Self-Reported Menstrual Health, Symptomatology, and Perceived Effects of the Menstrual Cycle for Elite Junior and Senior Football Players.

PURPOSE: To describe the self-reported menstrual health, symptomatology, and perceived effects of the menstrual cycle on athletic performance for national and international Australian football (soccer) players. METHODS: Players from national and domestic teams were invited to complete an online questionnaire regarding menstrual health, use of hormonal contraceptives (HCs), negative symptomatology, and perceived disruption of the menstrual cycle to performance. Descriptive statistics and binomial regressions with odds ratios (OR) were used to report the relationship of menstrual-related variables with perceived performance disruption. RESULTS: A total of 199 players (20.9 [5.1] y) completed the questionnaire, with 18% of players reporting using HCs. One primary amenorrhea case was detected, and 26% of players reported menarche at age ≥15 years. For non-HC users, the prevalence of secondary amenorrhea was 2%, oligomenorrhea was 19%, and heavy menstrual bleeding was 11%. Ninety-seven percent of players reported experiencing physical or affective menstrual symptoms (5 [1.3] per player), and 40% of all players reported that menstrual symptoms impacted their ability to work, study, train, or compete. Furthermore, 40% of players perceived their training or performance to be disrupted by the menstrual cycle. Increasing number of menstrual symptoms (OR = 1.43; 95% CI, 1.28-1.62; P < .001), heavy menstrual bleeding (OR = 12.73; 95% CI, 3.4-82.8; P < .001), and pelvic pain (OR = 3.40; 95% CI, 1.7-7.2; P < .001) increased the likelihood of perceiving the menstrual cycle to disrupt performance. CONCLUSION: Heavy menstrual bleeding and HC use were low among this cohort of national and international footballers, whereas amenorrhea and oligomenorrhoea were comparable with other football populations. Nearly all players reported menstrual symptoms, and increased symptomatology was associated with greater perceived effects on performance.

Treatment-Switching Adjustment of Overall Survival in CheckMate 227 Part 1 Evaluating First-Line Nivolumab Plus Ipilimumab Versus Chemotherapy for Metastatic Nonsmall Cell Lung Cancer.

OBJECTIVES: CheckMate 227 (NCT02477826) evaluated first-line nivolumab-plus-ipilimumab versus chemotherapy in patients with metastatic nonsmall cell lung cancer (NSCLC) with programmed death ligand 1 (PD-L1) expression ≥ 1% or < 1% and no EGFR/ALK alterations. However, many patients randomized to chemotherapy received subsequent immunotherapy. Here, overall survival (OS) and relative OS benefit of nivolumab-plus-ipilimumab were adjusted for potential bias introduced by treatment switching. MATERIALS AND METHODS: Treatment-switching adjustment analyses were conducted following the NICE Decision Support Unit Technical Support Document 16, for CheckMate 227 Part 1 OS data from treated patients (database lock, July 2, 2019). Inverse probability of censoring weighting (IPCW) was used in the base-case analysis; other methods were explored as sensitivity analyses. RESULTS: Of 1166 randomized patients, 391 (PD-L1 ≥ 1%) and 185 (PD-L1 < 1%) patients received nivolumab-plus-ipilimumab; 387 (PD-L1 ≥ 1%) and 183 (PD-L1 < 1%) patients received chemotherapy, with 29.3-month minimum follow-up. Among chemotherapy-treated patients, 169/387 (43.7%; PD-L1 ≥ 1%) and 66/183 (36.1%; PD-L1 < 1%) switched to immunotherapy poststudy. Among treated patients, median OS was 17.4 months with nivolumab-plus-ipilimumab versus 14.9 months with chemotherapy (hazard ratio [HR], 0.80; 95% confidence interval [CI], 0.68-0.95) in the PD-L1 ≥ 1% subgroup and 17.1 versus 12.4 months (HR, 0.62; 95% CI, 0.49-0.80) in the PD-L1 < 1% subgroup. After treatment-switching adjustment using IPCW, the HR (95% CI) for OS for nivolumab-plus-ipilimumab versus chemotherapy was reduced to 0.68 (0.56-0.83; PD-L1 ≥ 1%) and 0.53 (0.40-0.69; PD-L1 < 1%). Sensitivity analyses supported the robustness of the results. CONCLUSION: Treatment-switching adjustments resulted in a greater estimated relative OS benefit with first-line nivolumab-plus-ipilimumab versus chemotherapy in patients with metastatic NSCLC.

