Thyroid hormone T4 mitigates traumatic brain injury in mice by dynamically remodeling cell type specific genes, pathways, and networks in hippocampus and frontal cortex.

The complex pathology of mild traumatic brain injury (mTBI) is a main contributor to the difficulties in achieving a successful therapeutic regimen. Thyroxine (T4) administration has been shown to prevent the cognitive impairments induced by mTBI in mice but the mechanism is poorly understood. To understand the underlying mechanism, we carried out a single cell transcriptomic study to investigate the spatiotemporal effects of T4 on individual cell types in the hippocampus and frontal cortex at three post-injury stages in a mouse model of mTBI. We found that T4 treatment altered the proportions and transcriptomes of numerous cell types across tissues and timepoints, particularly oligodendrocytes, astrocytes, and microglia, which are crucial for injury repair. T4 also reversed the expression of mTBI-affected genes such as Ttr, mt-Rnr2, Ggn12, Malat1, Gnaq, and Myo3a, as well as numerous pathways such as cell/energy/iron metabolism, immune response, nervous system, and cytoskeleton-related pathways. Cell-type specific network modeling revealed that T4 mitigated select mTBI-perturbed dynamic shifts in subnetworks related to cell cycle, stress response, and RNA processing in oligodendrocytes. Cross cell-type ligand-receptor networks revealed the roles of App, Hmgb1, Fn1, and Tnf in mTBI, with the latter two ligands having been previously identified as TBI network hubs. mTBI and/or T4 signature genes were enriched for human genome-wide association study (GWAS) candidate genes for cognitive, psychiatric and neurodegenerative disorders related to mTBI. Our systems-level single cell analysis elucidated the temporal and spatial dynamic reprogramming of cell-type specific genes, pathways, and networks, as well as cell-cell communications as the mechanisms through which T4 mitigates cognitive dysfunction induced by mTBI.

The use of evidence to guide decision-making during the COVID-19 pandemic: divergent perspectives from a qualitative case study in British Columbia, Canada.

BACKGROUND: The challenges of evidence-informed decision-making in a public health emergency have never been so notable as during the COVID-19 pandemic. Questions about the decision-making process, including what forms of evidence were used, and how evidence informed-or did not inform-policy have been debated. METHODS: We examined decision-makers' observations on evidence-use in early COVID-19 policy-making in British Columbia (BC), Canada through a qualitative case study. From July 2021- January 2022, we conducted 18 semi-structured key informant interviews with BC elected officials, provincial and regional-level health officials, and civil society actors involved in the public health response. The questions focused on: (1) the use of evidence in policy-making; (2) the interface between researchers and policy-makers; and (3) key challenges perceived by respondents as barriers to applying evidence to COVID-19 policy decisions. Data were analyzed thematically, using a constant comparative method. Framework analysis was also employed to generate analytic insights across stakeholder perspectives. RESULTS: Overall, while many actors' impressions were that BC's early COVID-19 policy response was evidence-informed, an overarching theme was a lack of clarity and uncertainty as to what evidence was used and how it flowed into decision-making processes. Perspectives diverged on the relationship between 'government' and public health expertise, and whether or not public health actors had an independent voice in articulating evidence to inform pandemic governance. Respondents perceived a lack of coordination and continuity across data sources, and a lack of explicit guidelines on evidence-use in the decision-making process, which resulted in a sense of fragmentation. The tension between the processes involved in research and the need for rapid decision-making was perceived as a barrier to using evidence to inform policy. CONCLUSIONS: Areas to be considered in planning for future emergencies include: information flow between policy-makers and researchers, coordination of data collection and use, and transparency as to how decisions are made-all of which reflect a need to improve communication. Based on our findings, clear mechanisms and processes for channeling varied forms of evidence into decision-making need to be identified, and doing so will strengthen preparedness for future public health crises.

Analytical propagation model for underwater free-space optical communication through realistic levels of oceanic absorption and scattering.

