Age of hepatitis B e antigen loss in Aboriginal, Torres Strait Islander and non-Indigenous residents of tropical Australia; implications for clinical care.

Abstract: This study determined the hepatitis B e antigen (HBeAg) status of people living with chronic hepatitis B (CHB) in Far North Queensland (FNQ), Australia and their age of HBeAg loss. It was hoped that this would provide data to explain the stark difference in the incidence of hepatocellular carcinoma (HCC) between Aboriginal and Torres Strait Islander individuals living with CHB in FNQ, a finding that has been hypothesised to relate to differences in hepatitis B virus genotype. We identified every FNQ resident with CHB, determined their country of birth, their HBeAg status, the age they lost HBeAg and whether they identified as an Aboriginal, a Torres Strait Islander or a non-Indigenous individual. We then ascertained whether these demographic and virological variables were correlated. Of 1,474 individuals living with CHB in FNQ, 278 (19%) were Aboriginal, 507 (34%) were Torres Strait Islanders and 689 (47%) were non-Indigenous. Aboriginal individuals were less likely to be HBeAg positive (26/278, 9%) than Torres Strait Islander (91/507, 18%) and non-Indigenous (126/689, 18%) individuals, p < 0.0001. Aboriginal individuals lost HBeAg at an earlier age (median (interquartile range): 30 (23-39) years) than Torres Strait Islander (38 (29-49) years) and non-Indigenous (36 (29-47) years) individuals, p < 0.0001. Aboriginal individuals with CHB in FNQ are more likely to be HBeAg negative than Torres Strait Islander and non-Indigenous individuals and lose HBeAg at a younger age. This provides a biological basis for local clinicians' observation that Aboriginal individuals with CHB in FNQ are at a lower risk of HCC and data to support the principle of genotype-based care in the region.

Sculpting the tumour microenvironment by combining radiotherapy and ATR inhibition for curative-intent adjuvant immunotherapy.

The combination of radiotherapy/chemoradiotherapy and immune checkpoint blockade can result in poor outcomes in patients with locally advanced head and neck squamous cell carcinoma (HNSCC). Here, we show that combining ATR inhibition (ATRi) with radiotherapy (RT) increases the frequency of activated NKG2A+PD-1+ T cells in animal models of HNSCC. Compared with the ATRi/RT treatment regimen alone, the addition of simultaneous NKG2A and PD-L1 blockade to ATRi/RT, in the adjuvant, post-radiotherapy setting induces a robust antitumour response driven by higher infiltration and activation of cytotoxic T cells in the tumour microenvironment. The efficacy of this combination relies on CD40/CD40L costimulation and infiltration of activated, proliferating memory CD8+ and CD4+ T cells with persistent or new T cell receptor (TCR) signalling, respectively. We also observe increased richness in the TCR repertoire and emergence of numerous and large TCR clonotypes that cluster based on antigen specificity in response to NKG2A/PD-L1/ATRi/RT. Collectively, our data point towards potential combination approaches for the treatment of HNSCC.

Exploring the Clinical Usefulness of Undergraduate Medical Research: A Mixed-Methods Study.

A significant amount of published clinical research has no measurable impact on health and disease outcomes, and research in undergraduate medical education is viewed as especially susceptible. The aims of this mixed methods study were to (a) to use group concept mapping (GCM) to explore key features identified by hospital physicians, medical educators, and medical students as central to clinical usefulness in an undergraduate medical research context, and (b) review a sample of undergraduate medical research projects based on usefulness criteria described by Ioannidis (2016). In the GCM procedure, 54 respondents (39 students, 15 physicians) from an Irish medical school participated across each of three phases: brainstorming, sorting, and rating. Data was analysed using multidimensional scaling and hierarchical clustering. A retrospective analysis of 252 student projects was also completed using a rubric based on Ioannidis's (2016) six domains of "clinical usefulness": problem base, context placement and information gain, pragmatism, patient-centredness, feasibility, and transparency. Projects were scored for each domain by three assessors. Results were analysed and presented using descriptive analysis.GCM analysis revealed the following "clinically useful" research characteristics: optimal design and methodology, practicality, research skills development, translational impact, patient-centredness, and asking a clinical question. Following a rubric-based analysis of projects, the highest scoring categories (mean rating; range of 1-4) were feasibility (3.57), transparency (3.32), and problem base (3.05). The lowest scoring areas were context placement and information gain (2.73), pragmatism (2.68), and patient-centredness (212). We identified considerable conceptual overlap between stakeholder consensus views on "clinical usefulness" as applied to undergraduate research and Ioannidis's criteria. Patient-centredness was identified as a domain requiring greater emphasis during the design of undergraduate medical research. Supplementary Information: The online version contains supplementary material available at 10.1007/s40670-024-02035-7.