Cranberry Juice, Cranberry Tablets, or Liquid Therapies for Urinary Tract Infection: A Systematic Review and Network Meta-analysis.

BACKGROUND AND OBJECTIVE: With over 50% of women suffering from at least one episode of urinary tract infection (UTI) each year and an increasing prevalence of antimicrobial resistance, efforts need to be made to clearly identify the evidence supporting potential non-drug interventions. This study aims to compare the effects of cranberry juice, cranberry tablets, and increased liquids for the management of UTIs. METHODS: PubMed, Embase, and Cochrane CENTRAL were searched for randomised controlled trials. The primary outcome was the number of UTIs, and the secondary outcomes were UTI symptoms and antimicrobial consumption. A risk of bias assessment was performed using the Cochrane risk of bias tool, and the certainty of evidence was assessed using Grading of Recommendations Assessment, Development and Evaluation. KEY FINDINGS AND LIMITATIONS: A total of 20 trials (3091 participants) were included, with 18 studies highlighting a 54% lower rate of UTIs with cranberry juice consumption than no treatment and a 27% lower rate than placebo liquid. Cranberry juice also resulted in a 49% lower rate of antibiotic use than placebo liquid and a 59% lower rate than no treatment, based on a network meta-analysis of six studies. The use of cranberry compounds also reduced the prevalence of symptoms associated with UTIs. CONCLUSIONS AND CLINICAL IMPLICATIONS: With moderate to low certainty, the evidence supports the use of cranberry juice for the prevention of UTIs. While increased liquids reduce the rate of UTIs compared with no treatment, cranberry in liquid form provides even better clinical outcomes in terms of reduction in UTIs and antibiotic use and should be considered for the management of UTIs. PATIENT SUMMARY: With the increasing prevalence of antimicrobial-resistant UTIs, alternate non-drug treatment options for its management are required. Available evidence supports the use of cranberry compounds and increases in fluid intake for managing UTIs.

Sarcoidosis versus Granulomatous and Lymphocytic Interstitial Lung Disease in Common Variable Immunodeficiency: A Comparative Review.

Sarcoidosis and Granulomatous and Lymphocytic Interstitial Lung Diseases (GLILD) are two rare entities primarily characterised by the development of Interstitial Lung Disease (ILD) in the context of systemic immune dysregulation. These two conditions partially share the immunological background and pathologic findings, with granuloma as the main common feature. In this narrative review, we performed a careful comparison between sarcoidosis and GLILD, with an overview of their main similarities and differences, starting from a clinical perspective and ending with a deeper look at the immunopathogenesis and possible target therapies. Sarcoidosis occurs in immunocompetent individuals, whereas GLILD occurs in patients affected by common variable immunodeficiency (CVID). Moreover, peculiar extrapulmonary manifestations and radiological and histological features may help distinguish the two diseases. Despite that, common pathogenetic pathways have been suggested and both these disorders can cause progressive impairment of lung function and variable systemic granulomatous and non-granulomatous complications, leading to significant morbidity, reduced quality of life, and survival. Due to the rarity of these conditions and the extreme clinical variability, there are still many open questions concerning their pathogenesis, natural history, and optimal management. However, if studied in parallel, these two entities might benefit from each other, leading to a better understanding of their pathogenesis and to more tailored treatment approaches.

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 .

Financial incentives to motivate treatment for hepatitis C with direct acting antivirals among Australian adults (The Methodical evaluation and Optimisation of Targeted IncentiVes for Accessing Treatment of Early-stage hepatitis C: MOTIVATE-C): protocol for a dose-response randomised controlled study.