Optical communications (OC) through water bodies is an attractive technology for a variety of applications. Thanks to current single-photon detection capabilities, OC receiver systems can reliably decode very weak transmitted signals. This is the regime where pulse position modulation is an ideal scheme. However, there has to be at least one photon that goes through the pupil of the fore optics and lands in the assigned time bin. We estimate the detectable photon budget as a function of range for propagation through ocean water, both open and coastal. We make realistic assumptions about the water's inherent optical properties, specifically, absorption and scattering coefficients, as well as the strong directionality of the scattering phase function for typical hydrosol populations. We adopt an analytical (hence very fast) path-integral small-angle solution of the radiative transfer equation for multiple forward-peaked scattering across intermediate to large optical distances. Integrals are performed both along the directly transmitted beam (whether or not it is still populated) and radially away from it. We use this modeling framework to estimate transmission of a 1 J pulse of 532 nm light through open ocean and coastal waters. Thresholds for single-photon detection per time bin are a few km and a few 100 m. These are indicative estimates that will be reduced in practice due to sensor noise, background light, turbulence, bubbles, and so on, to be included in future work.

Microplastics in Hong Kong's marine waters: Impact of rainfall and Pearl River discharge.

This study provided a systematic investigation of microplastics in Hong Kong's surface marine waters during the pandemic from 2019 to 2021. Microplastics (2.07 ± 4.00 particles/m3) exhibited significant temporal variations with higher abundance in the wet season, without a consistent trend after the mandatory mask-wearing requirement was announced. The impact of pandemic restrictions on microplastic distribution was found to be relatively minor. However, significant correlations between microplastic abundances and rainfall highlighted the substantial contribution of local emissions through surface runoff. Notably, sites in closer proximity to the Pearl River Delta exhibited higher microplastic abundances, indicating their association with emission sources. The influence of rainfall and adverse weather on marine microplastic loads demonstrated different sensitivities among various locations but can generally last for one month. These results revealed the impact of seasonal rainfall on coastal microplastics and emphasized the need for efforts to reduce microplastic discharge from land-based sources.

The association between olfactory subdomains and frailty: A prospective case‒control study investigation.

BACKGROUND: Amidst the rise of frailty among a globally aging population, olfactory decline has emerged as a harbinger of frailty and mortality in population-level studies. However, the relationships between frailty and the olfactory subdomains of identification (OI), discrimination (OD), and threshold (OT) remain unexplored. This study prospectively examined the association between olfactory subdomains and the physical frailty phenotype (PFP) to investigate olfactory evaluation as a means of frailty screening. METHODS: A case‒control study of 45 frail and 45 non-frail individuals matched by age and sex. OT, OD, OI (range 0‒16), and composite sum (threshold, discrimination, and identification scores [TDI], range 0‒48) were measured with Sniffin' Sticks. PFP was defined by presence of three or more criteria: physical inactivity, self-reported exhaustion, muscle weakness, slow gait, and unintentional weight loss. Conditional logistic regression evaluated associations between olfactory subdomains and frailty. RESULTS: Ninety individuals with mean age of 83.1 ± 4.9 years, 60% female (n = 54), and 87.8% white (n = 79) were included. Olfactory scores were significantly lower in the frail group for OI (9.2 vs. 12.1, p < 0.001), OD (8.1 vs. 11.6, p < 0.001), OT (4.4 vs. 8.5, p < 0.001), and TDI (21.7 vs. 32.2, p < 0.001) than in the non-frail group. A single-point decrease in olfactory score was associated with increased odds of frailty in OT (odds ratio [OR]: 2.21, 95% confidence interval: [1.22, 3.98]), OD (OR: 2.19, 95% CI: [1.32, 3.65]), OI (OR: 2.29, 95% CI: [1.19, 4.39]), and TDI (OR: 1.54, 95% CI: [1.14, 2.08]). CONCLUSION: The robust association between olfactory subdomain scores and frailty suggests that olfaction may be an accessible signifier of frailty. Future studies should investigate this relationship longitudinally to assess predictive relationships.

A Practical Review of Encorafenib and Binimetinib Therapy Management in Patients with BRAF V600E-Mutant Metastatic Non-Small Cell Lung Cancer.

