Rapid respiratory microbiological point-of-care-testing and antibiotic prescribing in primary care: Protocol for the RAPID-TEST randomised controlled trial.

BACKGROUND: Antibiotics are prescribed for over 50% of respiratory tract infections in primary care, despite good evidence of there being no benefit to the patient, and evidence of over prescribing driving microbial resistance. The high treatment rates are attributed to uncertainty regarding microbiological cause and clinical prognosis. Point-of-care-tests have been proposed as potential antibiotic stewardship tools, with some providing microbiological results in 15 minutes. However, there is little research on their impact on antibiotic use and clinical outcomes in primary care. METHODS: This is a multi-centre, individually randomised controlled trial with mixed-methods investigation of microbial, behavioural and antibiotic mechanisms on outcomes in patients aged 12 months and over presenting to primary care in the UK with a suspected respiratory tract infection, where the clinician and/or patient thinks antibiotic treatment may be, or is, necessary. Once consented, all participants are asked to provide a combined nose and throat swab sample and randomised to have a rapid microbiological point-of-care-test or no point-of-care-test. For intervention patients, clinicians review the result of the test, before contacting the patient to finalise treatment. Treatment decisions are made as per usual care in control group patients. The primary outcome is whether an antibiotic is prescribed at this point. All swab samples are sent to the central laboratory for further testing. Patients are asked to complete a diary to record the severity and duration of symptoms until resolution or day 28, and questionnaires at 2 months about their beliefs and intention to consult for similar future illnesses. Primary care medical records are also reviewed at 6-months to collect further infection consultations, antibiotic prescribing and hospital admissions. The trial aims to recruit 514 patients to achieve 90% power with 5% significance to detect a 15% absolute reduction in antibiotic prescribing. Qualitative interviews are being conducted with approximately 20 clinicians and 30 participants to understand any changes in beliefs and behaviour resulting from the point-of-care-test and generate attributes for clinician and patient discrete choice experiments. DISCUSSION: This trial will provide evidence of efficacy, acceptability and mechanisms of action of a rapid microbiological point-of-care test on antibiotic prescribing and patient symptoms in primary care. TRIAL REGISTRATION: ISRCTN16039192, prospectively registered on 08/11/2022.

What recovery domains are important following a total knee replacement? A qualitative, interview-based study.

OBJECTIVES: To explore people's views of recovery from total knee replacement (TKR) and which recovery domains they felt were important. DESIGN: Semi-structured interviews exploring the views of individuals about to undergo or who have undergone TKR. A constant-comparative approach with thematic analysis was used to identify themes. The process of sampling, collecting data and analysis were continuous and iterative throughout the study, with interviews ceasing once thematic saturation was achieved. SETTING: Tertiary care centre. PARTICIPANTS: A purposive sample was used to account for variables including pre, early or late postoperative status. RESULTS: 12 participants were interviewed, 4 who were preoperative, 4 early postoperative and 4 late postoperative. Themes of pain, function, fear of complications, awareness of the artificial knee joint and return to work were identified. Subthemes of balancing acute and chronic pain were identified. CONCLUSIONS: The results of this interview-based study identify pain and function, in particular mobility, that were universally important to those undergoing TKR. Surgeons should consider exploring these domains when taking informed consent to enhance shared decision-making. Researchers should consider these recovery domains when designing interventional studies.

Survey of awareness and attitudes to the management of fragility fractures among the membership of the Asia Pacific Orthopaedic Association.

