Phylodynamic signatures in the emergence of community-associated MRSA.

Community-associated, methicillin-resistant Staphylococcus aureus (MRSA) lineages have emerged in many geographically distinct regions around the world during the past 30 y. Here, we apply consistent phylodynamic methods across multiple community-associated MRSA lineages to describe and contrast their patterns of emergence and dissemination. We generated whole-genome sequencing data for the Australian sequence type (ST) ST93-MRSA-IV from remote communities in Far North Queensland and Papua New Guinea, and the Bengal Bay ST772-MRSA-V clone from metropolitan communities in Pakistan. Increases in the effective reproduction number (Re) and sustained transmission (Re > 1) coincided with spread of progenitor methicillin-susceptible S. aureus (MSSA) in remote northern Australian populations, dissemination of the ST93-MRSA-IV genotype into population centers on the Australian East Coast, and subsequent importation into the highlands of Papua New Guinea and Far North Queensland. Applying the same phylodynamic methods to existing lineage datasets, we identified common signatures of epidemic growth in the emergence and epidemiological trajectory of community-associated S. aureus lineages from America, Asia, Australasia, and Europe. Surges in Re were observed at the divergence of antibiotic-resistant strains, coinciding with their establishment in regional population centers. Epidemic growth was also observed among drug-resistant MSSA clades in Africa and northern Australia. Our data suggest that the emergence of community-associated MRSA in the late 20th century was driven by a combination of antibiotic-resistant genotypes and host epidemiology, leading to abrupt changes in lineage-wide transmission dynamics and sustained transmission in regional population centers.

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.

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.

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.

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.

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.

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.

Clinical Manifestations and Genomic Evaluation of Melioidosis Outbreak among Children after Sporting Event, Australia.

Melioidosis, caused by the environmental gram-negative bacterium Burkholderia pseudomallei, usually develops in adults with predisposing conditions and in Australia more commonly occurs during the monsoonal wet season. We report an outbreak of 7 cases of melioidosis in immunocompetent children in Australia. All the children had participated in a single-day sporting event during the dry season in a tropical region of Australia, and all had limited cutaneous disease. All case-patients had an adverse reaction to oral trimethoprim/sulfamethoxazole treatment, necessitating its discontinuation. We describe the clinical features, environmental sampling, genomic epidemiologic investigation, and public health response to the outbreak. Management of this outbreak shows the potential benefits of making melioidosis a notifiable disease. The approach used could also be used as a framework for similar outbreaks in the future.

Phylodynamic Inference of Bacterial Outbreak Parameters Using Nanopore Sequencing.

Nanopore sequencing and phylodynamic modeling have been used to reconstruct the transmission dynamics of viral epidemics, but their application to bacterial pathogens has remained challenging. Cost-effective bacterial genome sequencing and variant calling on nanopore platforms would greatly enhance surveillance and outbreak response in communities without access to sequencing infrastructure. Here, we adapt random forest models for single nucleotide polymorphism (SNP) polishing developed by Sanderson and colleagues (2020. High precision Neisseria gonorrhoeae variant and antimicrobial resistance calling from metagenomic nanopore sequencing. Genome Res. 30(9):1354-1363) to estimate divergence and effective reproduction numbers (Re) of two methicillin-resistant Staphylococcus aureus (MRSA) outbreaks from remote communities in Far North Queensland and Papua New Guinea (PNG; n = 159). Successive barcoded panels of S. aureus isolates (2 × 12 per MinION) sequenced at low coverage (>5× to 10×) provided sufficient data to accurately infer genotypes with high recall when compared with Illumina references. Random forest models achieved high resolution on ST93 outbreak sequence types (>90% accuracy and precision) and enabled phylodynamic inference of epidemiological parameters using birth-death skyline models. Our method reproduced phylogenetic topology, origin of the outbreaks, and indications of epidemic growth (Re > 1). Nextflow pipelines implement SNP polisher training, evaluation, and outbreak alignments, enabling reconstruction of within-lineage transmission dynamics for infection control of bacterial disease outbreaks on portable nanopore platforms. Our study shows that nanopore technology can be used for bacterial outbreak reconstruction at competitive costs, providing opportunities for infection control in hospitals and communities without access to sequencing infrastructure, such as in remote northern Australia and PNG.