According to current guidelines, targeted therapy with a combination of BRAF plus MEK inhibitors is the preferred first-line treatment for patients with BRAF V600E-mutant metastatic non-small cell lung cancer (NSCLC). In the open-label, single-arm, phase 2 PHAROS trial (NCT03915951), the combination of encorafenib, a potent BRAF inhibitor, and binimetinib, a potent MEK inhibitor, demonstrated durable antitumor activity with a manageable safety profile in this patient population. On the basis of the results of this study, the combination of encorafenib plus binimetinib was approved by the US Food and Drug Administration on October 11, 2023, for patients with BRAF V600E-mutant metastatic NSCLC. In this review, we summarize the efficacy and safety of encorafenib plus binimetinib from the PHAROS study. In addition, we discuss strategies to manage adverse reactions with this combination therapy with the intent of minimizing unnecessary treatment discontinuations in these patients.

Development and evaluation of a text analytics algorithm for automated application of national COVID-19 shielding criteria in rheumatology patients.

INTRODUCTION: At the beginning of the COVID-19 pandemic, the UK's Scientific Committee issued extreme social distancing measures, termed 'shielding', aimed at a subpopulation deemed extremely clinically vulnerable to infection. National guidance for risk stratification was based on patients' age, comorbidities and immunosuppressive therapies, including biologics that are not captured in primary care records. This process required considerable clinician time to manually review outpatient letters. Our aim was to develop and evaluate an automated shielding algorithm by text-mining outpatient letter diagnoses and medications, reducing the need for future manual review. METHODS: Rheumatology outpatient letters from a large UK foundation trust were retrieved. Free-text diagnoses were processed using Intelligent Medical Objects software (Concept Tagger), which used interface terminology for each condition mapped to Systematized Medical Nomenclature for Medicine-Clinical Terminology (SNOMED-CT) codes. We developed the Medication Concept Recognition tool (Named Entity Recognition) to retrieve medications' type, dose, duration and status (active/past) at the time of the letter. Age, diagnosis and medication variables were then combined to calculate a shielding score based on the most recent letter. The algorithm's performance was evaluated using clinical review as the gold standard. The time taken to deploy the developed algorithm on a larger patient subset was measured. RESULTS: In total, 5942 free-text diagnoses were extracted and mapped to SNOMED-CT, with 13 665 free-text medications (n=803 patients). The automated algorithm demonstrated a sensitivity of 80% (95% CI: 75%, 85%) and specificity of 92% (95% CI: 90%, 94%). Positive likelihood ratio was 10 (95% CI: 8, 14), negative likelihood ratio was 0.21 (95% CI: 0.16, 0.28) and F1 score was 0.81. Evaluation of mismatches revealed that the algorithm performed correctly against the gold standard in most cases. The developed algorithm was then deployed on records from an additional 15 865 patients, which took 18 hours for data extraction and 1 hour to deploy. DISCUSSION: An automated algorithm for risk stratification has several advantages including reducing clinician time for manual review to allow more time for direct care, improving efficiency and increasing transparency in individual patient communication. It has the potential to be adapted for future public health initiatives that require prompt automated review of hospital outpatient letters.

Recurrent Stent Thrombosis Following Myocardial Infarction Associated With VITT-Like Antibodies.

Early stent thrombosis is a rare complication of percutaneous intervention and is associated with significant 30-day mortality. We present a novel case of multiple recurrent early stent thrombosis consistent with spontaneous vaccine-induced thrombotic thrombocytopenia. We were successfully able to manage this unusual condition through an interdisciplinary collaboration.

Convergent evolution of BRCA2 reversion mutations under therapeutic pressure by PARP inhibition and platinum chemotherapy.