Bone and joint infections due to melioidosis; diagnostic and management strategies to optimise outcomes.

BACKGROUND: Melioidosis, a life-threatening infection caused by the gram negative bacterium Burkholderia pseudomallei, can involve almost any organ. Bone and joint infections (BJI) are a recognised, but incompletely defined, manifestation of melioidosis that are associated with significant morbidity and mortality in resource-limited settings. METHODOLOGY/PRINCIPAL FINDINGS: We identified all individuals with BJI due to B. pseudomallei managed at Cairns Hospital in tropical Australia between January 1998 and June 2023. The patients' demographics, their clinical findings and their treatment were correlated with their subsequent course. Of 477 culture-confirmed cases of melioidosis managed at the hospital during the study period, 39 (8%) had confirmed BJI; predisposing risk factors for melioidosis were present in 37/39 (95%). However, in multivariable analysis only diabetes mellitus was independently associated with the presence of BJI (odds ratio (95% confidence interval): 4.04 (1.81-9.00), p = 0.001). BJI was frequently only one component of multi-organ involvement: 29/39 (74%) had infection involving other organs and bacteraemia was present in 31/39 (79%). Of the 39 individuals with BJI, 14 (36%) had osteomyelitis, 8 (20%) had septic arthritis and 17 (44%) had both osteomyelitis and septic arthritis; in 32/39 (83%) the lower limb was involved. Surgery was performed in 30/39 (77%). Readmission after the initial hospitalisation was necessary in 11/39 (28%), 5/39 (13%) had disease recrudescence and 3/39 (8%) had relapse; 4/39 (10%) developed pathological fractures. ICU admission was necessary in 11/39 (28%) but all 11 of these patients survived. Only 1/39 (3%) died, 138 days after admission, due to his significant underlying comorbidity. CONCLUSIONS: The case-fatality rate from melioidosis BJI in Australia's well-resourced health system is very low. However, recrudescence, relapse and orthopaedic complications are relatively common and emphasise the importance of collaborative multidisciplinary care that includes early surgical review, aggressive source control, prolonged antibiotic therapy, and thorough, extended follow-up.

Sleep deprivation and recovery: Endurance racing as a novel model.

The aim of this study was to investigate sleep-wake behavior and gain insights into perceived impairment (sleep, fatigue, and cognitive function) of athletes competing in two international multi-day adventure races. Twenty-four athletes took part across two independent adventure races: Queensland, Australia and Alaska, USA. Individual sleep periods were determined via actigraphy, and racers self-reported their perceived sleep disturbances, sleep impairment, fatigue and cognitive function. Each of these indices was calculated for pre-, during- and post-race periods. Sleep was severely restricted during the race period compared to pre-race (Queensland, 7:46 [0:29] vs. 2:50 [1:01]; Alaska, 7:39 [0:58] vs. 2:45 [2:05]; mean [SD], hh:mm). As a result, there was a large cumulative sleep debt at race completion, which was not 'reversed' in the post-race period (up to 1 week). The deterioration in all four self-reported scales of perceived impairment during the race period was largely restored in the post-race period. This is the first study to document objective sleep-wake behaviors and subjective impairment of adventure racers, in the context of two geographically diverse, multi-day, international adventure races. Measures of sleep deprivation indicate that sleep debt was extreme and did not recover to pre-race levels within 1 week following each race. Despite this objective debt continuing, perceived impairment returned to pre-race levels quickly post-race. Therefore, further examination of actual and perceived sleep recovery is warranted. Adventure racing presents a unique scenario to examine sleep, performance and recovery.

Does Adjunctive Clindamycin Have a Role in Staphylococcus aureus Bacteremia? A Protocol for the Adjunctive Treatment Domain of the Staphylococcus aureus Network Adaptive Platform (SNAP) Randomized Controlled Trial.