Increased recognition of Q fever aortitis as a chronic manifestation of Q fever in tropical North Queensland, Australia.

Aortitis is a life-threatening, manifestation of chronic Q fever. We report a series of 5 patients with Q fever aortitis who have presented to our hospital in tropical Australia since 2019. All diagnoses were confirmed with polymerase chain reaction (PCR) testing of aortic tissue. Only one had a previous diagnosis of acute Q fever, and none had classical high-risk exposures that might increase clinical suspicion for the infection. All patients underwent surgery: one died and 3 had significant complications. Q fever aortitis may be underdiagnosed; clinicians should consider testing for Coxiella burnetii in people with aortic pathology in endemic areas.

The aetiology and incidence of infective endocarditis in people living with rheumatic heart disease in tropical Australia.

PURPOSE: To define the incidence and microbiological aetiology of infective endocarditis (IE) in patients with rheumatic heart disease (RHD) in tropical Australia. METHODS: A retrospective study that examined all episodes of IE between January 1998 and June 2021 among individuals on the RHD register in Far North Queensland, Australia. RESULTS: There were 1135 individuals with a diagnosis of RHD on the register during the study period, representing 10962 patient-years at risk. Overall, there were 18 episodes of definite IE occurring in 16 individuals, although only 7 episodes occurred in native valves (11 occurred in prosthetic valves) equating to 0.7 episodes of native valve IE/1000 patient-years. No patient with mild RHD - and only one child with RHD - developed IE during the study period. Despite the study's tropical location, the causative organism was usually typical skin or oral flora. Among individuals with an indication for benzathine penicillin G (BPG) prophylaxis, only 1/6 episodes of IE due to a penicillin-susceptible organism received BPG in the month before presentation. CONCLUSION: Although RHD predisposes individuals to IE, the absolute risk of IE in native valve disease in tropical Australia is low and might be reduced further by improved adherence to secondary BPG prophylaxis.

Australasian genetic counselors' attitudes toward disability and prenatal testing: Findings from a cross-sectional survey.

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.

COVID-19 pandemic impacts on global inland fisheries.

The COVID-19 pandemic has led to environmental recovery in some ecosystems from a global "anthropause," yet such evidence for natural resources with extraction or production value (e.g., fisheries) is limited. This brief report provides a data-driven global snapshot of expert-perceived impacts of COVID-19 on inland fisheries. We distributed an online survey assessing perceptions of inland fishery pressures in June and July 2020 to basin-level inland fishery experts (i.e., identified by the Food and Agriculture Organization of the United Nations across the global North and South); 437 respondents from 79 countries addressed 93 unique hydrological basins, accounting for 82.1% of global inland fish catch. Based on the responses analyzed against extrinsic fish catch and human development index data, pandemic impacts on inland fisheries 1) add gradation to the largely positive environmental narrative of the global pandemic and 2) identify that basins of higher provisioning value are perceived to experience greater fishery pressures but may have limited compensatory capacity to mitigate COVID-19 impacts along with negative pressures already present.

Objective Measurement of Posture and Movement in Young Children Using Wearable Sensors and Customised Mathematical Approaches: A Systematic Review.

Given the importance of young children's postures and movements to health and development, robust objective measures are required to provide high-quality evidence. This study aimed to systematically review the available evidence for objective measurement of young (0-5 years) children's posture and movement using machine learning and other algorithm methods on accelerometer data. From 1663 papers, a total of 20 papers reporting on 18 studies met the inclusion criteria. Papers were quality-assessed and data extracted and synthesised on sample, postures and movements identified, sensors used, model development, and accuracy. A common limitation of studies was a poor description of their sample data, yet over half scored adequate/good on their overall study design quality assessment. There was great diversity in all aspects examined, with evidence of increasing sophistication in approaches used over time. Model accuracy varied greatly, but for a range of postures and movements, models developed on a reasonable-sized (n > 25) sample were able to achieve an accuracy of >80%. Issues related to model development are discussed and implications for future research outlined. The current evidence suggests the rapidly developing field of machine learning has clear potential to enable the collection of high-quality evidence on the postures and movements of young children.