Reversion mutations that restore wild-type function of the BRCA gene have been described as a key mechanism of resistance to Poly(ADP-ribose) polymerase (PARP) inhibitor therapy in BRCA-associated cancers. Here, we report a case of a patient with metastatic castration-resistant prostate cancer (mCRPC) with a germline BRCA2 mutation who developed acquired resistance to PARP inhibition. Extensive genomic interrogation of cell-free DNA (cfDNA) and tissue at baseline, post-progression, and postmortem revealed ten unique BRCA2 reversion mutations across ten sites. While several of the reversion mutations were private to a specific site, nine out of ten tumors contained at least one mutation, suggesting a powerful clonal selection for reversion mutations in the presence of therapeutic pressure by PARP inhibition. Variable cfDNA shed was seen across tumor sites, emphasizing a potential shortcoming of cfDNA monitoring for PARPi resistance. This report provides a genomic portrait of the temporal and spatial heterogeneity of prostate cancer under the selective pressure of a PARP inhibition and exposes limitations in the current strategies for detection of reversion mutations.

The role of private healthcare sector actors in health service delivery and financing policy processes in low-and middle-income countries: a scoping review.

The expansion of the private healthcare sector in some low-income and middle-income countries (LMICs) has raised key questions and debates regarding the governance of this sector, and the role of actors representing the sector in policy processes. Research on the role played by this sector, understood here as private hospitals, pharmacies and insurance companies, remains underdeveloped in the literature. In this paper, we present the results of a scoping review focused on synthesising scholarship on the role of private healthcare sector actors in health policy processes pertaining to health service delivery and financing in LMICs. We explore the role of organisations or groups-for example, individual companies, corporations or interest groups-representing healthcare sector actors, and use a conceptual framework of institutions, ideas, interests and networks to guide our analysis. The screening process resulted in 15 papers identified for data extraction. We found that the literature in this domain is highly interdisciplinary but nascent, with largely descriptive work and undertheorisation of policy process dynamics. Many studies described institutional mechanisms enabling private sector participation in decision-making in generic terms. Some studies reported competing institutional frameworks for particular policy areas (eg, commerce compared with health in the context of medical tourism). Private healthcare actors showed considerable heterogeneity in their organisation. Papers also referred to a range of strategies used by these actors. Finally, policy outcomes described in the cases were highly context specific and dependent on the interaction between institutions, interests, ideas and networks. Overall, our analysis suggests that the role of private healthcare actors in health policy processes in LMICs, particularly emerging industries such as hospitals, holds key insights that will be crucial to understanding and managing their role in expanding health service access.

How Public Health Organizational Structure Affected the Response to the COVID-19 Pandemic: A Case Study in British Columbia, Canada.

Objectives: This study sought to examine how public health organizational structures affected decision-making and provides recommendations to strengthen future public health crisis preparedness. Methods: The Institutions-Politics-Organizations-Governance (IPOG) framework and an organizational lens was applied to the analysis of COVID-19 governance within British Columbia (BC). Organizational charts detailing the structure of public health systems were compiled using available data and supplemented with data collected through key informant interviews. Results: In response to the COVID-19 pandemic, BC initiated several changes in its public health organization. BC's COVID-19 response attempted to utilize a centralized command structure within a decentralized health system. Four key themes were identified pertaining to the 1) locus of decision-making and action; 2) role of emergency structures; 3) challenges in organizational structure; and 4) balance between authority and participation in decision-making. Conclusion: The organizational adaptations enabled a substantively effective response. However, our findings also illustrate deficiencies in organizational structure in the current public health system. Two recommendations for consideration are: 1) a more formal vertical organizational structure; and 2) developing new mechanisms to link health and general emergency response structures.

Immune Modulation with RANKL Blockade through Denosumab Treatment in Patients with Cancer.