A survey of awareness and attitudes to the management of fragility fractures among the membership of the Asia Pacific Orthopaedic Association conducted in 2022 found considerable variation in care across the region. A Call to Action is proposed to improve acute care, rehabilitation and secondary fracture prevention across Asia Pacific. PURPOSE: Fragility fractures impose a substantial burden on older people and their families, healthcare systems and national economies. The current incidence of hip and other fragility fractures across the Asia Pacific region is enormous and set to escalate rapidly in the coming decades. This publication describes findings of a survey of awareness and attitudes to the management of fragility fractures among the membership of the Asia Pacific Orthopaedic Association (APOA) conducted in 2022. METHODS: The survey was developed as a collaboration between the Asia Pacific Osteoporosis and Fragility Fracture Society and the Asia Pacific Fragility Fracture Alliance, and included questions relating to aspects of care upon presentation, during surgery and mobilisation, secondary fracture prevention, and access to specific services. RESULTS: In total, 521 APOA members completed the survey and marked variation in delivery of care was evident. Notable findings included: Fifty-nine percent of respondents indicated that analgesia was routinely initiated in transit (by paramedics) or within 30 minutes of arrival in the Emergency Department. One-quarter of respondents stated that more than 80% of their patients underwent surgery within 48 hours of admission. One-third of respondents considered non-hip, non-vertebral fractures to merit assessment of future fracture risk. One-third of respondents reported the presence of an Orthogeriatric Service in their hospital, and less than a quarter reported the presence of a Fracture Liaison Service. CONCLUSION: A Call to Action for all National Orthopaedic Associations affiliated with APOA is proposed to improve the care of fragility fracture patients across the region.

Inpatient management of iron deficiency anemia in pediatric patients with inflammatory bowel disease: A single center experience.

BACKGROUND: Screening for iron deficiency anemia (IDA) is important in managing pediatric patients with inflammatory bowel disease (IBD). Concerns related to adverse reactions may contribute to a reluctance to prescribe intravenous (IV) iron to treat IDA in this population. AIM: To track the efficacy and safety of IV iron therapy in treating IDA in pediatric IBD patients admitted to our center. METHODS: A longitudinal observational cohort study was performed on 236 consecutive pediatric patients admitted to our tertiary IBD care center between September 2017 and December 2019. 92 patients met study criteria for IDA, of which 57 received IV iron, 17 received oral iron, and 18 were discharged prior to receiving iron therapy. RESULTS: Patients treated with IV iron during their hospitalization experienced a significant increase of 1.9 (± 0.2) g/dL in mean (± SE) hemoglobin (Hb) concentration by the first ambulatory follow-up, compared to patients who received oral iron 0.8 (± 0.3) g/dL or no iron 0.8 (± 0.3) g/dL (P = 0.03). One out of 57 (1.8%) patients that received IV iron therapy experienced an adverse reaction. CONCLUSION: Our findings demonstrate that treatment with IV iron therapy is safe and efficacious in improving Hb and iron levels in pediatric patients with IDA and active IBD.

Key Insights into Developing Qualitative Concept Elicitation Work for Outcome Measures with Children and Young People.

Qualitative concept elicitation can develop meaningful patient-reported outcome measures for children and young people; however, the methods used for concept elicitation are often underreported for this population. This paper provides in-depth insight into the methods used for concept elicitation with children and young people, with a focus on key stages of concept elicitation that are challenging or unique to doing this research with children. Drawing on our experiences of developing wellbeing measures for children and young people aged 6-15 years, we detail the processes followed in our qualitative concept elicitation work, covering issues related to sampling and recruitment, encouraging informed assent and freedom over children and young people's involvement in concept elicitation, and the use of creative and participatory methods to develop measure items. We provide reflections on the approaches taken to navigate challenging aspects of concept elicitation with children and young people. Our reflections suggest that using existing links and online recruitment methods can help to navigate organisational gatekeepers, and using appropriate processes to develop study information and obtain informed assent can ensure that research is inclusive and that children have the freedom to decide whether to be involved. Our adaptation of a creative and participatory activity to generate concepts for measure items suggests that such approaches can be engaging and may help to give children greater control over their participation. In detailing our methods, we hope to have developed a useful resource for other researchers, while highlighting the value of transparent reporting in this area.

Lurbinectedin in small cell lung cancer: real-world experience of a multicentre national early access programme.