BACKGROUND: Untreated hepatitis C virus (HCV) infection can result in cirrhosis and hepatocellular cancer. Direct-acting antiviral (DAA) therapies are highly effective and have few side effects compared to older interferon-based therapy. Despite the Australian government providing subsidised and unrestricted access to DAA therapy for chronic HCV infection, uptake has not been sufficient to meet the global target of eliminating HCV as a public health threat by 2030. This study will offer people with HCV financial incentives of varying values in order to evaluate its effect on initiation of DAA therapy in primary care. METHODS: Australian adults (18 years or older) who self-report as having current untreated HCV infection can register to participate via an automated SMS-based system. Following self-screening for eligibility, registrants are offered a financial incentive of randomised value (AUD 0 to 1000) to initiate DAA therapy. Study treatment navigators contact registrants who have consented to be contacted, to complete eligibility assessment, outline the study procedures (including the requirement for participants to consult a primary care provider), obtain consent, and finalise enrolment. Enrolled participants receive their offered incentive on provision of evidence of DAA therapy initiation within 12 weeks of registration (primary endpoint). Balanced randomisation is used across the incentive range until the first analysis, after which response-adaptive randomisation will be used to update the assignment probabilities. For the primary analysis, a Bayesian 4-parameter EMAX model will be used to estimate the dose-response curve and contrast treatment initiation at each incentive value against the control arm (AUD 0). Specified secondary statistical and economic analyses will evaluate the effect of incentives on adherence to DAA therapy, virological response, and cost-effectiveness. DISCUSSION: This project seeks to gain an understanding of the dose-response relationship between incentive value and DAA treatment initiation, while maximising the number of people treated for HCV within fixed budget and time constraints. In doing so, we hope to offer policy-relevant recommendation(s) for the use of financial incentives as a pragmatic, efficient, and cost-effective approach to achieving elimination of HCV from Australia. TRIAL REGISTRATION: ANZCTR (anzctr.org.au), Identifier ACTRN12623000024640, Registered 11 January 2023 ( https://anzctr.org.au/Trial/Registration/TrialReview.aspx?id=384923&isReview=true ).

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.

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).

High-flow nasal oxygen for children's airway surgery to reduce hypoxaemic events: a randomised controlled trial.

BACKGROUND: Tubeless upper airway surgery in children is a complex procedure in which surgeons and anaesthetists share the same operating field. These procedures are often interrupted for rescue oxygen therapy. The efficacy of nasal high-flow oxygen to decrease the frequency of rescue interruptions in children undergoing upper airway surgery is unknown. METHODS: In this multicentre randomised trial conducted in five tertiary hospitals in Australia, children aged 0-16 years who required tubeless upper airway surgery were randomised (1:1) by a web-based randomisation tool to either nasal high-flow oxygen delivery or standard oxygen therapy (oxygen flows of up to 6 L/min). Randomisation was stratified by site and age (<1 year, 1-4 years, and 5-16 years). Subsequent tubeless upper airway surgery procedures in the same child could be included if there were more than 2 weeks between the procedures, and repeat surgical procedures meeting this condition were considered to be independent events. The oxygen therapy could not be masked, but the investigators remained blinded until outcome data were locked. The primary outcome was successful anaesthesia without interruption of the surgical procedure for rescue oxygenation. A rescue oxygenation event was defined as an interruption of the surgical procedure to deliver positive pressure ventilation using either bag mask technique, insertion of an endotracheal tube, or laryngeal mask to improve oxygenation. There were ten secondary outcomes, including the proportion of procedures with a hypoxaemic event (SpO2 <90%). Analyses were done on an intention-to-treat (ITT) basis. Safety was assessed in all enrolled participants. This trial is registered in the Australian New Zealand Clinical Trials Registry, ACTRN12618000949280, and is completed. FINDINGS: From Sept 4, 2018, to April 12, 2021, 581 procedures in 487 children were randomly assigned to high-flow oxygen (297 procedures) or standard care (284 procedures); after exclusions, 528 procedures (267 assigned to high-flow oxygen and 261 assigned to standard care) in 483 children (293 male and 190 female) were included in the ITT analysis. The primary outcome of successful anaesthesia without interruption for tubeless airway surgery was achieved in 236 (88%) of 267 procedures on high-flow oxygen and in 229 (88%) of 261 procedures on standard care (adjusted risk ratio [RR] 1·02, 95% CI 0·96-1·08, p=0·82). There were 51 (19%) procedures with a hypoxaemic event in the high-flow oxygen group and 57 (22%) in the standard care group (RR 0·86, 95% CI 0·58-1·24). Of the other prespecified secondary outcomes, none showed a significant difference between groups. Adverse events of epistaxis, laryngospasm, bronchospasm, hypoxaemia, bradycardia, cardiac arrest, hypotension, or death were similar in both study groups. INTERPRETATION: Nasal high-flow oxygen during tubeless upper airway surgery did not reduce the proportion of interruptions of the procedures for rescue oxygenation compared with standard care. There were no differences in adverse events between the intervention groups. These results suggest that both approaches, nasal high-flow or standard oxygen, are suitable alternatives to maintain oxygenation in children undergoing upper airway surgery. FUNDING: Thrasher Research Fund, the Australian and New Zealand College of Anaesthetists, the Society for Paediatric Anaesthesia in New Zealand and Australia.