Denosumab is a fully human mAb that binds receptor activator of NFκB ligand (RANKL). It is routinely administered to patients with cancer to reduce the incidence of new bone metastasis. RANK-RANKL interactions regulate bone turnover by controlling osteoclast recruitment, development, and activity. However, these interactions also can regulate immune cells including dendritic cells and medullary thymic epithelial cells. Inhibition of the latter results in reduced thymic negative selection of T cells and could enhance the generation of tumor-specific T cells. We examined whether administering denosumab could modify modulate circulating immune cells in patients with cancer. Blood was collected from 23 patients with prostate cancer and 3 patients with renal cell carcinoma, all of whom had advanced disease and were receiving denosumab, prior to and during denosumab treatment. Using high-dimensional mass cytometry, we found that denosumab treatment by itself induced modest effects on circulating immune cell frequency and activation. We also found minimal changes in the circulating T-cell repertoire and the frequency of new thymic emigrants with denosumab treatment. However, when we stratified patients by whether they were receiving chemotherapy and/or steroids, patients receiving these concomitant treatments showed significantly greater immune modulation, including an increase in the frequency of natural killer cells early and classical monocytes later. We also saw broad induction of CTLA-4 and TIM3 expression in circulating lymphocytes and some monocyte populations. These findings suggest that denosumab treatment by itself has modest immunomodulatory effects, but when combined with conventional cancer treatments, can lead to the induction of immunologic checkpoints. See related Spotlight by Nasrollahi and Davar, p. 383.

Initial Chemotherapy for Locally Advanced and Metastatic NUT Carcinoma.

INTRODUCTION: NUT carcinoma (NC) is an underdiagnosed and aggressive poorly differentiated or squamous cell cancer. A subset of NC is sensitive to chemotherapy, but the optimal regimen is unknown. Experts have recommended platinum- and ifosfamide-based therapy based on case reports. METHODS: Patients with pathologically confirmed NC with known survival outcomes after chemotherapy and consented to participate in a worldwide registry were studied. Results were summarized using descriptive methods. RESULTS: The study included 118 patients with NC. Median age was 34 (range: 1-82) years, 39% were women, and 61% harbored a BRD4::NUTM1 fusion. Patients received platinum (74%) or ifosfamide (26%, including regimens with both, 13%). Of 62 patients with nonmetastatic disease, 40% had a thoracic primary. Compared with platinum-based chemotherapy, patients who received ifosfamide-based chemotherapy had nominally higher progression-free survival (12 mo: 59% [95% CI: 32-87] versus 37% [95% CI: 22-52], hazard ratio = 0.68 [0.32, 1.42], p = 0.3) but not overall survival (OS). Among the 56 patients with metastatic disease, 80% had a thoracic primary. Ifosfamide had an objective response rate (ORR) of 75% (six of eight) and platinum had an ORR of 31% (11 of 36). Nevertheless, there was no difference in progression-free survival or OS. The 3-year OS of the entire cohort was 19% (95% CI: 10%-28%). Of the 11 patients alive greater than 3 years, all presented with nonmetastatic and operable or resectable disease. CONCLUSION: There is a numerically higher ORR for ifosfamide-based therapy compared with platinum-based therapy, with limited durability. OS at 3 years is only 19%, and development of effective therapies is an urgent unmet need for this patient population.

Pan-cancer landscape of epigenetic factor expression predicts tumor outcome.

Oncogenic pathways that drive cancer progression reflect both genetic changes and epigenetic regulation. Here we stratified primary tumors from each of 24 TCGA adult cancer types based on the gene expression patterns of epigenetic factors (epifactors). The tumors for five cancer types (ACC, KIRC, LGG, LIHC, and LUAD) separated into two robust clusters that were better than grade or epithelial-to-mesenchymal transition in predicting clinical outcomes. The majority of epifactors that drove the clustering were also individually prognostic. A pan-cancer machine learning model deploying epifactor expression data for these five cancer types successfully separated the patients into poor and better outcome groups. Single-cell analysis of adult and pediatric tumors revealed that expression patterns associated with poor or worse outcomes were present in individual cells within tumors. Our study provides an epigenetic map of cancer types and lays a foundation for discovering pan-cancer targetable epifactors.

Gene Regulatory Networks in Coronary Artery Disease.

