysema) scored on computed tomography identified CPFE patients (CPFE/non-CPFE: derivation cohort n=317/n=183, replication cohort n=358/n=152), who were subgrouped using 10% or 15% visual emphysema thresholds, and an unsupervised machine-learning model considering emphysema and interstitial lung disease extents. Baseline characteristics, 1-year relative FVC and diffusing capacity of the lung for carbon monoxide (D LCO) decline (linear mixed-effects models), and their associations with mortality (multivariable Cox regression models) were compared across non-CPFE and CPFE subgroups. RESULTS: In both IPF cohorts, CPFE patients with ≥10% emphysema had a greater smoking history and lower baseline D LCO compared to CPFE patients with <10% emphysema. Using multivariable Cox regression analyses in patients with ≥10% emphysema, 1-year D LCO decline showed stronger mortality associations than 1-year FVC decline. Results were maintained in patients suitable for therapeutic IPF trials and in subjects subgrouped by ≥15% emphysema and using unsupervised machine learning. Importantly, the unsupervised machine-learning approach identified CPFE patients in whom FVC decline did not associate strongly with mortality. In non-CPFE IPF patients, 1-year FVC declines ≥5% and ≥10% showed strong mortality associations. CONCLUSION: When assessing disease progression in IPF, D LCO decline should be considered in patients with ≥10% emphysema and a ≥5% 1-year relative FVC decline threshold considered in non-CPFE IPF patients.

Systematic Review of Shoulder Imaging Abnormalities in Asymptomatic Adult Shoulders (SCRUTINY): Abnormalities of the glenohumeral joint.

OBJECTIVE: The primary objective was to determine the population prevalence of glenohumeral joint imaging abnormalities in asymptomatic adults. METHOD: We systematically reviewed studies reporting the prevalence of X-ray, ultrasound (US), computed tomography, and magnetic resonance imaging (MRI) abnormalities in adults without shoulder symptoms (PROSPERO registration number CRD42018090041). This report presents the glenohumeral joint imaging findings. We searched Ovid MEDLINE, Embase, CINAHL and Web of Science from inception to June 2023 and assessed risk of bias using a tool designed for prevalence studies. The primary analysis was planned for the general population. The certainty of evidence was assessed using a modified Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) for prognostic studies. RESULTS: Thirty-five studies (4 X-ray, 10 US, 20 MRI, 1 X-ray and MRI) reported useable prevalence data. Two studies were population-based (846 shoulders), 15 studies included miscellaneous study populations (1715 shoulders) and 18 included athletes (727 shoulders). All were judged to be at high risk of bias. Clinical diversity precluded pooling. Population prevalence of glenohumeral osteoarthritis ranged from 15% to 75% (2 studies, 846 shoulders, 1 X-ray, 1 X-ray and MRI; low certainty evidence). Prevalence of labral abnormalities, humeral head cysts and long head of biceps tendon abnormalities were 20%, 5%, 30% respectively (1 study, 20 shoulders, X-ray and MRI; very low certainty evidence). CONCLUSION: The population-based prevalence of glenohumeral joint imaging abnormalities in asymptomatic individuals remains uncertain, but may range between 30% and 75%. Better estimates are needed to inform best evidence-based management of people with shoulder pain.

A randomized, open-label, phase 3 trial of pembrolizumab plus epacadostat versus sunitinib or pazopanib as first-line treatment for metastatic renal cell carcinoma (KEYNOTE-679/ECHO-302).