BACKGROUND AND AIMS: Lurbinectedin is a novel oncogenic transcription inhibitor active in several cancers, including small cell lung cancer (SCLC). We aimed to describe the first Australian experience of the clinical efficacy and tolerability of lurbinectedin for the treatment of SCLC after progression on platinum-containing therapy. METHODS: Multicentre real-world study of individuals with SCLC initiating lurbinectedin monotherapy (3.2 mg/m2 three-weekly) on an early access programme between May 2020 and December 2021. Key outcomes were clinical utilisation, efficacy and tolerability. Progression-free survival (PFS) and overall survival (OS) were calculated using the Kaplan-Meier method. Outcome data were collected within the AUstralian Registry and biObank of thoRacic cAncers (AURORA). RESULTS: Data were analysed for 46 individuals across seven sites. Lurbinectedin was given as second- (83%, 38/46) or subsequent- (17%, 8/46) line therapy, mostly with prior chemoimmunotherapy (87%, 40/46). We report dose modifications (17%, 8/46), interruptions/delays (24%, 11/46), high-grade toxicities (28%, 13/46) and hospitalisations (54%, 25/46) during active treatment. The overall response rate was 33% and the disease control rate was 50%. Six-month OS was 44% (95% confidence interval (CI): 29.0-57.1). Twelve-month OS was 15% (95% CI: 6.5-26.8). From lurbinectedin first dose, the median PFS was 2.5 months (95% CI: 1.8-2.9) and OS was 4.5 months (95% CI: 3.5-7.2). From SCLC diagnosis, the median OS was 12.9 months (95% CI: 11.0-17.2). Individuals with a longer chemotherapy-free interval prior to lurbinectedin had longer PFS and OS. CONCLUSION: This real-world national experience of lurbinectedin post-platinum chemotherapy and immunotherapy for individuals with SCLC was similar to that reported in clinical trials.

Prevalence and risk factors for impaired activities of daily living in patients with neo-vascular age-related macular degeneration who present for anti-VEGF treatment.

BACKGROUND/OBJECTIVES: To assess the prevalence and correlates of impaired activities of daily living (ADLs) in patients with neovascular age-related macular degeneration (nAMD) who present for anti-vascular endothelial growth factor (VEGF) therapy. METHODS: In a clinic-based cohort of 437 patients with nAMD who presented for anti-VEGF therapy, the Older American Resources and Services Scale (OARS) was administered to assess for impairments in basic, instrumental and total ADL. Logistic regression analyses were conducted to determine odds ratios (OR) and 95% confidence intervals (CI) for factors associated with ADL impairment. RESULTS: The prevalence of impaired basic, instrumental and total ADL was 37.76%, 67.82% and 39.59%, respectively. In multivariate-adjusted models, moderate visual impairment [OR 5.65, 95% CI (2.31-13.83) and blindness [OR 5.43, 95% CI (2.09-14.12)] were associated with greater odds of impaired total ADL. Depressive symptoms [OR 2.08, 95% CI (1.08-4.00)], the presence of any disability [OR 3.16, 95% CI (1.64-0.07)] and never driving [OR 4.00, 95% CI (1.60-10.00)] were also positively associated with total ADL impairment. Better vision-related quality of life (QoL) was inversely associated with impaired instrumental ADL whilst higher health-related QoL scores were associated with decreased odds of total ADL impairment. CONCLUSIONS: There is a high prevalence rate of ADL impairment among nAMD patients presenting for therapy. Visual impairment, never driving, poor physical and mental health increased the odds of experiencing ADL impairment whilst better VRQoL and HRQoL reduced the odds of impairment.

Is well-becoming important for children and young people? Evidence from in-depth interviews with children and young people and their parents.