PURPOSE OF REVIEW: Coronary artery disease is a complex disorder and the leading cause of mortality worldwide. As technologies for the generation of high-throughput multiomics data have advanced, gene regulatory network modeling has become an increasingly powerful tool in understanding coronary artery disease. This review summarizes recent and novel gene regulatory network tools for bulk tissue and single cell data, existing databases for network construction, and applications of gene regulatory networks in coronary artery disease. RECENT FINDINGS: New gene regulatory network tools can integrate multiomics data to elucidate complex disease mechanisms at unprecedented cellular and spatial resolutions. At the same time, updates to coronary artery disease expression data in existing databases have enabled researchers to build gene regulatory networks to study novel disease mechanisms. Gene regulatory networks have proven extremely useful in understanding CAD heritability beyond what is explained by GWAS loci and in identifying mechanisms and key driver genes underlying disease onset and progression. Gene regulatory networks can holistically and comprehensively address the complex nature of coronary artery disease. In this review, we discuss key algorithmic approaches to construct gene regulatory networks and highlight state-of-the-art methods that model specific modes of gene regulation. We also explore recent applications of these tools in coronary artery disease patient data repositories to understand disease heritability and shared and distinct disease mechanisms and key driver genes across tissues, between sexes, and between species.

Domiciliary transcutaneous electrical stimulation in patients with obstructive sleep apnoea and limited adherence to continuous positive airway pressure therapy: a single-centre, open-label, randomised, controlled phase III trial.

Background: Hypoglossal nerve stimulation (HNS) for obstructive sleep apnoea (OSA) is a novel way to manage the condition. We hypothesised that in patients with OSA and limited adherence to continuous positive airway pressure (CPAP) therapy, domiciliary transcutaneous electrical stimulation (TESLA) would control sleep apnoea and provide health benefits. Methods: We undertook a single-centre, open-label, randomised, controlled phase III trial in patients with OSA (apnoea-hypopnoea-index [AHI] 5-35 h-1), a BMI of 18.5-32 kg∗m-2, and a documented lack of adherence to CPAP therapy (<4 h∗night-1) at Guy's & St Thomas' NHS Foundation Trust (hospital), UK. Patients were randomly assigned (1:1) using minimisation (gender and OSA severity) to receive TESLA or usual care (CPAP) for at least 3 months; sleep study analysis was provided without knowledge of the assignment arm. The primary outcome was change in AHI at 3-months. The primary outcome and safety were analysed in the intention-to-treat population. Data are reported as median (interquartile range), unless otherwise explained. This trial is registered at ClinicalTrials.gov, NCT03160456. Findings: Between 6 June 2018 and 7 February 2023, 56 participants were enrolled and randomly assigned (29 patients in the intervention group and 27 in the usual care group). Patients were followed up for a median of 3.0 months (IQR 3.0; 10.0). The groups were similar in terms of age (55.8 (48.2; 66.0) vs 59.3 (47.8; 64.4) years), gender (male:female, 19:10 vs 18:9) and BMI (28.7 (26.4; 31.9) vs 28.4 (24.4; 31.9) kg∗m-2). The unadjusted group difference in the ΔAHI was -11.5 (95% CI -20.7; -2.3) h-1 (p = 0.016). Adjusted for the baseline value, the difference was ΔAHI -7.0 (-15.7; 1.8) h-1 (p = 0.12), in favour of the intervention. Minor adverse events were found in one of the participants who developed mild headaches related to the intervention. Interpretation: Domiciliary TESLA can be used safely and effectively in OSA patients with poor adherence to CPAP, with favourable impact on sleepiness and sleep fragmentation. Despite pandemic-related limitations of the amended protocol this trial provides the evidence that TESLA improves clinically meaningful outcomes over the observed follow up period, and the transcutaneous approach is likely to offer an affordable alternative for responders to electrical stimulation in clinical practice. Funding: British Lung Foundation, United Kingdom Clinical Research Collaboration-registered King's Clinical Trials Unit at King's Health Partners.

Screening and treatment of pre-bariatric surgical patients with obesity related sleep disordered breathing.