BACKGROUND: The use of adjunctive antibiotics directed against exotoxin production in Staphylococcus aureus bacteremia (SAB) is widespread, and it is recommended in many guidelines, but this is based on limited evidence. Existing guidelines are based on the theoretical premise of toxin suppression, as many strains of S. aureus produce toxins such as leukocidins (eg, Panton-Valentine leukocidin, toxic shock syndrome toxin 1, exfoliative toxins, and various enterotoxins). Many clinicians therefore believe that limiting exotoxin production release by S. aureus could reduce its virulence and improve clinical outcomes. Clindamycin, a protein synthesis inhibitor antibiotic, is commonly used for this purpose. We report the domain-specific protocol, embedded in a large adaptive, platform trial, seeking to definitively answer this question. METHODS AND ANALYSIS: The Staphylococcus aureus Network Adaptive Platform (SNAP) trial is a pragmatic, randomized, multicenter adaptive platform trial that aims to compare different SAB therapies, simultaneously, for 90-day mortality rates. The adjunctive treatment domain aims to test the effectiveness of adjunctive antibiotics, initially comparing clindamycin to no adjunctive antibiotic, but future adaptations may include other agents. Individuals will be randomized to receive either 5 days of adjunctive clindamycin (or lincomycin) or no adjunctive antibiotic therapy alongside standard-of-care antibiotics. Most participants with SAB (within 72 hours of index blood culture and with no contraindications) will be eligible to participate in this domain. Prespecified analyses are defined in the statistical appendix to the core protocol, and domain-specific secondary analyses will be adjusted for resistance to clindamycin, disease phenotype (complicated or uncomplicated SAB) and Panton-Valentine leukocidin-positive isolate.

Modelled impact of virtual fractional flow reserve in patients undergoing coronary angiography (VIRTU-4).

BACKGROUND: The practical application of 'virtual' (computed) fractional flow reserve (vFFR) based on invasive coronary angiogram (ICA) images is unknown. The objective of this cohort study was to investigate the potential of vFFR to guide the management of unselected patients undergoing ICA. The hypothesis was that it changes management in >10% of cases. METHODS: vFFR was computed using the Sheffield VIRTUheart system, at five hospitals in the North of England, on 'all-comers' undergoing ICA for non-ST-elevation myocardial infarction acute coronary syndrome (ACS) and chronic coronary syndrome (CCS). The cardiologists' management plan (optimal medical therapy, percutaneous coronary intervention (PCI), coronary artery bypass surgery or 'more information required') and confidence level were recorded after ICA, and again after vFFR disclosure. RESULTS: 517 patients were screened; 320 were recruited: 208 with ACS and 112 with CCS. The median vFFR was 0.82 (0.70-0.91). vFFR disclosure did not change the mean number of significantly stenosed vessels per patient (1.16 (±0.96) visually and 1.18 (±0.92) with vFFR (p=0.79)). A change in intended management following vFFR disclosure occurred in 22% of all patients; in the ACS cohort, there was a 62% increase in the number planned for medical management, and in the CCS cohort, there was a 31% increase in the number planned for PCI. In all patients, vFFR disclosure increased physician confidence from 8 of 10 (7.33-9) to 9 of 10 (8-10) (p<0.001). CONCLUSION: The addition of vFFR to ICA changed intended management strategy in 22% of patients, provided a detailed and specific 'all-in-one' anatomical and physiological assessment of coronary artery disease, and was accompanied by augmentation of the operator's confidence in the treatment strategy.

Significant healthcare resource utilisation in the management of skin and soft tissue infections in the Torres Strait, Australia.

INTRODUCTION: Aboriginal and Torres Strait Islander Peoples (First Nations Australians) living in remote communities are hospitalised with skin and soft tissue infections (SSTIs) at three times the rate of non-First Nations Australians. The Torres Strait in tropical northern Australia has a highly dispersed population mainly comprising First Nations Australians. This study aimed to define the health service utilisation and health system costs associated with SSTIs in the Torres Strait and to improve the quality of regional healthcare delivery. METHODS: The research team conducted a retrospective, de-identified audit of health records for a 2-year period, 2018-2019. The aim was to define health service utilisation, episodes of outpatient care, emergency department care, inpatient care and aeromedical retrieval services for SSTIs. RESULTS: Across 2018 - 2019, there were 3509 outpatient episodes of care for SSTIs as well as 507 emergency department visits and 100 hospitalisations. For individuals with an SSTI, the mean outpatient clinic episode cost $240; the mean emergency department episode cost $400.85, the mean inpatient episode cost $8403.05 while an aeromedical retrieval service cost $18,670. The total costs to the health system for all services accessed for SSTI management was $6,169,881 per year, 3% of the total annual health service budget. CONCLUSION: Healthcare costs associated with SSTIs in the Torres Strait are substantial. The implementation of effective preventative and primary care interventions may enable resources to be reallocated to address other health priorities in the Torres Strait.