PURPOSE: This study explores how important well-becoming factors appear to be to children during childhood. We define well-becoming as the indicators which predict children and young people's future wellbeing and opportunities. The priority for this work was to explore whether well-becoming might be an important factor to include in outcome measures for children and young people. The inclusion of well-becoming indicators could ensure that opportunities to invest in promoting wellbeing in children's futures are not missed. METHODS: In-depth, qualitative interviews (N = 70) were undertaken with children and young people aged 6-15 years and their parents. Analysis used constant comparison and framework methods to investigate whether well-becoming factors were considered important by informants to children and young people's current wellbeing. RESULTS: The findings of the interviews suggested that children and young people and their parents are concerned with future well-becoming now, as factors such as future achievement, financial security, health, independence, identity, and relationships were identified as key to future quality of life. Informants suggested that they considered it important during childhood to aspire towards positive outcomes in children and young people's futures. CONCLUSION: The study findings, taken alongside relevant literature, have generated evidence to support the notion that future well-becoming is important to current wellbeing. We have drawn on our own work in capability wellbeing measure development to demonstrate how we have incorporated a well-becoming attribute into our measures. The inclusion of well-becoming indicators in measures could aid investment in interventions which more directly improve well-becoming outcomes for children and young people.

XTEND: Two-Year Results from a Global Observational Study Investigating Proactive Dosing of Intravitreal Aflibercept in Neovascular Age-Related Macular Degeneration.

INTRODUCTION: XTEND (NCT03939767) is a multicenter, observational, prospective study of patients with treatment-naïve neovascular age-related macular degeneration (nAMD) in routine clinical practice. The study aims to examine treatment outcomes of proactive intravitreal aflibercept (IVT-AFL) treatment regimens (fixed dosing or treat-and-extend) according to local marketing labels. METHODS: Study eyes received IVT-AFL injections as per the local label. The mean changes in best-corrected visual acuity (BCVA) and central subfield thickness (CST) from baseline to month (M) 12 and M24 were measured and stratified by baseline factors. Treatment exposure and safety data were evaluated. Statistical analysis was descriptive. RESULTS: Overall, 1466 patients from 17 countries were treated. For the overall population, the mean ± standard deviation (SD) age was 78.7 ± 8.5 (range 50-100) years, and 891 patients (60.8%) were female. The mean ± SD baseline BCVA was 54.3 ± 20.3 letters and CST was 374 ± 126 µm. At M12 and M24, mean (95% confidence interval [CI]) BCVA change was + 4.3 (3.4, 5.3) and + 2.3 (1.3, 3.3) letters, respectively. Mean (95% CI) CST was - 106 (- 114, - 99) µm and - 109 (- 117, - 102) µm at M12 and M24, respectively. At M24, 41.5% of patients had a BCVA ≥ 70 letters. Patients received a mean ± SD of 7.7 ± 2.7 injections by M12 and 10.8 ± 5.0 injections by M24 (3.1 injections between M12 and M24). Adverse events were consistent with the known safety profile of IVT-AFL. CONCLUSION: The 24-month results indicate that, in routine clinical practice, a proactive IVT-AFL regimen achieves functional improvements in patients with treatment-naïve nAMD. The proportion of patients achieving ≥ 70 letters at M24 increased, and patients with baseline BCVA ≥ 70 letters maintained vision regardless of the followed IVT-AFL label. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03939767. A video abstract is available for this article. Supplementary file2 (MP4 364624 KB).

Illness and (hyper)masculinity in 'HIMM' comics from the USA.

In this essay, I analyse HIMM comics from the USA, a specific textualisation of graphic medicine/pathography that deals with a variety of illness experiences by male cartoonists. It is my contention that, in the existing literature, the motif of masculinity in autobiographical health-related comics is an underdeveloped area of academic enquiry. As a result, my analysis focuses on how three North American men depict ill health in their work in relation to existing sociological understandings of male behaviour. The texts I discuss are John Porcellino's The Hospital Suite (2014), a story about his abdominal tumour; Matt Freedman's exploration of adenoid cystic carcinoma in Relatively Indolent but Relentless (2014); and Peter Dunlap-Shohl's My Degeneration (2015), which discusses the cartoonist's experience of Parkinson's disease. At the same time, I use the concept of hypermasculinity to explore the similar visual and verbal strategies through which these men respond to their physical and emotional suffering. It is my intention to illustrate how HIMM comics provide an important, non-medicalised lens through which clinical practitioners and lay readers alike can better see the subjectivised experience of male illness in the early 21st century. With a focus on the concept of bracketing, the representation of pain and vulnerability, men's loss of self-identity and hardiness, I explore how HIMM comics act as important counter-narratives to biomedical discourse by visualising the phenomenological aspects of men's ill health. In this way, the texts in my analytical corpus offer a valuable gender-oriented understanding of the connection between illnesses and (hyper)masculinity.