Background: There is a significant burden of sleep disordered breathing (SDB) in patients living with severe and complex obesity undergoing pre-bariatric surgery assessment. This longitudinal observational study evaluated the burden of obesity hypoventilation syndrome (OHS) in this cohort of patients and the therapeutic compliance of patients commenced on positive airway pressure treatment. Methods: All pre-bariatric surgery patients referred to the sleep clinic for review after an abnormal screening study between 2018 and 2022 were included. We collected data on their sleep study results, anthropometrics, co-morbid medical conditions, clinical observations, spirometry and arterial blood gas (ABG). Patients commenced on therapy were followed-up longitudinally and compliance data collected via remote monitoring. Results: A total of 116 patients were included [age: mean ± standard deviation (SD) 48.8±10.8 years; body mass index (BMI) 49.2±8.5 kg/m2; Epworth Sleepiness Scale (ESS) 8.7±5.1 points]. Fifteen patients (12.9% of cohort) were diagnosed with hypercapnic respiratory failure (pH 7.40±0.02; pO2 11.00±1.04 kPa; pCO2 6.15±0.08 kPa). Compared to eucapnic obstructive sleep apnoea (OSA) patients, they were older (51.1 vs. 48.5 years; P=0.311), had a higher BMI (51.5 vs. 48.9 kg/m2; P=0.266), more likely to be female (66.7% vs. 53.5%; P=0.275) and had a higher ESS score (10.4 vs. 8.5 points; P=0.177). On binomial regression analysis insulin dependent diabetes was the only patient characteristic of significance with prevalence increased in patients with OHS (26.7% vs. 8.9%; P=0.042). Forced vital capacity (FVC) and oxygen saturation (SpO2) cut-offs demonstrated high specificity (96.8%) but low sensitivity (13.3%) to diagnosed hypercapnia. Fifty percent of the patients with hypercapnia required bi-level ventilation. On follow-up 44.9% of patients were compliant with therapy (>4 hours usage/night). Conclusions: In minimally symptomatic patients living with severe and complex obesity who have an abnormal overnight oximetry, over 1 in 10 demonstrated chronic respiratory failure. Clinic spirometry and daytime SpO2 excluded those with hypercapnia. Overall adherence to prescribed therapy is low. Screening, appropriate pre-operative optimisation and peri-operative planning are important in preventing complications in this patient cohort.

Single-Agent Divarasib (GDC-6036) in Solid Tumors with a KRAS G12C Mutation.

BACKGROUND: Divarasib (GDC-6036) is a covalent KRAS G12C inhibitor that was designed to have high potency and selectivity. METHODS: In a phase 1 study, we evaluated divarasib administered orally once daily (at doses ranging from 50 to 400 mg) in patients who had advanced or metastatic solid tumors that harbor a KRAS G12C mutation. The primary objective was an assessment of safety; pharmacokinetics, investigator-evaluated antitumor activity, and biomarkers of response and resistance were also assessed. RESULTS: A total of 137 patients (60 with non-small-cell lung cancer [NSCLC], 55 with colorectal cancer, and 22 with other solid tumors) received divarasib. No dose-limiting toxic effects or treatment-related deaths were reported. Treatment-related adverse events occurred in 127 patients (93%); grade 3 events occurred in 15 patients (11%) and a grade 4 event in 1 patient (1%). Treatment-related adverse events resulted in a dose reduction in 19 patients (14%) and discontinuation of treatment in 4 patients (3%). Among patients with NSCLC, a confirmed response was observed in 53.4% of patients (95% confidence interval [CI], 39.9 to 66.7), and the median progression-free survival was 13.1 months (95% CI, 8.8 to could not be estimated). Among patients with colorectal cancer, a confirmed response was observed in 29.1% of patients (95% CI, 17.6 to 42.9), and the median progression-free survival was 5.6 months (95% CI, 4.1 to 8.2). Responses were also observed in patients with other solid tumors. Serial assessment of circulating tumor DNA showed declines in KRAS G12C variant allele frequency associated with response and identified genomic alterations that may confer resistance to divarasib. CONCLUSIONS: Treatment with divarasib resulted in durable clinical responses across KRAS G12C-positive tumors, with mostly low-grade adverse events. (Funded by Genentech; ClinicalTrials.gov number, NCT04449874.).