Lincosamide monotherapy treatment of methicillin-resistant Staphylococcus aureus pneumonia in tropical Australia: a case series.

Existing recommended first-line antibiotic agents for MRSA pneumonia have several shortcomings. We reviewed 29 cases of community- and hospital-acquired MRSA pneumonia managed at our hospital. Lincosamide monotherapy was administered to 21/29 (72%) and was the predominant antibiotic regimen (> 50% course duration) in 19/29 (66%). Patients receiving lincosamide-predominant monotherapy were no more likely to die or require intensive care unit admission than patients receiving vancomycin-predominant monotherapy (5/19 (26%) versus 4/7 (57%), p = 0.19); 5/7 (71%) patients admitted to ICU and 4/5 (80%) bacteraemic patients received lincosamide-predominant monotherapy. MRSA pneumonia can be safely treated with lincosamide monotherapy if the isolate is susceptible.

Melioidosis masquerading as malignancy in tropical Australia; lessons for clinicians and implications for clinical management.

Melioidosis is a life-threatening, emerging infectious disease caused by the environmental bacterium Burkholderia pseudomallei. Melioidosis is hyperendemic in tropical Australia and southeast Asia, however the disease is increasingly encountered beyond these regions. Early diagnosis is essential as the infection has a case-fatality rate of up to 50 %. Melioidosis most commonly involves the lungs, although almost any organ can be affected. Most patients present acutely but an insidious presentation over weeks to months is also well described. We present a case series of 7 patients from tropical Australia whom local clinicians initially believed to have cancer ‒ most commonly lung cancer ‒ only for further investigation to establish a diagnosis of melioidosis. All 7 patients had comorbidities that predisposed them to developing melioidosis and all survived, but their delayed diagnosis resulted in 3 receiving anti-cancer therapies that resulted in significant morbidity. The study emphasises the importance of thorough diagnostic evaluation and repeated collection of microbiological samples. It is hoped that our experience will encourage other clinicians ‒ in the appropriate clinical context ‒ to consider melioidosis as a potential explanation for a patient's presentation, expediting its diagnosis and the initiation of potentially life-saving therapy.

Low-dose CT: A safe and effective imaging modality in post-operative pelvic & acetabular fixation.

INTRODUCTION: Post-operative pelvic & acetabular fixation patients are conventionally imaged using 3-view radiographs (AP, inlet and outlet). The efficacy of such radiographs is inconsistent due to technical difficulties capturing an adequate view, often necessitating repeat radiographs and therefore increasing radiation exposure. Radiographs can be difficult to interpret, limiting the assessment of fracture reduction and fixation, especially with respect to metalwork positioning around articular surfaces. Traditionally, post-operative pelvic & acetabular fixation patients undergo repeat 3-view radiographs post-operatively, at 6 weeks, followed by at 3, 6, 12, 18 and 24 months. We propose a new pathway, in which patients have one low-dose pelvic CT immediately post-operatively, followed by one radiograph (AP pelvis) at the same time points. METHODS: A new pelvic CT protocol was created to provide high quality 3D imaging whilst delivering a 5 times lower radiation dose (compared to normal pelvic CT). Data for all pelvic radiographs and CTs between January 2021 and March 2022 was exported. Using dose area product values, effective radiation dose and attributable lifetime cancer risk were calculated. RESULTS: There were 42 patients included in the analysis (age range 15 to 87).The average effective dose for the 3-view pelvic X-rays was 0.6mSv (range 0.2 to 2.8mSv), and 1.1mSv (range 0.5 to 2.2mSv) for the low-dose pelvic CT. Traditional 7 × 3-view post-operative radiographs: 7 × 0.6mSv = 4.2mSv (corresponding to 1 in 11,000 cancer risk) Low dose post-operative CT and 6 × 1-view radiographs: 1.1mSv + (6 × 0.6mSv / 3) = 2.3mSv (corresponding to 1 in 20,000 cancer risk) CONCLUSION: Low-dose CT scanning (in conjunction with 1-view radiographs) is an effective and safe imaging modality in the post-operative assessment of pelvic & acetabular fracture fixation, conferring a lower radiation burden, easier logistics, and higher quality images when compared to the traditional pathway of 3-view radiographs.