Ten-year incidence, predictors and impact of dizziness and vertigo in community-dwelling adults.

OBJECTIVES: We used a cohort of community-dwelling adults to establish the 10-year incidence and predictors of dizziness/vertigo, and its impacts on health-related quality of life. STUDY DESIGN: Of the 1152 participants aged 55 + years who did not have dizziness/vertigo at baseline, 799 and 377 participants were followed up after 5 and 10 years, respectively, and had complete data and so were included in the incidence analysis. Hearing loss was determined as the pure-tone average of audiometric hearing thresholds at 500, 1000, 2000 and 4000 Hz, and any hearing loss was defined as >25 dB hearing level. Tinnitus and migraine were assessed by a positive response to a single question. MAIN OUTCOME MEASURES: Audiologists screened participants for reported dizziness using a single question. Quality of life was measured using the Short Form 36-item Health Survey (SF-36). RESULTS: The cumulative 10-year incidence of dizziness/vertigo, vestibular vertigo and non-vestibular vertigo were 39.8 %, 27.1 %, and 11.9 %, respectively. Age and presence of migraine were significant predictors of incident dizziness/vertigo: multivariable-adjusted hazard ratio (HR) 1.03 (95 % confidence interval, CI, 1.01-1.06) and HR 1.63 (95 % CI 1.13-2.35), respectively. A significant decrease in scores for the following SF-36 domains was observed over the 10 years among participants reporting baseline dizziness/vertigo: physical functioning (P-trend ≤ 0.0001), role limitation due to physical problems (P-trend ≤ 0.0001), general health (P-trend = 0.01), and vitality (P-trend = 0.01). CONCLUSIONS: Dizziness/vertigo was a frequent and detrimental symptom in this population of community-dwelling adults. Our study highlights the burden imposed by dizziness, as evidenced by a significant prospective association with poorer quality of life.

Direct thrombin inhibitors fail to reverse the negative effects of heparin on lung growth and function after murine left pneumonectomy.

Neonates with congenital diaphragmatic hernia (CDH) frequently require cardiopulmonary bypass and systemic anticoagulation. We previously demonstrated that even subtherapeutic heparin impairs lung growth and function in a murine model of compensatory lung growth (CLG). The direct thrombin inhibitors (DTIs) bivalirudin and argatroban preserved growth in this model. Although DTIs are increasingly used for systemic anticoagulation clinically, patients with CDH may still receive heparin. In this experiment, lung endothelial cell proliferation was assessed following treatment with heparin-alone or mixed with increasing concentrations of bivalirudin or argatroban. The effects of subtherapeutic heparin with or without DTIs in the CLG model were also investigated. C57BL/6J mice underwent left pneumonectomy and subcutaneous implantation of osmotic pumps. Pumps were preloaded with normal saline, bivalirudin, or argatroban; treated animals received daily intraperitoneal low-dose heparin. In vitro, heparin-alone decreased endothelial cell proliferation and increased apoptosis. The effect of heparin on proliferation, but not apoptosis, was reversed by the addition of bivalirudin and argatroban. In vivo, low-dose heparin decreased lung volume compared with saline-treated controls. All three groups that received heparin demonstrated decreased lung function on pulmonary function testing and impaired exercise performance on treadmill tolerance testing. These findings correlated with decreases in alveolarization, vascularization, angiogenic signaling, and gene expression in the heparin-exposed groups. Together, these data suggest that bivalirudin and argatroban fail to reverse the inhibitory effects of subtherapeutic heparin on lung growth and function. Clinical studies on the impact of low-dose heparin with DTIs on CDH outcomes are warranted.NEW & NOTEWORTHY Infants with pulmonary hypoplasia frequently require cardiopulmonary bypass and systemic anticoagulation. We investigate the effects of simultaneous exposure to heparin and direct thrombin inhibitors (DTIs) on lung growth and pulmonary function in a murine model of compensatory lung growth (CGL). Our data suggest that DTIs fail to reverse the inhibitory effects of subtherapeutic heparin on lung growth and function. Clinical studies on the impact of heparin with DTIs on clinical outcomes are thus warranted.