BACKGROUND: Immunotherapy-based combinations have emerged as standard therapies for patients with metastatic renal cell carcinoma (mRCC). Pembrolizumab, a PD-1 inhibitor, combined with epacadostat, an indoleamine 2,3-deoxygenase 1 selective inhibitor, demonstrated promising antitumor activity in a phase 1 study in advanced solid tumors, including mRCC. METHODS: KEYNOTE-679/ECHO-302 was a randomized, open-label, parallel-group, multicenter, phase 3 study (NCT03260894) that compared pembrolizumab plus epacadostat with sunitinib or pazopanib as first-line treatment for mRCC. Eligible patients had histologically confirmed locally advanced or metastatic clear cell RCC and had not received systemic therapy. Patients were randomly assigned 1:1 to pembrolizumab 200 mg IV every 3 weeks plus epacadostat 100 mg orally twice daily versus sunitinib 50 mg orally once daily (4 weeks on treatment followed by 2 weeks off treatment) or pazopanib 800 mg orally once daily. Original dual primary end points were progression-free survival and overall survival. Enrollment was stopped when a phase 3 study in melanoma of pembrolizumab plus epacadostat compared with pembrolizumab monotherapy did not meet its primary end point. This protocol was amended, and primary end point was changed to investigator-assessed objective response rate (ORR) per RECIST 1.1. RESULTS: One-hundred-twenty-nine patients were randomly assigned to receive pembrolizumab plus epacadostat (n = 64) or sunitinib/pazopanib (n = 65). Median (range) follow-up, defined as time from randomization to data cutoff, was 10.3 months (2.2-14.3) and 10.3 months (2.7-13.8) in the pembrolizumab plus epacadostat and sunitinib/pazopanib arms, respectively. ORRs were similar between pembrolizumab plus epacadostat (31.3% [95% CI 20.2-44.1] and sunitinib/pazopanib (29.2% [18.6-41.8]). Grade 3-5 treatment-related adverse events occurred in 34.4% and 42.9% of patients in the pembrolizumab plus epacadostat and sunitinib/pazopanib arms, respectively. One patient in the sunitinib/pazopanib arm died of septic shock (not treatment-related). Circulating kynurenine levels decreased in the pembrolizumab plus epacadostat arm, but not to levels observed in healthy subjects. CONCLUSIONS: ORRs were similar between pembrolizumab plus epacadostat and sunitinib/pazopanib as first-line treatment in patients with mRCC. Safety and tolerability appeared similar between treatment arms; no new safety concerns were identified. Antitumor responses observed in patients with RCC receiving pembrolizumab plus epacadostat may be driven primarily by pembrolizumab. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov; NCT03260894 .

Associations between healthy food groups and platelet-activating factor, lipoprotein-associated phospholipase A2 and C-reactive protein: a cross-sectional study.

PURPOSE: To investigate the association between pro-inflammatory markers platelet-activating factor (PAF), lipoprotein-associated phospholipase A2 (Lp-PLA2), hsCRP, and intake of core food groups including fruit, cruciferous and other vegetables, grains, meat and poultry, fish and seafood, nuts and legumes, and dairy. METHODS: A cross-sectional study was conducted. 100 adults (49 ± 13 years, 31% male) with variable cardiovascular disease risk were recruited. Data were collected in 2021 and 2022. Fasting PAF, Lp-PLA2 activity, hsCRP and usual dietary intake (via a validated food frequency questionnaire) were measured. Intake of foods were converted into serves and classified into food groups. Correlations and multiple regressions were performed with adjustment for confounders. RESULTS: A one-serve increase in cruciferous vegetables per day was associated with 20-24% lower PAF levels. An increase of one serve per day of nuts and legumes was associated with 40% lower hsCRP levels. There were small correlations with PAF and Lp-PLA2 and cheese, however, these were not significant at the Bonferroni-adjusted P < 0.005 level. CONCLUSION: The lack of associations between PAF and Lp-PLA2 and other healthy foods may be due to confounding by COVID-19 infection and vaccination programs which prevents any firm conclusion on the relationship between PAF, Lp-PLA2 and food groups. Future research should aim to examine the relationship with these novel markers and healthy food groups in a non-pandemic setting.

Residual Lung Abnormalities after COVID-19 Hospitalization: Interim Analysis of the UKILD Post-COVID-19 Study.

Rationale: Shared symptoms and genetic architecture between coronavirus disease (COVID-19) and lung fibrosis suggest severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may lead to progressive lung damage. Objectives: The UK Interstitial Lung Disease Consortium (UKILD) post-COVID-19 study interim analysis was planned to estimate the prevalence of residual lung abnormalities in people hospitalized with COVID-19 on the basis of risk strata. Methods: The PHOSP-COVID-19 (Post-Hospitalization COVID-19) study was used to capture routine and research follow-up within 240 days from discharge. Thoracic computed tomography linked by PHOSP-COVID-19 identifiers was scored for the percentage of residual lung abnormalities (ground-glass opacities and reticulations). Risk factors in linked computed tomography were estimated with Bayesian binomial regression, and risk strata were generated. Numbers within strata were used to estimate posthospitalization prevalence using Bayesian binomial distributions. Sensitivity analysis was restricted to participants with protocol-driven research follow-up. Measurements and Main Results: The interim cohort comprised 3,700 people. Of 209 subjects with linked computed tomography (median, 119 d; interquartile range, 83-155), 166 people (79.4%) had more than 10% involvement of residual lung abnormalities. Risk factors included abnormal chest X-ray (risk ratio [RR], 1.21; 95% credible interval [CrI], 1.05-1.40), percent predicted DlCO less than 80% (RR, 1.25; 95% CrI, 1.00-1.56), and severe admission requiring ventilation support (RR, 1.27; 95% CrI, 1.07-1.55). In the remaining 3,491 people, moderate to very high risk of residual lung abnormalities was classified at 7.8%, and posthospitalization prevalence was estimated at 8.5% (95% CrI, 7.6-9.5), rising to 11.7% (95% CrI, 10.3-13.1) in the sensitivity analysis. Conclusions: Residual lung abnormalities were estimated in up to 11% of people discharged after COVID-19-related hospitalization. Health services should monitor at-risk individuals to elucidate long-term functional implications.