Reducing crash risk for young drivers: Protocol for a pragmatic randomised controlled trial to improve young driver sleep.

Background: Road trauma is a leading cause of death and disability for young Australians (15-24 years). Young adults are overrepresented in crashes due to sleepiness, with two-thirds of their fatal crashes attributed to sleepy driving. This trial aims to examine the effectiveness of a sleep extension and education program for improved road safety in young adults. Methods: Young adults aged 18-24 years (n = 210) will be recruited for a pragmatic randomised controlled trial employing a placebo-controlled, parallel-groups design. The intervention group will undergo sleep extension and receive education on sleep, whereas the placebo control group will be provided with information about diet and nutrition. The primary outcomes of habitual sleep and on-road driving performance will be assessed via actigraphy and in-vehicle accelerometery. A range of secondary outcomes including driving behaviours (driving simulator), sleep (diaries and questionnaire) and socio-emotional measures will be assessed. Discussion: Sleep is a modifiable factor that may reduce the risk of sleepiness-related crashes. Modifying sleep behaviour could potentially help to reduce the risk of young driver sleepiness-related crashes. This randomised control trial will objectively assess the efficacy of implementing sleep behaviour manipulation and education on reducing crash risk in young adult drivers.

Exploring the Relationship Between Age at Nap Cessation and Social-Emotional Functioning in Children.

OBJECTIVE: The objective of this study was to examine variations in age at nap cessation and identify whether there is an association with social-emotional functioning (SEF) as measured by internalizing/externalizing behavior, child temperament, and social skills in a sample of early childhood education and care-attending children. METHODS: The sample comprised 1117 children from the Australian Effectiveness Early Educational Experiences for Children longitudinal early childhood study. We used children's age at nap cessation as retrospectively recalled by caregivers in 2011 or 2013 when children were between ages 2 and 7 years. Each child's SEF was reported by a caregiver using the Strengths and Difficulties Questionnaire, the Short Temperament Scale for Children, and the Social Skills Inventory Scale. Associations between children's age of nap cessation and SEF were tested using linear regressions. RESULTS: The children's age at nap cessation ranged from 6 months to 6 years. For each additional year of napping, children's total , conduct , externalizing , and peer behavior problems decreased by 0.39 (95% confidence interval [CI], -0.70 to -0.09), 0.11 (95% CI, -0.21 to -0.01), 0.11 (95% CI, -0.51 to -0.06), and 0.11 (95% CI, -0.20 to -0.02) units on the Strengths and Difficulties Questionnaire scale, respectively. No further significant associations were found. CONCLUSION: This is the first study reporting the age range of nap cessation and its associations with social-emotional functioning. Our findings demonstrate earlier cessation ages in Australian children attending Early Childhood Education and Care programs than previously reported and a small association with externalizing and peer problems.

Data from four consecutive cohorts of students in Australia (2019-2022) show the impact of the COVID-19 pandemic on domestic and international university students' mental health.

INTRODUCTION: COVID-19 and related travel and social restrictions caused significant stress for university students in Australia and globally. Learning quickly moved online and many students (particularly international students) were separated from social and economic support. This study examined the impact of the pandemic from pre-pandemic (2019) to the COVID-19 Omicron wave (2022) on domestic and international students' mental health. METHODS: Participants were 1540 students (72% females, 28% international) in four first-year cohorts (2019, 2020, 2021, 2022). We screened for mental health concerns (% positive) and symptom scores for depression, anxiety and somatic distress using the PsyCheck, and general wellbeing using the Warwick-Edinburgh Mental Well-being scale. RESULTS: From pre-COVID (2019) to the first wave of COVID-19 (2020), the proportion of students screening positive for mental health problems rose in both domestic students (66-76%) and international students (46-67%). Depression symptoms and wellbeing were worse in 2020 than in 2019, 2021 and 2022. Anxiety symptoms increased from 2019 to 2020 and continued to rise in 2021 and 2022. Somatic symptoms did not show an effect of cohort. Contrary to expectations, domestic students reported higher distress and lower wellbeing than international students across cohorts. CONCLUSION: The pandemic was associated with a marked increase in psychological distress in first-year university students, not all of which settled with the easing of restrictions. Post-pandemic recovery in the Australian university sector must include university-wide access to mental health information and support for incoming students.

