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BACKGROUND. Phase 1 study of ATR inhibition 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. METHODS. The 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). RESULTS. Intermittent 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 damageresponse defects. Treatment-modulated tumor and systemic immune markers and responding tumors were more immune inflamed than nonresponding. CONCLUSION. Ceralasertib monotherapy was tolerated at 160 mg BD intermittently and associated with antitumor activity. TRIAL REGISTRATION. Clinicaltrials.gov: NCT02223923, EudraCT: 2013-003994-84. FUNDING. Cancer Research UK, AstraZeneca, UK Department of Health (National Institute for Health Research), Rosetrees Trust, Experimental Cancer Medicine Centre., Introduction ATR (ataxia telangiectasia and Rad3-related) is a critical kinase in the DNA damage response (DDR) (1, 2). Preclinical data have identified multiple cancer-related phenotypes sensitizing tumor cells to monotherapy [...]

Technological change is a feature of contemporary life encompassing interactivity, collaboration and, above all, real-time content sharing and live streaming. The COVID-19 pandemic has introduced new dynamics in relation to digitisation and technology usage. Within organisations, these changes have been swift and profound, leading to online meetings, events and virtual team management. An explosion of literature has accompanied these changes and their human impacts. However, the generational and intergenerational issues remain under-examined and therefore constitute an important gap. The paper examines the literature on workplace technology, digitalisation and human impacts in relation to the COVID-19, and particularly, through the lens of different generational adoptive patterns. Taking an inductive qualitative approach, the paper's empirical focus is analyses of semi-structured questionnaire data from intergenerational senior executives. The findings showcase alternative understandings of technology in the late-COVID-19 era and of Xer generational (i.e. born 1961–1981) resilience and operational change dynamics. This allows a number of contributions and implications to be developed. [ABSTRACT FROM AUTHOR]

We develop a new Bayesian approach to estimate noncommon structural breaks in panel regression models. Any subset of the cross-section may be hit at different times within a break window. Break-specific parameters are learned from the cross-section. They reflect whether (i) breaks hit many or few series and (ii) there is a long or short lag between the first and final series hit by a break. In an empirical application to international stock return predictability, the method generates significantly more accurate forecasts than several benchmarks that yield economically meaningful utility gains for a risk averse investor with power utility. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. Immune checkpoint blockade can result in good outcomes in patients with metastatic head and neck squamous cell carcinoma (HNSCC), but not those with locally advanced disease. Here, the authors demonstrate that the addition of anti-NKG2A and anti-PD-L1 blockade to ATR inhibition and radiotherapy in the adjuvant setting can induce a robust antitumour immune response in mice. [ABSTRACT FROM AUTHOR]

Diagnostic genetic testing and non‐invasive prenatal testing (NIPT) for conditions associated with disability are becoming increasingly available to consumers. This genetic information can be used in the disability setting to inform factors such as prognosis, management, and reproductive decision‐making. Genetic counselors (GCs) play an important role in the provision of genetic testing and NIPT, and their attitudes toward disability can influence how genetic information is communicated and shape patients' responses. This study aimed to evaluate and describe Australasian GCs' experience with and attitudes toward disabilities to identify potential biases and training needs. A cross‐sectional survey was distributed to 400 GCs registered with the Human Genetics Society of Australasia. Of the 106 respondents (participation rate: 26%), a significantly greater proportion were more comfortable interacting with individuals with physical disability as compared to intellectual disability (p < 0.001). GCs with personal experiences with disabilities reported significantly greater comfort interacting with people with intellectual disability than those without experience (p = 0.012). Qualitative analysis revealed discomfort was less reflective of bias than inexperience and apprehension about communicating disrespectfully. GCs believed people with disabilities experience discrimination and that having a disability could make a person stronger, wiser, and more motivated. Most GCs viewed prenatal testing for disabilities positively as it allowed for decisions regarding continuing the pregnancy and/or provided opportunity to prepare. Challenges identified for prenatal counseling included negative societal attitudes and the low visibility of disability. GCs felt that 'personal beliefs' was the primary factor influencing the decision to terminate a pregnancy affected by disability. These findings highlight important education and training needs for GCs to improve preparedness and comfort when communicating with people with a disability. [ABSTRACT FROM AUTHOR]

Addressing ecological impacts with effective conservation actions requires information on the links between human pressures and localized responses. Understanding links is a priority for many conservation contexts, including the world's fresh waters, which face intensifying threats to disproportionately high species diversity, including more than half of the world's fish species. Literature synthesis can uncover links and highlight potential research gaps, yet can be very cumbersome and time consuming. Emerging tools like text mining can improve efficiency in extracting relevant information from vast scientific outputs. This study synthesizes evidence of direct anthropogenic threats to major inland fisheries and examines driver‐impact‐response patterns using coupled automated and manual text classification methods. We screened 9336 abstracts from 45 river basins of high importance to inland fish production; 1152 abstracts contained evidence of direct threats to fish. The most common documented drivers were pollution, dams, and fishing pressure, which were most strongly linked to decreased fitness, altered reproduction, and mortality, respectively. Strong impact‐response links to pollution signal potential bias toward documenting acute threats that generate more visible and immediate impacts. The use of machine learning‐based text classification performed best in classifying extraneous information. Results can inform the development of inland fisheries indicators and threat‐based metrics, highlight possible evidence gaps in linking global drivers to fishery‐level responses, and illustrate the application of a coupled synthesis approach for improved efficiency and extraction of information relevant to conservation outcomes. The associated user and interpretation guides address accessibility and technical barriers faced by conservation scientists to improve efficiency in evidence synthesis. [ABSTRACT FROM AUTHOR]