"I am in favour of organ donation, but I feel you should opt-in"-qualitative analysis of the #options 2020 survey free-text responses from NHS staff toward opt-out organ donation legislation in England.

BACKGROUND: In May 2020, England moved to an opt-out organ donation system, meaning adults are presumed to be an organ donor unless within an excluded group or have opted-out. This change aims to improve organ donation rates following brain or circulatory death. Healthcare staff in the UK are supportive of organ donation, however, both healthcare staff and the public have raised concerns and ethical issues regarding the change. The #options survey was completed by NHS organisations with the aim of understanding awareness and support of the change. This paper analyses the free-text responses from the survey. METHODS: The #options survey was registered as a National Institute of Health Research (NIHR) portfolio trial [IRAS 275992] 14 February 2020, and was completed between July and December 2020 across NHS organisations in the North-East and North Cumbria, and North Thames. The survey contained 16 questions of which three were free-text, covering reasons against, additional information required and family discussions. The responses to these questions were thematically analysed. RESULTS: The #options survey received 5789 responses from NHS staff with 1404 individuals leaving 1657 free-text responses for analysis. The family discussion question elicited the largest number of responses (66%), followed by those against the legislation (19%), and those requiring more information (15%). Analysis revealed six main themes with 22 sub-themes. CONCLUSIONS: The overall #options survey indicated NHS staff are supportive of the legislative change. Analysis of the free-text responses indicates that the views of the NHS staff who are against the change reflect the reasons, misconceptions, and misunderstandings of the public. Additional concerns included the rationale for the change, informed decision making, easy access to information and information regarding organ donation processes. Educational materials and interventions need to be developed for NHS staff to address the concepts of autonomy and consent, organ donation processes, and promote family conversations. Wider public awareness campaigns should continue to promote the positives and refute the negatives thus reducing misconceptions and misunderstandings. TRIAL REGISTRATION: National Institute of Health Research (NIHR) [IRAS 275992].

Diagnostic performance of clinical prediction rules to detect group A beta-haemolytic streptococci in people with acute pharyngitis: a systematic review.

OBJECTIVE: To assess and compare the diagnostic performance of Clinical Prediction Rules (CPRs) developed to detect group A Beta-haemolytic streptococci in people with acute pharyngitis (or sore throat). STUDY DESIGN: A systematic review. METHODS: We searched PubMed, Embase and Web of Science (inception-September 2022) for studies deriving and/or validating CPRs comprised of ≥2 predictors from an individual's history or physical examination. Two authors independently screened articles, extracted data and assessed risk of bias in included studies. A meta-analysis was not possible due to heterogeneity. Instead we compared the performance of CPRs when they were validated in the same study population (head-to-head comparisons). We used a modified grading of recommendations, assessment, development, and evaluations (GRADE) approach to assess certainty of the evidence. RESULTS: We included 63 studies, all judged at high risk of bias. Of 24 derived CPRs, 7 were externally validated (in 46 external validations). Five validation studies provided data for head-to-head comparison of four pairs of CPRs. Very low certainty evidence favoured the Centor CPR over the McIsaac (2 studies) and FeverPain CPRs (1 study) and found the Centor CPR was equivalent to the Walsh CPR (1 study). The AbuReesh and Steinhoff 2005 CPRs had a similar poor discriminative ability (1 study). Within and between study comparisons suggested the performance of the Centor CPR may be better in adults (>18 years). CONCLUSION: Very low certainty evidence suggests a better performance of the Centor CPR. When deciding about antibiotic prescribing for pharyngitis patients, involving patients in a shared decision making discussion about the likely benefits and harms, including antibiotic resistance, is recommended. Further research of higher rigour, which compares CPRs across multiple settings, is needed.

Susceptibility and Yield Response of Commercial Corn Hybrids to Maize Dwarf Mosaic Disease.