Perceived Neighborhood Characteristics and Sleep in Australian Adults.

BACKGROUND: Poor sleep can contribute to poorer health and socioemotional outcomes. Sleep health can be influenced by a range of individual and other socioecological factors. Perceptions of neighborhood physical and social characteristics reflect broader social-level factors that may influence sleep, which have not been well studied in the Australian context. This study examined the association between perceived neighborhood characteristics and sleep in a large sample of Australians. METHODS: Data were from 9,792 people aged 16 years or older, from Waves 16 and 17 of the nationally representative Household, Income and Labour Dynamics in Australia Survey. Associations between perceived neighborhood characteristics (neighborly interaction and support, environmental noise, physical condition, and insecurity) and self-reported sleep duration, sleep disturbance, and napping were examined using multiple logistic regression models. RESULTS: "Neighborhood interaction and support" and "neighborhood physical condition" were not significantly associated with any sleep outcomes after adjusting for relevant covariates. However, "environmental noise" and "neighborhood insecurity" remained significantly associated with sleep duration and sleep disturbance. None of the neighborhood characteristics were associated with napping. Furthermore, associations did not significantly vary by gender. CONCLUSIONS: This study highlights the potential benefit of public health policies to address noise and safety in neighborhoods to improve sleep.

Hepatitis B genotypes in Aboriginal and Torres Strait Islander Australians: correlation with clinical course and implications for management.

BACKGROUND: The prevalence of chronic hepatitis B (CHB) in Aboriginal and Torres Strait Islander Australians in Far North Queensland (FNQ) is greater than twice that of the general Australian population. CHB is common in Torres Strait Islanders diagnosed with hepatocellular carcinoma (HCC) - and in Aboriginals with HCC living in the Northern Territory - however, Aboriginals diagnosed with HCC in FNQ very rarely have CHB. The explanation for this apparent disparity is uncertain. AIMS: To determine the HBV genotypes in the FNQ Aboriginal and Torres Strait Islander population and their correlation with clinical phenotype. METHODS: We determined the HBV genotype of Aboriginal and Torres Strait Islander Australians living with CHB in FNQ and correlated this with demographic and clinical findings. RESULTS: 134/197 (68%) enrolled individuals had a sufficient viral load for genotyping. All 40 people with HBV/D genotype had Aboriginal heritage, whereas 85/93 (91%) with HBV/C had Torres Strait Islander heritage (P < 0.0001). Individuals with HBV/D were younger than those with HBV/C (median (interquartile range) age: 43 (39-48) vs 53 (42-66) years, P = 0.0002). However, they were less likely to be HBeAg positive (1/40 (3%) vs 23/93 (25%), P = 0.001). All three HCCs developed in Torres Strait Islanders; two-thirds were infected with HBV/C14; genotyping was not possible in the other individual. All 10 diagnoses of cirrhosis occurred in Torres Strait Islanders, 6/10 were infected with HBV/C14, genotyping was not possible in the other four individuals. CONCLUSIONS: HBV genotypes in Aboriginal and Torres Strait Islander Australians in FNQ differ markedly, which could explain the significant differences in the clinical phenotype in the two populations and might be used to inform cost-effective CHB care in the region.

Durable responses to ATR inhibition with ceralasertib in tumors with genomic defects and high inflammation.