What's important for recovery after a total knee replacement? A systematic review of mixed methods studies.

BACKGROUND: Understanding how patients perceive and prioritise various aspects of recovery following total knee replacement, including pain, function and return to activity, will help clinicians in pre-operative consultations by ensuring they effectively address patient concerns and managing their expectations. AIMS: The aim of this study is to identify aspects of recovery that are important to people after a total knee replacement. METHODS: Studies were identified from Medline, Embase, PsycInfo, Cochrane Library and Web of Science. This mixed methods review included all original study types (quantitative, qualitative, discrete choice experiments and mixed methods design). Reviews and non-peer-reviewed publications were excluded. Studies with participants (age ≥ 18 years) who had a primary TKR for osteoarthritis were included. Studies of people with unicompartmental knee, patella-femoral or revision knee replacement were excluded. Recovery attributes were extracted from individual papers and grouped into recovery themes. RESULTS: A total of 23 studies with 8404 participants and 18 recovery themes were developed. The most frequently identified overarching theme was pain, followed by activities of daily living, mobility (walking), recreational activities, specific functional movements of the knee, use of walking aids, sexual activity and range of motion of the knee. Medical complications were an infrequently reported theme, however, was deemed to be high importance. CONCLUSIONS: Reducing pain, returning of activities and daily living and mobility are the three most frequently reported recovery domains for people after TKR. Clinicians should be aware of recovery themes, to ensure they are explored sufficiently when consenting for a TKR. Future research should aim to determine the relative importance of these attributes compared to each other. Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021253699.

Sensitivity to direction and velocity of fast frequency chirps in the inferior colliculus of awake rabbit.

Neurons in the mammalian inferior colliculus (IC) are sensitive to the velocity (speed and direction) of fast frequency chirps contained in Schroeder-phase harmonic complexes (SCHR). However, IC neurons are also sensitive to stimulus periodicity, a prominent feature of SCHR stimuli. Here, to disentangle velocity sensitivity from periodicity tuning, we introduced a novel stimulus consisting of aperiodic random chirps. Extracellular, single-unit recordings were made in the IC of Dutch-belted rabbits in response to both SCHR and aperiodic chirps. Rate-velocity functions were constructed from aperiodic-chirp responses and compared to SCHR rate profiles, revealing interactions between stimulus periodicity and neural velocity sensitivity. A generalized linear model analysis demonstrated that periodicity tuning influences SCHR response rates more strongly than velocity sensitivity. Principal component analysis of rate-velocity functions revealed that neurons were more often sensitive to the direction of lower-velocity chirps and were less often sensitive to the direction of higher-velocity chirps. Overall, these results demonstrate that sensitivity to chirp velocity is common in the IC. Harmonic sounds with complex phase spectra, such as speech and music, contain chirps, and velocity sensitivity would shape IC responses to these sounds.

No relationship between socioeconomic status, education level and development and progression of diabetic retinopathy in type 2 diabetes: a FIELD trial substudy.

In 6002 Australian adults with type 2 diabetes and a median 5-year follow-up in the FIELD (Fenofibrate Intervention and Event Lowering in Diabetes) trial, baseline socioeconomic status (SES) and self-reported education level were not related to development of on-trial sight-threatening diabetic retinopathy. Similarly, in a retinal photography substudy (n = 549), two-step diabetic retinopathy progression was not related to SES or education.