Maize dwarf mosaic (MDM) is one of the most important virus diseases of maize worldwide. Caused by the potyviruses maize dwarf mosaic virus (MDMV) or sugarcane mosaic virus (SCMV), MDM can cause up to 90% yield loss in susceptible hybrids. One of the most effective management strategies for MDM is growing potyvirus-resistant corn varieties. However, yield impacts associated with MDM and the corresponding efficacy of genetic resistance present in modern United States commercial hybrid lines is uncharacterized. In this study, we evaluated the disease response of 78 commercial hybrids to MDMV and SCMV and quantified yield losses associated with infection over multiple trials. We determined that while 97% of the hybrids tested were resistant to MDMV, 100% were susceptible to SCMV, with mean disease incidence per line averaging between 45 and 78% across six trial years. Despite only one hybrid displaying visible mosaic symptoms when inoculated with MDMV, MDMV reduced average yields by approximately 5% across all hybrids compared with the mock-inoculated treatment. The yield impact of SCMV was more severe, reducing average yields by 10% across replicated experiments. These results indicate that while most commercial hybrids are resistant to MDMV, possibly due to the presence of the major Scmv1 resistance locus on chromosome 6, additional potyvirus resistance genes are needed to manage SCMV-induced MDM. Pyramiding resistance loci, such as Scmv2 on chromosome 3 or Scmv3 on chromosome 10 in addition to Scmv1, could be an effective strategy to mitigate the yield impact of MDM disease.

Racial and socioeconomic disparities in kyphoplasty among the Medicare population.

INTRODUCTION: Kyphoplasty is a minimally invasive treatment for chronic refractory pain secondary to spinal compression fracture. This study investigates racial and socioeconomic disparities in kyphoplasty among the Medicare population. MATERIALS AND METHODS: This study utilized data from the Medicare Limited Data Sets (LDS), a CMS administrative claims database. Patients aged 18 and older with ICD code consistent with spinal pathology and compression fractures were included. Outcome was defined as kyphoplasty by race and socioeconomic status (SES) with low SES defined by dual enrollment in Medicare/Medicaid. RESULTS: There was a total of 215,502 patients gathered from CMS data, and 717 (0.33%) of these patients underwent kyphoplasty during the study period. Of these patients, 458 (63.8%) were female, the average age was 76.5 years old, 655 (91.3%) were White, 20 (2.7%) were Black, 9 (1.3%) were Hispanic, and 98 (13.7%) were Medicare/Medicaid dual eligible. White patients (32,317/157,177 [20.6%]) were less likely to be dual enrollment eligible in Medicare and Medicaid than Black (5407/13,522 [39.9%]), Hispanic (2833/3675 [77.1%]), Asian (2087/3312 [63.0%]), or North American Native patients (778/1578 [49.1%]). Multivariate regression (MVR) analysis was performed and showed that Blacks were less likely than Whites to have a kyphoplasty performed (OR 0.46 [95% CI: 0.29-0.72], p-value <0.001). Although Hispanics (OR 0.95 [0.49-1.86]), North American Native (OR 0.82 [0.3-2.19]), and unknown race had a decreased odd of undergoing kyphoplasty, it was not statistically significant. CONCLUSION: Our study showed after adjustment for pertinent comorbidities, Medicare/Medicaid dual-eligible patients and Black patients were significantly less likely to receive kyphoplasty than White patients with Medicare.

Topological data analysis identifies molecular phenotypes of idiopathic pulmonary fibrosis.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a debilitating, progressive disease with a median survival time of 3-5 years. Diagnosis remains challenging and disease progression varies greatly, suggesting the possibility of distinct subphenotypes. METHODS AND RESULTS: We analysed publicly available peripheral blood mononuclear cell expression datasets for 219 IPF, 411 asthma, 362 tuberculosis, 151 healthy, 92 HIV and 83 other disease samples, totalling 1318 patients. We integrated the datasets and split them into train (n=871) and test (n=477) cohorts to investigate the utility of a machine learning model (support vector machine) for predicting IPF. A panel of 44 genes predicted IPF in a background of healthy, tuberculosis, HIV and asthma with an area under the curve of 0.9464, corresponding to a sensitivity of 0.865 and a specificity of 0.89. We then applied topological data analysis to investigate the possibility of subphenotypes within IPF. We identified five molecular subphenotypes of IPF, one of which corresponded to a phenotype enriched for death/transplant. The subphenotypes were molecularly characterised using bioinformatic and pathway analysis tools identifying distinct subphenotype features including one which suggests an extrapulmonary or systemic fibrotic disease. CONCLUSIONS: Integration of multiple datasets, from the same tissue, enabled the development of a model to accurately predict IPF using a panel of 44 genes. Furthermore, topological data analysis identified distinct subphenotypes of patients with IPF which were defined by differences in molecular pathobiology and clinical characteristics.