BACKGROUNDPhase 1 study of ATRinhibition alone or with radiation therapy (PATRIOT) was a first-in-human phase I study of the oral ATR (ataxia telangiectasia and Rad3-related) inhibitor ceralasertib (AZD6738) in advanced solid tumors.METHODSThe primary objective was safety. Secondary objectives included assessment of antitumor responses and pharmacokinetic (PK) and pharmacodynamic (PD) studies. Sixty-seven patients received 20-240 mg ceralasertib BD continuously or intermittently (14 of a 28-day cycle).RESULTSIntermittent dosing was better tolerated than continuous, which was associated with dose-limiting hematological toxicity. The recommended phase 2 dose of ceralasertib was 160 mg twice daily for 2 weeks in a 4-weekly cycle. Modulation of target and increased DNA damage were identified in tumor and surrogate PD. There were 5 (8%) confirmed partial responses (PRs) (40-240 mg BD), 34 (52%) stable disease (SD), including 1 unconfirmed PR, and 27 (41%) progressive disease. Durable responses were seen in tumors with loss of AT-rich interactive domain-containing protein 1A (ARID1A) and DNA damage-response defects. Treatment-modulated tumor and systemic immune markers and responding tumors were more immune inflamed than nonresponding.CONCLUSIONCeralasertib monotherapy was tolerated at 160 mg BD intermittently and associated with antitumor activity.TRIAL REGISTRATIONClinicaltrials.gov: NCT02223923, EudraCT: 2013-003994-84.FUNDINGCancer Research UK, AstraZeneca, UK Department of Health (National Institute for Health Research), Rosetrees Trust, Experimental Cancer Medicine Centre.

Biomarker-driven phase 2 umbrella trial: Clinical efficacy of olaparib monotherapy and combination with ceralasertib (AZD6738) in small cell lung cancer.

BACKGROUND: Based on a high incidence of genomic alteration in the cell cycle and DNA damage and response (DDR)-related pathways in small cell lung cancer (SCLC), the clinical efficacy of the DDR-targeting agent olaparib (PARP inhibitor) as monotherapy and in combination with ceralasertib (ATR inhibitor) in relapsed or refractory SCLC was evaluated. METHODS: As part of a phase 2 biomarker driven umbrella study, patients with SCLC and predefined DDR gene alterations who failed to benefit from prior platinum-based regimens were allocated to the olaparib monotherapy arm and nonbiomarker-selected patients were allocated to the olaparib and ceralasertib combination arm. RESULTS: In the olaparib monotherapy arm (n = 15), the objective response rate was 6.7% (one partial response), and the disease control rate was 33.3%, including three patients with stable disease. The median progression-free survival was 1.3 months (95% CI, 1.2-NA). In the combination arm (n = 26), the objective response rate and disease control rate were 3.8% and 42.3%, respectively, with one partial response and 10 patients with stable disease. The median progression-free survival was 2.8 months (95% CI, 1.8-5.4). Treatment was generally well tolerated except for one fatal case of neutropenic fever in the combination arm. CONCLUSIONS: Targeting DDR pathways with olaparib as a single agent or in combination with ceralasertib did not meet the predefined efficacy end point. However, disease stabilization was more evident in the combination arm. Further investigation of the combination of olaparib in SCLC should be performed with diverse combinations and patient selection strategies to maximize efficacy.

Patient-healthcare provider communication and age-related hearing loss: a qualitative study of patients' perspectives.

BACKGROUND: The prevalence of age-related hearing loss (ARHL) significantly increases in people aged 60 and older. Medical errors are frequently reported because of communication breakdown, especially for patients with ARHL. AIMS: This qualitative study focuses on identifying the communication challenges faced by people aged over 65 with ARHL and potential ameliorative strategies based on the participants' personal experiences. METHODS: Thirteen participants, attending a support service for older adults with hearing loss in the South of Ireland, were recruited using convenience sampling. Semi-structured interviews were conducted with participants. Interviews were audio-recorded and transcribed using NVivo 12 software. Braun and Clarke's thematic analysis methodology was used to identify themes arising from two main study domains: difficulties faced during the most recent healthcare interaction and suggestions for improving overall healthcare communication. RESULTS: Older adults with hearing loss identified general mishearing, lack of awareness and use of medical terminology to be the cause of ineffective communication. Raising awareness of the impact of presbycusis on clinical interaction among healthcare professionals was cited as being of crucial importance. Other helpful strategies include repeat and rephrase, use of written information, providing context, minimizing ambient noise, continuity of care, longer consultation length and good body language. CONCLUSION: Effective clinical communication can be achieved through a clear understanding of the patient's perspective. Healthcare providers should be made aware of the hearing issues and associated communication difficulties posed, within the context of the development of patient-centred strategies to improve patient safety.