Melioidosis of the central nervous system; impact of the bimABm allele on patient presentation and outcome.

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 two sites in tropical Australia after 1989 were reviewed. Demographic, clinical and radiological data of the patients with CNS melioidosis were recorded. The bimA allele (bimABm or bimABp) of the B. pseudomallei isolated from each patient was determined. RESULTS: Of the 1587 cases diagnosed at the two 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 bimABm allele and 30 (63.8%) had the bimABp allele. Patients with a bimABm variant were more likely to have a predominantly neurological presentation (odds ratio (OR) (95% confidence interval (CI)): 5.60 (1.52-20.61), p=0.01), to have brainstem involvement (OR (95%CI): 7.33 (1.92-27.95), p=0.004) and to have encephalomyelitis (OR (95%CI): 4.69 (1.30-16.95), p=0.02. Patients with a bimABm variant were more likely to die or have residual disability (odds ratio (95%CI): 4.88 (1.28-18.57), p=0.01). CONCLUSIONS: The bimA allele of B. pseudomallei has a significant impact on the clinical presentation and outcome of patients with CNS melioidosis.

Catalytic, asymmetric azidations at carbonyls: achiral and meso-anhydride desymmetrisation affords enantioenriched γ-lactams.

An unprecedented organocatalytic process involving the asymmetric addition of azide to meso-anhydrides has been developed, promoted by novel sulfamide-substituted Cinchona alkaloid-based catalysts. Readily available glutaric anhydrides can be smoothly converted to enantioenriched hemi-acyl azides and from there to either γ-amino acids or γ-lactams.

Sleep and health-related quality of life in women following a cancer diagnosis: results from the Women's Wellness after Cancer Program in Australia.

PURPOSE: Sleep disturbance after cancer treatment could compromise recovery. This paper examined the associations between post-treatment sleep problems and health-related quality of life (HRQoL), and the effectiveness of an e-enabled lifestyle intervention on sleep outcomes. METHODS: The Women's Wellness after Cancer Program (WWACP) was examined in a single blinded, multi-centre randomised controlled trial. Data were collected from 351 women (Mage = 53.2, SD = 8.8; intervention n = 175, control group n = 176) who had completed surgery, chemotherapy and/or radiotherapy for breast, gynaecological or blood cancers within the previous 24 months. Participants completed the Pittsburgh Sleep Quality Index (PSQI) at baseline (prior to intervention randomisation), and at 12 and 24 weeks later. Sociodemographic information, menopausal symptoms (Greene Climacteric Scale) and HRQoL (36-Item Short Form Health Survey; SF-36) were also collected. Linear panel regression was used to examine the association between sleep variables and SF36 Physical Component Summary (PCS) and Mental Component Summary (MCS) scores. A difference-in-difference regression model approach was used to examine the intervention effect on the sleep outcomes. RESULTS: After adjustment for potential confounders, the sleep variables (except sleep duration) significantly predicted physical, but not mental, HRQoL. There was no statistically significant effect of the intervention on sleep outcomes at 12 or 24 weeks. CONCLUSION: Women who have completed treatment for cancer experience sleep problems that are associated with decreased physical HRQoL. Improving sleep through targeted interventions should improve their physical HRQoL. Improved targeting of the sleep components of the WWACP should be explored.

Increased Incidence of Melioidosis in Far North Queensland, Queensland, Australia, 1998-2019.

During January 1998-December 2019, the annual incidence of melioidosis in Far North Queensland, Queensland, Australia, more than doubled. Because climate and prevalence of predisposing medical conditions remained stable during that time, we hypothesize that the increased incidence was caused by urban expansion and increased construction, resulting in greater exposure to Burkholderia pseudomallei.