Physical interventions to interrupt or reduce the spread of respiratory viruses.

BACKGROUND: Viral epidemics or pandemics of acute respiratory infections (ARIs) pose a global threat. Examples are influenza (H1N1) caused by the H1N1pdm09 virus in 2009, severe acute respiratory syndrome (SARS) in 2003, and coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 in 2019. Antiviral drugs and vaccines may be insufficient to prevent their spread. This is an update of a Cochrane Review last published in 2020. We include results from studies from the current COVID-19 pandemic. OBJECTIVES: To assess the effectiveness of physical interventions to interrupt or reduce the spread of acute respiratory viruses. SEARCH METHODS: We searched CENTRAL, PubMed, Embase, CINAHL, and two trials registers in October 2022, with backwards and forwards citation analysis on the new studies. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and cluster-RCTs investigating physical interventions (screening at entry ports, isolation, quarantine, physical distancing, personal protection, hand hygiene, face masks, glasses, and gargling) to prevent respiratory virus transmission.  DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodological procedures. MAIN RESULTS: We included 11 new RCTs and cluster-RCTs (610,872 participants) in this update, bringing the total number of RCTs to 78. Six of the new trials were conducted during the COVID-19 pandemic; two from Mexico, and one each from Denmark, Bangladesh, England, and Norway. We identified four ongoing studies, of which one is completed, but unreported, evaluating masks concurrent with the COVID-19 pandemic. Many studies were conducted during non-epidemic influenza periods. Several were conducted during the 2009 H1N1 influenza pandemic, and others in epidemic influenza seasons up to 2016. Therefore, many studies were conducted in the context of lower respiratory viral circulation and transmission compared to COVID-19. The included studies were conducted in heterogeneous settings, ranging from suburban schools to hospital wards in high-income countries; crowded inner city settings in low-income countries; and an immigrant neighbourhood in a high-income country. Adherence with interventions was low in many studies. The risk of bias for the RCTs and cluster-RCTs was mostly high or unclear. Medical/surgical masks compared to no masks We included 12 trials (10 cluster-RCTs) comparing medical/surgical masks versus no masks to prevent the spread of viral respiratory illness (two trials with healthcare workers and 10 in the community). Wearing masks in the community probably makes little or no difference to the outcome of influenza-like illness (ILI)/COVID-19 like illness compared to not wearing masks (risk ratio (RR) 0.95, 95% confidence interval (CI) 0.84 to 1.09; 9 trials, 276,917 participants; moderate-certainty evidence. Wearing masks in the community probably makes little or no difference to the outcome of laboratory-confirmed influenza/SARS-CoV-2 compared to not wearing masks (RR 1.01, 95% CI 0.72 to 1.42; 6 trials, 13,919 participants; moderate-certainty evidence). Harms were rarely measured and poorly reported (very low-certainty evidence). N95/P2 respirators compared to medical/surgical masks We pooled trials comparing N95/P2 respirators with medical/surgical masks (four in healthcare settings and one in a household setting). We are very uncertain on the effects of N95/P2 respirators compared with medical/surgical masks on the outcome of clinical respiratory illness (RR 0.70, 95% CI 0.45 to 1.10; 3 trials, 7779 participants; very low-certainty evidence). N95/P2 respirators compared with medical/surgical masks may be effective for ILI (RR 0.82, 95% CI 0.66 to 1.03; 5 trials, 8407 participants; low-certainty evidence). Evidence is limited by imprecision and heterogeneity for these subjective outcomes. The use of a N95/P2 respirators compared to medical/surgical masks probably makes little or no difference for the objective and more precise outcome of laboratory-confirmed influenza infection (RR 1.10, 95% CI 0.90 to 1.34; 5 trials, 8407 participants; moderate-certainty evidence). Restricting pooling to healthcare workers made no difference to the overall findings. Harms were poorly measured and reported, but discomfort wearing medical/surgical masks or N95/P2 respirators was mentioned in several studies (very low-certainty evidence).  One previously reported ongoing RCT has now been published and observed that medical/surgical masks were non-inferior to N95 respirators in a large study of 1009 healthcare workers in four countries providing direct care to COVID-19 patients.  Hand hygiene compared to control Nineteen trials compared hand hygiene interventions with controls with sufficient data to include in meta-analyses. Settings included schools, childcare centres and homes. Comparing hand hygiene interventions with controls (i.e. no intervention), there was a 14% relative reduction in the number of people with ARIs in the hand hygiene group (RR 0.86, 95% CI 0.81 to 0.90; 9 trials, 52,105 participants; moderate-certainty evidence), suggesting a probable benefit. In absolute terms this benefit would result in a reduction from 380 events per 1000 people to 327 per 1000 people (95% CI 308 to 342). When considering the more strictly defined outcomes of ILI and laboratory-confirmed influenza, the estimates of effect for ILI (RR 0.94, 95% CI 0.81 to 1.09; 11 trials, 34,503 participants; low-certainty evidence), and laboratory-confirmed influenza (RR 0.91, 95% CI 0.63 to 1.30; 8 trials, 8332 participants; low-certainty evidence), suggest the intervention made little or no difference. We pooled 19 trials (71, 210 participants) for the composite outcome of ARI or ILI or influenza, with each study only contributing once and the most comprehensive outcome reported. Pooled data showed that hand hygiene may be beneficial with an 11% relative reduction of respiratory illness (RR 0.89, 95% CI 0.83 to 0.94; low-certainty evidence), but with high heterogeneity. In absolute terms this benefit would result in a reduction from 200 events per 1000 people to 178 per 1000 people (95% CI 166 to 188). Few trials measured and reported harms (very low-certainty evidence). We found no RCTs on gowns and gloves, face shields, or screening at entry ports. AUTHORS' CONCLUSIONS: The high risk of bias in the trials, variation in outcome measurement, and relatively low adherence with the interventions during the studies hampers drawing firm conclusions. There were additional RCTs during the pandemic related to physical interventions but a relative paucity given the importance of the question of masking and its relative effectiveness and the concomitant measures of mask adherence which would be highly relevant to the measurement of effectiveness, especially in the elderly and in young children. There is uncertainty about the effects of face masks. The low to moderate certainty of evidence means our confidence in the effect estimate is limited, and that the true effect may be different from the observed estimate of the effect. The pooled results of RCTs did not show a clear reduction in respiratory viral infection with the use of medical/surgical masks. There were no clear differences between the use of medical/surgical masks compared with N95/P2 respirators in healthcare workers when used in routine care to reduce respiratory viral infection. Hand hygiene is likely to modestly reduce the burden of respiratory illness, and although this effect was also present when ILI and laboratory-confirmed influenza were analysed separately, it was not found to be a significant difference for the latter two outcomes. Harms associated with physical interventions were under-investigated. There is a need for large, well-designed RCTs addressing the effectiveness of many of these interventions in multiple settings and populations, as well as the impact of adherence on effectiveness, especially in those most at risk of ARIs.