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. Highlights: Adventure, or expedition, racing is an ultra‐endurance sport, carried out over multiple days, which presents an extreme test of athletic performance under conditions of severe sleep restriction and deprivation. However, limited research has been conducted to examine sleep and perceived impairment of athletes who choose this sport.Using actigraphy, the team‐based nature of adventure racing was evident with severe sleep restriction synchronized between team members during the race.There was significant sleep debt accumulated across the race and was not recovered by the end of the measurement period. Furthermore, perceived impairment returned to pre‐race levels quickly after race completion, despite the remaining sleep debt objectively observed.This study posits that adventure racing presents a unique context to study sleep, performance, and recovery. [ABSTRACT FROM AUTHOR]

This article is a review of the book "Remedies against the Pandemic: How Politicians Communicate Crisis Management." The book contains ten case studies on political communication during the Covid-19 pandemic. While the individual chapters offer interesting insights, the book lacks coherence and fails to demonstrate the unique nature of pandemic communication or the general features of political communication during a crisis. The title is misleading as it focuses more on the discourse of political leaders rather than public health messages. The book also suffers from weak integration, inadequate indexing, and lack of attention to detail. However, the pandemic provides an ideal context to study discourse and argumentation during a crisis. The article discusses various chapters in the book, providing a critical evaluation of each one and highlighting their strengths and weaknesses. The importance of careful curation and peer review is emphasized, and the article acknowledges the funding support for the work. [Extracted from the article]

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. Author summary: Bone and joint infections (BJI) are a recognised and life-threatening manifestation of melioidosis but frequently only one component of multi-organ involvement. Almost all patients with BJI due to Burkholderia pseudomallei have risk factors that predispose them to developing melioidosis, but diabetes appears to be the most closely associated with BJI. The vasculopathy, neuropathy, structural deformity and decreased immunity that is seen in many individuals with diabetes increases their risk of lower limb infection and these factors–combined with greater exposure to B. pseudomallei in the soil and surface water–might explain the lower limb predominance that is seen in many series of melioidosis-related BJI. Patients require early multimodal imaging, appropriate microbiological sampling, early surgical review, prompt source control and an adequate duration of antibiotic therapy–and, in many cases, critical care support–to ensure optimal outcomes. Collaborative, multidisciplinary care reduces the case-fatality rate of melioidosis BJI, but recrudescence, relapse and orthopaedic complications are common in survivors and therefore extended patient follow up is essential. [ABSTRACT FROM AUTHOR]

AbstractThere is a growing consensus that the end of empire did not necessarily equate with a severing of imperial ties. Some historians have even argued that there was a shift from formal to informal empire in Britain’s relations with the emerging Gulf States. This is especially so with respect to Bahrain which had represented the epicentre of Britain’s position in the Gulf. Nevertheless, an analysis of British relations with Bahrain from the withdrawal East of Suez to the Iranian Revolution belies any notion that Britain succeeded in establishing an informal imperial position after 1971. Not only were Britain’s economic interests in Bahrain eroded by growing competition from its industrial rivals, but also its political and military position was challenged by the encroachment of regional powers. Any hope that Britain could retain an imperial role in Bahrain was undermined still further by the emergence of new internal political forces in Bahrain beyond the direct control of either the ruling family or Britain itself. The unfeasibility of maintaining an imperial relationship with Bahrain after 1971 persuaded British policymakers to seek to establish recognizably post-imperial relations with the Emirate in the decade following the withdrawal from East of Suez. [ABSTRACT FROM AUTHOR]

Background The autotransporter protein Burkholderia intracellular motility A (BimA) facilitates the entry of Burkholderia pseudomallei into the central nervous system (CNS) in mouse models of melioidosis. Its role in the pathogenesis of human cases of CNS melioidosis is incompletely defined. Methods Consecutive culture-confirmed cases of melioidosis at 2 sites in tropical Australia after 1989 were reviewed. Demographic, clinical, and radiological data of the patients with CNS melioidosis were recorded. The bimA allele (bimA Bm or bimA Bp ) of the B. pseudomallei isolated from each patient was determined. Results Of the 1587 cases diagnosed at the 2 sites during the study period, 52 (3.3%) had confirmed CNS melioidosis: 20 (38.5%) had a brain abscess, 18 (34.6%) had encephalomyelitis, 4 (7.7%) had isolated meningitis, and 10 (19.2%) had extra-meningeal disease. Among the 52 patients, there were 8 (15.4%) deaths; 17/44 (38.6%) survivors had residual disability. The bimA allele was characterized in 47/52; 17/47 (36.2%) had the bimA Bm allele and 30 (63.8%) had the bim A Bp allele. Patients with a bimA Bm variant were more likely to have a predominantly neurological presentation (odds ratio [OR]: 5.60; 95% confidence interval: 1.52–20.61; P  = .01), to have brainstem involvement (OR: 7.33; 1.92–27.95; P  = .004), and to have encephalomyelitis (OR: 4.69; 1.30–16.95; P  = .02). Patients with a bimA Bm variant were more likely to die or have residual disability (OR: 4.88; 1.28–18.57; P  = .01). Conclusions The bimA allele of B. pseudomallei has a significant impact on the clinical presentation and outcome of patients with CNS melioidosis. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. This study provides clinical evidence that current approaches targeting DNA damage and response pathway as either olaparib alone or in combination with ceralasertib therapy are insufficient to achieve a satisfactory response in small cell lung cancer. However, this study supports the evidence for further investigation, searching for an appropriate combination partner of DNA damage and response pathway targeting agent and relevant predictive biomarkers in small cell lung cancer. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]