"Don't keep me waiting": estimating the impact of reduced vein-to-vein time on lifetime US 3L+ LBCL patient outcomes.

ABSTRACT: Chimeric antigen receptor T-cell therapy (CAR T) has revolutionized the treatment of hematological cancers. Its production requires a complex logistical process, and the time from leukapheresis to patient infusion (known as the vein-to-vein time [V2VT]) can be long during which a patients clinical condition may deteriorate. This study was designed to estimate the benefits of reduced V2VT for third-line or later (3L+) relapsed/refractory large B-cell lymphoma (R/R LBCL) patients treated with CAR T. A mathematical model was developed to estimate the lifetime outcomes of a hypothetical cohort of patients who had either a long or short V2VT. Life-years (LYs), quality-adjusted LYs (QALYs), and costs were estimated. Scenario analyses were performed to assess the robustness of results to key assumptions. The results of the model show that reducing V2VT from 54 days (tisa-cel median V2VT; JULIET) to 24 days (axi-cel median V2VT; ZUMA-1) led to a 3.2-year gain in life expectancy (4.2 vs 7.7 LYs), and 2.4 additional QALYs (3.2 vs 5.6) per patient. Furthermore, a shorter V2VT was shown to be cost-effective under conventional willingness-to-pay thresholds in the United States. Results are driven by a higher infusion rate and a better efficacy of CAR T for those infused. Scenario analyses using a smaller difference in V2VT (24 vs 36 days) produced consistent results. Our study is the first to quantify lifetime V2VT-related outcomes for 3L+ R/R LBCL patients treated with CAR T utilizing currently available evidence. Shorter V2VTs led to improved outcomes, demonstrating the importance of timely infusion achievable by faster manufacturing times and optimization of hospital delivery.

Lidcombe Program telehealth treatment for children 6-12 years of age: A Phase II trial.

BACKGROUND: For children older than 6 years who stutter, there is a gap in clinical research. This is an issue for speech-language pathologists because the tractability of stuttering decreases and the risk of long-term psychological consequences increase with age. PURPOSE: To report a Phase II trial of a telehealth version of the Lidcombe Program with school-age children. METHODS: Participants were 37 children who stuttered, 6-12 years of age, from Australia, New Zealand, Hong Kong, and Singapore. Parents were trained by video telehealth how to deliver the Lidcombe Program to their child. Primary and secondary outcomes were stuttering severity and psychosocial functioning measured pre-treatment and at 6 months and 12 months after starting treatment. Parents submitted two 10-minute recordings of their child speaking in conversation, and three measures of anxiety, impact of stuttering, and communication attitude. RESULTS: Six months after starting treatment, seven children (18.9%) attained Lidcombe Program Stage 2 criteria, 25 children (67.6%) showed a partial response to treatment, and five children (13.5%) showed no response. By 12 months, 12 children (32.4%) had reached Stage 2 criteria. Psychosocial improvements were observed 6 and 12 months after starting treatment. CONCLUSIONS: The Lidcombe Program may eliminate or nearly eliminate stuttering for about one third of children 6-12 years of age. Randomized controlled trials with this age group involving the Lidcombe Program are warranted. In the interim, the Lidcombe Program is a clinical option clinicians can implement with this age group to reduce stuttering and its psychosocial impacts.