Lidcombe Program translation to community clinics in Australia and England.

BACKGROUND: Early intervention is essential healthcare for stuttering, and the translation of research findings to community settings is a potential roadblock to it. AIMS: This study was designed to replicate and extend the Lidcombe Program community translation findings of O'Brian et al. (2013) but with larger participant numbers, incorporating clinicians (speech pathologists/speech anlanguage therapists) and their clients from Australia and England. METHODS & PROCEDURES: Participants were 51 clinicians working in public and private clinics across Australia (n = 36) and England (n = 15), and 121 of their young stuttering clients and their families. Outcome measures were percentage of syllables stuttered (%SS), parent severity ratings at 9 months post-recruitment, number of clinic visits to complete Stage 1 of the Lidcombe Program, and therapist drift. OUTCOMES & RESULTS: Community clinicians in both countries achieved similar outcomes to those from randomized controlled trials. Therapist drift emerged as an issue with community translation. Speech and language therapists in England attained outcomes 1.0%SS above the speech pathologists in Australia, although their scores were within the range attained in randomized trials. CONCLUSIONS & IMPLICATIONS: Community clinicians from Australia and England can attain Lidcombe Program outcome benchmarks established in randomized trials. This finding is reassuring in light of the controlled conditions in clinical trials of the Lidcombe Program compared with its conduct in community practice. The long-term impact of therapist drift in community clinical practice with the Lidcombe Program has yet to be determined. WHAT THIS PAPER ADDS: What is already known on the subject The Lidcombe Program is an efficacious early stuttering intervention. Translation to clinical communities has been studied with one Australian cohort. What this paper adds to existing knowledge A larger translation cohort is studied, comprising community clinicians and children in Australia and England. What are the potential or actual clinical implications of this work? Community clinicians from Australia and England can attain Lidcombe Program outcome benchmarks established in randomized trials. This finding is reassuring in light of the controlled conditions in clinical trials of the Lidcombe Program compared with its conduct in community practice.