A pneumonectomy model to study flow-induced pulmonary hypertension and compensatory lung growth.

In newborns, developmental disorders such as congenital diaphragmatic hernia (CDH) and specific types of congenital heart disease (CHD) can lead to defective alveolarization, pulmonary hypoplasia, and pulmonary arterial hypertension (PAH). Therapeutic options for these patients are limited, emphasizing the need for new animal models representative of disease conditions. In most adult mammals, compensatory lung growth (CLG) occurs after pneumonectomy; however, the underlying relationship between CLG and flow-induced pulmonary hypertension (PH) is not fully understood. We propose a murine model that involves the simultaneous removal of the left lung and right caval lobe (extended pneumonectomy), which results in reduced CLG and exacerbated reproducible PH. Extended pneumonectomy in mice is a promising animal model to study the cellular response and molecular mechanisms contributing to flow-induced PH, with the potential to identify new treatments for patients with CDH or PAH-CHD.

Absorption of an engineered medium-chain fatty acid analogue in two short bowel syndrome minipig models.

BACKGROUND: Enteral drug therapy is challenging in short bowel syndrome with intestinal failure (SBS-IF) because of unpredictable absorption. SEFA-6179 is an enterally administered medium-chain fatty acid analogue under development for intestinal failure-associated liver disease. We investigate the pharmacokinetics of two SEFA-6179 formulations in two large-animal models of SBS-IF, including a new pseudojejunostomy model. METHODS: Twenty Yucatan minipigs were obtained. Half underwent pre-resection pharmacokinetic study with single-dose SEFA-6179 administration. All minipigs then underwent 90% jejunoileal resection, with either a jejunoileal anastomosis or bypass of the intraperitoneal colon with anastomosis just proximal to the rectum (pseudojejunostomy). On postoperative day 3, a single-dose pharmacokinetic study was performed. RESULTS: Both SBS-IF models were well tolerated. Compared with the jejunoileal anastomosis minipigs, pseudojejunostomy minipigs had a more severe malabsorptive phenotype with weight loss by postoperative day 4 (+0.1 vs -0.9 kg, P = 0.03) and liquid diarrhea (Bristol 5 vs Bristol 7, P = 0.0007). Compared with pre-resection minipigs, both jejunoileal and pseudojejunostomy minipigs had lower total plasma exposure of SEFA-6179 measured by area under the curve (jejunoileal: 37% less, P = 0.049; pseudojejunostomy: 74% less, P = 0.0001). Peak plasma concentration was also lower in the pseudojejunostomy group compared with pre-resection (65% less, P = 0.04), but not lower in the jejunoileal group (P = 0.47). CONCLUSION: In two SBS-IF minipig models, SEFA-6179 had substantially decreased absorption compared with pre-resection minipigs. Dose optimization for different intestinal anatomy and function may be required. We describe a new SBS-IF pseudojejunostomy model that may improve the translation of preclinical research to patients with SBS-IF who have enterostomies.

Real-World Analysis of Clinical Characteristics and Survival Outcomes in Patients With Extensive-Stage SCLC Treated With First-Line Chemoimmunotherapy.