Kidney trajectory charts improve GP management of patients with reduced kidney function: a randomised controlled vignette study.

BACKGROUND: The stages of chronic kidney disease (CKD) and estimated glomerular filtration rate (eGFR) reference ranges are currently determined without considering age. AIM: To determine whether a chart that graphs age with eGFR helps GPs make better decisions about managing patients with declining eGFR. DESIGN & SETTING: A randomised controlled vignette study among Australian GPs using a percentile chart plotting the trajectory of eGFR by age. METHOD: Three hundred and seventy-three GPs received two case studies of patients with declining renal function. They were randomised to receive the cases with the chart or without the chart, and asked a series of questions about how they would manage the cases. RESULTS: In an older female patient with stable but reduced kidney function, use of the chart was associated with GPs in the study recommending a longer follow-up period, and longer time until repeat pathology testing. In a younger male First Nations patient with normal but decreasing kidney function, use of the chart was associated with GPs in the study recommending a shorter follow-up period, shorter time to repeat pathology testing, increased management of blood pressure and lifestyle, and avoidance of nephrotoxic medications. This represents more appropriate care in both cases. CONCLUSION: Having access to a chart of percentile eGFR by age was associated with more appropriate management review periods of patients with reduced kidney function, either by greater compliance with current guidelines or greater awareness of a clinically relevant kidney problem.

"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].

Dysregulated bidirectional epithelial-mesenchymal crosstalk: a core determinant of lung fibrosis progression.

Progressive lung fibrosis is characterised by dysregulated extracellular matrix (ECM) homeostasis. Understanding of disease pathogenesis remains limited and has prevented the development of effective treatments. While an abnormal wound healing response is strongly implicated in lung fibrosis initiation, factors that determine why fibrosis progresses rather than regular tissue repair occurs are not fully explained. Within human lung fibrosis there is evidence of altered epithelial and mesenchymal lung populations as well as cells undergoing epithelial-mesenchymal transition (EMT), a dynamic and reversible biological process by which epithelial cells lose their cell polarity and down-regulate cadherin-mediated cell-cell adhesion to gain migratory properties. This review will focus upon the role of EMT and dysregulated epithelial-mesenchymal crosstalk in progressive lung fibrosis.

Coverage gaps in empiric antibiotic regimens used to treat serious bacterial infections in neonates and children in Southeast Asia and the Pacific.

Background: High levels of antimicrobial resistance (AMR) are propagating deaths due to neonatal and paediatric infections globally. This is of particular concern in Southeast Asia and the Pacific, where healthcare resources are constrained and access to newer agents to treat multidrug-resistant pathogens is limited. Methods: To assess the coverage provided by commonly prescribed empiric antibiotic regimens for children in low- and middle-income countries in Southeast Asia and the Pacific, we built a weighted incidence syndromic combination antibiogram (WISCA), parameterised using data obtained from a systematic review of published literature incorporating WHO-defined SEARO and WPRO regions in Ovid MEDLINE, EMBASE, Global Health and PubMed. Susceptibility data for bacterial pathogens were extracted to provide coverage estimates for pre-specified antibiotics (aminopenicillins, gentamicin, third-generation cephalosporins and carbapenems), reported at the regional level. Findings: 6648 bacterial isolates from 11 countries across 86 papers were included in the Bayesian WISCA model, which weighted bacterial incidence and antimicrobial susceptibility of relevant isolates. Coverage provided by aminopenicillins in neonatal sepsis/meningitis was 26% (80% credible interval: 16-49) whilst gentamicin coverage was 45% (29-62). Third-generation cephalosporin coverage was only 29% (16-49) in neonatal sepsis/meningitis, 51% (38-64) in paediatric sepsis and 65% (51-77) in paediatric meningitis. Carbapenems were estimated to provide the highest coverage: 81% (65-90) in neonatal sepsis/meningitis, 83% (72-90) in paediatric sepsis and 79% (62-91) in paediatric meningitis. Interpretation: These findings reveal alarmingly high rates of resistance to commonly prescribed empirical therapies for neonatal and paediatric sepsis and meningitis in the Asia-Pacific region. Funding: This research was funded in whole, or in part, by the Wellcome Trust [220211]. For the purpose of Open Access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. PCMW is supported by a National Health and Medical Research Council (NHMRC) Investigator Grant. NHMRC had no involvement in the design or conduct of the research.