Effect of Early High-Flow Nasal Oxygen vs Standard Oxygen Therapy on Length of Hospital Stay in Hospitalized Children With Acute Hypoxemic Respiratory Failure: The PARIS-2 Randomized Clinical Trial.

Importance: Nasal high-flow oxygen therapy in infants with bronchiolitis and hypoxia has been shown to reduce the requirement to escalate care. The efficacy of high-flow oxygen therapy in children aged 1 to 4 years with acute hypoxemic respiratory failure without bronchiolitis is unknown. Objective: To determine the effect of early high-flow oxygen therapy vs standard oxygen therapy in children with acute hypoxemic respiratory failure. Design, Setting, and Participants: A multicenter, randomized clinical trial was conducted at 14 metropolitan and tertiary hospitals in Australia and New Zealand, including 1567 children aged 1 to 4 years (randomized between December 18, 2017, and March 18, 2020) requiring hospital admission for acute hypoxemic respiratory failure. The last participant follow-up was completed on March 22, 2020. Interventions: Enrolled children were randomly allocated 1:1 to high-flow oxygen therapy (n = 753) or standard oxygen therapy (n = 764). The type of oxygen therapy could not be masked, but the investigators remained blinded until the outcome data were locked. Main Outcomes and Measures: The primary outcome was length of hospital stay with the hypothesis that high-flow oxygen therapy reduces length of stay. There were 9 secondary outcomes, including length of oxygen therapy and admission to the intensive care unit. Children were analyzed according to their randomization group. Results: Of the 1567 children who were randomized, 1517 (97%) were included in the primary analysis (median age, 1.9 years [IQR, 1.4-3.0 years]; 732 [46.7%] were female) and all children completed the trial. The length of hospital stay was significantly longer in the high-flow oxygen group with a median of 1.77 days (IQR, 1.03-2.80 days) vs 1.50 days (IQR, 0.85-2.44 days) in the standard oxygen group (adjusted hazard ratio, 0.83 [95% CI, 0.75-0.92]; P < .001). Of the 9 prespecified secondary outcomes, 4 showed no significant difference. The median length of oxygen therapy was 1.07 days (IQR, 0.50-2.06 days) in the high-flow oxygen group vs 0.75 days (IQR, 0.35-1.61 days) in the standard oxygen therapy group (adjusted hazard ratio, 0.78 [95% CI, 0.70-0.86]). In the high-flow oxygen group, there were 94 admissions (12.5%) to the intensive care unit compared with 53 admissions (6.9%) in the standard oxygen group (adjusted odds ratio, 1.93 [95% CI, 1.35-2.75]). There was only 1 death and it occurred in the high-flow oxygen group. Conclusions and Relevance: Nasal high-flow oxygen used as the initial primary therapy in children aged 1 to 4 years with acute hypoxemic respiratory failure did not significantly reduce the length of hospital stay compared with standard oxygen therapy. Trial Registration: anzctr.org.au Identifier: ACTRN12618000210279.

Review of patients discharged post thoracic surgery with chest drain in situ and nurse-based follow-up clinic.

Persistent air leak and prolonged drainage are recognized complications of thoracic surgery, increasing hospital stay and costs. Patients can be discharged with a chest drain and followed up in a nurse-led clinic. We reviewed such patients and the rate of readmission after discharge to assess the effectiveness of the drain follow up clinic. Retrospective review of our prospective database for 22 months (March 2019 to January 2021). Analysis focussed on indication and duration of chest drainage, complications, and readmission for any reason. 62 patients (representing 5% of all thoracic surgery patients) were discharged with a chest drain. Median age was 67 years (range 22-85 years), 24 females and 38 males. 52% underwent video-assisted thoracoscopic surgery, 27% had a thoracotomy, and 21% had bedside chest drain insertion. Following discharge, median duration of chest drainage was 11 days [interquartile range (IQR) 7-18.75 days]. Patients had 106 review episodes in the ward-based nurse-led clinic. Indication was prolonged air leak (71 %; 72 clinic reviews), persistent fluid drainage following empyema evacuation (16%; 24 clinic reviews) and persistent fluid drainage for simple effusion (13%; 10 clinic reviews). Median length of drain stay was 30 days (IQR 19.75-54 days) for empyema, 10 days (IQR 6-16 days) for air leak and 8 days (IQR 6.5-12 days) days for simple effusion. 9 patients required readmission (14.5%) and empyema had developed in 3 patients (4.8%). Patients discharged with a chest drain in place can be followed up in a dedicated ward-based nurse-led monitoring clinic for optimal quality of care.