Introduction: There are no clinically validated prognostic biomarkers in the management of extensive-stage SCLC (ES-SCLC). We explored the association between clinical characteristics and survival outcomes in patients with ES-SCLC treated with chemoimmunotherapy. Methods: In this retrospective cohort study, patients with ES-SCLC treated with first-line platinum-etoposide chemotherapy and atezolizumab were identified from medical records. Pretreatment clinical characteristics, biochemical parameters, and tumor and treatment characteristics were collected. Univariate and multivariate Cox regression were used to evaluate treatment effect on progression-free survival (PFS) and overall survival (OS). Results: We evaluated 75 patients in total. The median PFS and OS were 6.1 months and 9.2 months, respectively. Statistically significant associations were found with lower lactate dehydrogenase and improved OS (hazard ratio [HR] = 1.0, 95% confidence interval [CI]: 1.0-1.01, p = 0.006), whereas higher age (HR = 0.94, 95% CI: 0.90-0.98, p = 0.006) and lower neutrophil-to-lymphocyte ratio (HR = 1.08, 95% CI: 1.02-1.14, p = 0.005) were associated with improved PFS. The number of chemotherapy cycles received were associated with both an improved PFS (HR = 0.57, 95% CI: 0.37-0.89, p = 0.011) and OS (HR = 0.5, 95% CI: 0.30-0.84, p = 0.008). Conclusions: This study highlights the important effect of chemotherapy on survival. Furthermore, the association between lactate dehydrogenase and neutrophil-to-lymphocyte ratio on survival further suggests that baseline tumor burden and optimizing sarcopenia are important factors for clinicians to consider as we seek to develop personalized treatment for this disease.

Helicobacter pylori Antimicrobial Resistance Using Next-Generation Sequencing in Stool Samples in a Pediatric Population.

Helicobacter pylori ( H pylori ) eradication rates have declined globally, stressing the importance of antimicrobial susceptibility testing to inform treatment. Molecular tests such as next-generation sequencing (NGS) provide susceptibility data for the antibiotics used in the treatment of H pylori in a noninvasive, effective, and rapid manner. We obtained stool susceptibility testing using a novel NGS-based analysis and compared results with the current "gold standard" of gastric biopsy culture via agar dilution in 20 pediatric patients with evidence of H pylori in gastric biopsies. Stool NGS-based antimicrobial susceptibility analysis was highly concordant with agar dilution for no resistance (100% agreement), as well as clarithromycin, levofloxacin, and amoxicillin resistance (100%, 67%, and 100% agreement, respectively) but not concordant for metronidazole in our cohort of patients. Future studies involving a larger number of patients and geographical regions are needed to further validate this analysis.

Dexamethasone intravitreal implant in diabetic macular oedema refractory to anti-vascular endothelial growth factors: the AUSSIEDEX study.

AIM: To evaluate effectiveness of dexamethasone intravitreal implant 0.7 mg (DEX) monotherapy in the AUSSIEDEX study non-responder subgroup, defined by diabetic macular oedema (DME) refractory to anti-vascular endothelial growth factor (anti-VEGF) agents. METHODS: This prospective, open-label, observational, real-world study included pseudophakic and phakic (scheduled for cataract surgery) eyes that did not achieve a ≥5-letter best corrected visual acuity (BCVA) gain and/or clinically significant central subfield retinal thickness (CRT) improvement after 3-6 anti-VEGF injections for DME (N=143 eyes), regardless of baseline BCVA and CRT. After an initial DEX injection (baseline visit), reinjection was permitted at ≥16-week intervals. PRIMARY ENDPOINTS: changes in mean BCVA and CRT from baseline to week 52. Safety assessments included adverse events. RESULTS: Of 143 eyes, 53 (37.1%) and 89 (62.2%) switched to DEX after 3-6 (early) and >6 (late) anti-VEGF injections, respectively; 1 (0.7%) had missing information. With 2.3 injections (mean) over 52 weeks, the change in mean BCVA from a baseline of 57.8 letters was not significant at week 52. Mean CRT improved significantly from a baseline of 417.8 µm at week 52 (mean change -60.9 µm; p<0.001). Outcomes were similar in eyes switched to DEX early and late. No unexpected adverse events were reported; no filtration surgeries were required. CONCLUSION: To date, AUSSIEDEX is the largest prospective, real-world study of DEX monotherapy for treatment-naïve or anti-VEGF-refractory DME. Following early or late switch from anti-VEGF agents, DEX significantly improved anatomic outcomes at 52 weeks without new safety concerns, supporting use in anti-VEGF-refractory DME. TRIAL REGISTRATION NUMBER: NCT02731911.