Efficacy and Safety of Intravenous Lincosamide Therapy in Methicillin-Resistant Staphylococcus aureus Bacteremia.

Methicillin-resistant Staphylococcus aureus (MRSA) bacteremia has a high case-fatality rate, but currently recommended antimicrobial therapies have many shortcomings. The efficacy and safety of lincosamide therapy for MRSA bacteremia is incompletely defined. A retrospective audit was done of the management of all adults with MRSA bacteremia at an Australian tertiary referral hospital between 1 January 2007 and 31 December 2020. A total of 176 patients were included. The case-fatality rate declined from 14/57 (25%) in the first half of the study to 12/119 (10%) in the second half (P = 0.01). Of the 172 patients receiving antibiotics, 62 (36%) received a lincosamide-predominant regimen (lincosamide monotherapy for >50% of the intravenous course). The patients receiving lincosamide-predominant intravenous therapy had lower in-hospital mortality (odds ratio [OR], 0.07; 95% confidence interval [CI], 0.01 to 0.53; P = 0.01) and a lower incidence of renal complications (OR [95% CI], 0.34 [0.15-0.75]; P = 0.008) than patients receiving an alternative regimen. In multivariate analysis that also considered age, disease severity, comorbidity, infectious diseases consultation, source control, and the year of admission, patients receiving a lincosamide-predominant regimen were still less likely to die in the hospital than those receiving an alternative regimen (OR [95% CI], 0.05 [0.00 to 0.65]; P = 0.02). Lincosamides appear to have utility, at least as stepdown therapy, in the treatment of MRSA bacteremia, particularly in young, clinically stable patients with few comorbidities in whom endocarditis has been excluded. Prospective studies will help define their optimal role.

Combination ATR and PARP Inhibitor (CAPRI): A phase 2 study of ceralasertib plus olaparib in patients with recurrent, platinum-resistant epithelial ovarian cancer.

OBJECTIVE: Platinum-resistant, high-grade serous ovarian cancer (HGSOC) has limited treatment options. Preclinical data suggest that poly(ADP-ribose) polymerase inhibitors (PARPi) and ataxia telangiectasia and Rad3-related kinase inhibitors (ATRi) are synergistic. CAPRI (NCT03462342) is an investigator-initiated study of olaparib plus ceralasertib in recurrent HGSOC. Herein, we present results from the platinum-resistant cohort. METHODS: A Simon 2-stage design was utilized. Platinum-resistant HGSOC patients received ceralasertib 160 mg orally daily, days 1-7 and olaparib 300 mg orally twice daily, days 1-28 of a 28-day cycle until toxicity or progression. Primary endpoints were toxicity and efficacy including objective response rate (ORR) by RECIST. Secondary endpoint was progression-free survival (PFS). The null hypothesis (≤5% ORR) would be rejected if there were ≥ 1 responses in 12 patients. RESULTS: Fourteen PARPi-naïve patients were evaluable for toxicity; 12 were evaluable for response. Three had BRCA1 mutations (1 germline, 2 somatic). Adverse events possibly related to treatment were primarily grade (G) 1/2. G3 toxicities included nausea (14.3%), fatigue (7.1%), anorexia (7.1%), and anemia (7.1%). No objective responses occurred. Best response was stable disease in 9 patients and progressive disease in three. Five patients had a ≥ 20% to <30% reduction in disease burden, including 3 with BRCA1 mutations. Three of 11 patients (27%; 2 with BRCA1 mutations) evaluable by Gynecologic Cancer Intergroup criteria had >50% CA-125 decline, including 2 with CA-125 normalization. Median PFS was 4.2 months overall (90% CI:3.5-8.2) and 8.2 months (3.6 months-not determined) for patients with BRCA1 mutations. CONCLUSIONS: Olaparib plus ceralasertib is well-tolerated. No objective responses occurred, though a signal of activity was seen particularly in disease associated with BRCA1. Further evaluation of this combination should include alternate dosing strategies in genomically-selected populations.