Redo aortic valve replacement versus valve-in-valve trans-catheter aortic valve implantation: a UK propensity-matched analysis.

This study sought to compare the morbidity and mortality of redo aortic valve replacement (redo-AVR) versus valve-in-valve trans-catheter aortic valve implantation (valve-in-valve TAVI) for patients with a failing bioprosthetic valve. A multicenter UK retrospective study of redo-AVR or valve-in-valve TAVI for patients referred for redo aortic valve intervention due to a degenerated aortic bioprosthesis. Propensity score matching was performed for confounding factors. From July 2005 to April 2021, 911 patients underwent redo-AVR and 411 patients underwent valve-in-valve TAVI. There were 125 pairs for analysis after propensity score matching. The mean age was 75.2±8.5 years. In-hospital mortality was 7.2% (n=9) for redo-AVR versus 0 for valve-in-valve TAVI, p=0.002. Surgical patients suffered more post-operative complications, including intra-aortic balloon pump support (p=0.02), early re-operation (p<0.001), arrhythmias (p<0.001), respiratory and neurological complications (p=0.02 and p=0.03) and multi-organ failure (p=0.01). The valve-in-valve TAVI group had a shorter intensive care unit and hospital stay (p<0.001 for both). However, moderate aortic regurgitation at discharge and higher post-procedural gradients were more common after valve-in-valve TAVI (p<0.001 for both). Survival probabilities in patients who were successfully discharged from the hospital were similar after valve-in-valve TAVI and redo-AVR over the 6-year follow-up (log-rank p=0.26). In elderly patients with a degenerated aortic bioprosthesis, valve-in-valve TAVI provides better early outcomes as opposed to redo-AVR, although there was no difference in mid-term survival in patients successfully discharged from the hospital.

The type and extent of travel for professional footballers undertaking national team duties for a national football federation.

Elite football (soccer) involves club, continental and international fixtures, requiring players to undertake extensive travel [1]. For a national football federation, this includes the transport of players between club and camp/tournament commitments, which is often a point of contention between respective organisations [2]. Partly this contention results from the effects of travel, whereby jet lag and travel fatigue can negatively affect physical performance [3-5] and athlete wellbeing [6, 7]. Given the scarcity of data on elite players following travel, an initial step for any national football federation is to understand the volume and nature of travel undertaken by national team players. Such insight may better identify the schedule, timelines and needs of athletes' post travel. Better awareness of these travel needs can help maximise availability for training and minimise the impact of travel related stresses on performance or wellbeing. However, the regularity and volume of travel to national football team commitments has not previously been described. Further, travel demands are likely to vary significantly based on the location of the athlete and the national team camp. For countries outside of Europe, such as Australia, the travel demands and ensuing effects on player preparation can be substantial for both arrival into national team and on return to clubs [7]. Hence, detailed information regarding the type, frequency, and extent of travel for national team duties is important to aid in planning optimal travel schedules and interventions to assist players for international or club duty.

Immunogenicity of a Third Scheduled Dose of Rotarix in Australian Indigenous Infants: A Phase IV, Double-blind, Randomized, Placebo-Controlled Clinical Trial.

BACKGROUND: Rotarix (GlaxoSmithKline) oral rotavirus vaccine is licensed as 2 doses in the first 6 months of life. In settings with high child mortality rates, clinical protection conferred by 2 doses of Rotarix is reduced. We assessed vaccine immune response when an additional dose of Rotarix was given to Australian Aboriginal children 6 to <12 months old. METHODS: ORVAC is a 2-stage, double-blind, randomized, placebo-controlled trial. Australian Aboriginal children 6 to <12 months old who had received 1 or 2 prior doses of Rotarix rotavirus vaccine were randomized 1:1 to receive an additional dose of Rotarix or matched placebo. The primary immunological end point was seroresponse defined as an anti-rotavirus immunoglobulin A level ≥20 AU/mL, 28-56 days after the additional dose of Rotarix or placebo. RESULTS: Between March 2018 and August 2020, a total of 253 infants were enrolled. Of these, 178 infants (70%) had analyzable serological results after follow-up; 89 were randomized to receive Rotarix, and 89 to receive placebo. The proportion with seroresponse was 85% after Rotarix compared with 72% after placebo. There were no occurrences of intussusception or any serious adverse events. CONCLUSIONS: An additional dose of Rotarix administered to Australian Aboriginal infants 6 to <12 months old increased the proportion with a vaccine seroresponse. CLINICAL TRIALS REGISTRATION: NCT02941107.