TMPRSS2 inhibitors for the treatment of COVID-19 in adults: a systematic review and meta-analysis of randomized clinical trials of nafamostat and camostat mesylate.

BACKGROUND: Synthetic serine protease inhibitors block the cellular enzyme transmembrane protease serine 2, thus preventing SARS-CoV-2 cell entry. There are two relevant drugs in this class, namely, nafamostat (intravenous formulation) and camostat (oral formulation). OBJECTIVE: To determine whether transmembrane protease serine 2 inhibition with nafamostat or camostat is associated with a reduced risk of 30-day all-cause mortality in adults with COVID-19. DATA SOURCES: Scientific databases and clinical trial registry platforms. STUDY ELIGIBILITY CRITERIA, INTERVENTIONS, AND PARTICIPANTS: Preprints or published randomized clinical trials (RCTs) of nafamostat or camostat vs. usual care or placebo in adults requiring treatment for COVID-19. METHODS OF DATA SYNTHESIS AND RISK-OF-BIAS ASSESSMENT: The primary outcome of the meta-analysis was 30-day all-cause mortality. Secondary outcomes included time to recovery, adverse events, and serious adverse events. Risk of bias (RoB) was assessed using the revised Cochrane RoB 2 tool for individually randomized trials. Meta-analysis was conducted in the R package meta (v7.0-0) using inverse variance and random effects. Protocol registration number was INPLASY202320120. RESULTS: Twelve RCTs were included. Overall, the number of available patients was small (nafamostat = 387; camostat = 1061), the number of enrolled patients meeting the primary outcome was low (nafamostat = 12; camostat = 13), and heterogeneity was high. In hospitalized adults, we did not identify differences in 30-day all-cause mortality (risk ratio [95% CI]: 0.58 [0.19, 1.80], p 0.34; I2 = 0%; n = 6) and time to recovery (mean difference [95% CI]: 0.08 days [-0.74, 0.89], p 0.86; n = 2) between nafamostat vs. usual care; and for 30-day all-cause mortality (risk ratio [95% CI]: 0.99 [0.31, 3.18], p 0.99; n = 2) between camostat vs. placebo. CONCLUSION: The RCT evidence is inconclusive to determine whether there is a mortality reduction and safety with either nafamostat or camostat for the treatment of adults with COVID-19. There were high RoB, small sample size, and high heterogeneity between RCTs.

Cr-Free Anticorrosive Primers for Marine Propeller Applications.

Marine propellers work under severe service conditions, where they commonly suffer from mechanical, electrochemical, and biological corrosion damage. The major mechanical corrosion involves cavitation, erosion, and impingement corrosion. On the other hand, the major electrochemical corrosion involves galvanic corrosion and electrolysis. As a result, consideration of both desired mechanical and electrochemical properties is necessary when designing a marine propeller coating. In this study, a PVB (polyvinyl butyral) and an epoxy coating were formulated without corrosion inhibitors to investigate the desired coating properties for marine propeller applications. The two coatings were compared with a Cr-containing commercial marine propeller coating to investigate the advantages and disadvantages of using PVB and epoxy for marine propeller coatings. It was found that it is desirable for marine propeller coatings to be flexible to avoid cracking and flaking; to be able to withstand high pH in order to resist cathodic disbondment (electrolysis); to have adequate primer-substrate adhesion; and, ideally, to be able to self-heal when the coating is damaged (cavitation). It was found that the PVB-ZO coating has more desirable properties, and introducing self-healing properties could be one of the options for further optimization in the future.