Insomnia is a prevalent sleep disorder that negatively affects quality of life. Multicomponent cognitive-behavioural therapy (CBT) is the recommended treatment but access remains limited, particularly in primary care. Sleep restriction therapy (SRT) is one of the principal active components of CBT and could be delivered by generalist staff in primary care. The aim of this randomised controlled trial is to establish whether nurse-delivered SRT for insomnia disorder is clinically and cost-effective compared with sleep hygiene advice.
Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is a cell-surface, oncofetal protein whose expression is correlated with oncogenic properties such as enhanced proliferation, survival, and chemoresistance. Despite its prevalence across many cancer indications, ROR1 has restricted expression in adult tissues, making it an ideal target for targeted therapies.
Methods
We have designed a novel ROR1-targeted ADC, STRO-003, which is composed of an anti-ROR1 human IgG1 antibody (SP11285) conjugated to an exatecan warhead via a stable, β-glucuronide linker (SC3417) with a drug-to-antibody ratio (DAR) of 8. SP11285 was discovered using Fab ribosome display as a selective and high affinity ROR1 antibody that exhibits favorable internalization activity upon cell binding, consistent with an ADC mechanism of action. The exatecan payload is a potent topoisomerase I inhibitor of the camptothecin class and has anti-proliferative activity against a variety of cancer cell lines in vitro. The SC3417 linker-payload releases exatecan upon glucuronidase linker cleavage and is site-specifically conjugated using strain promoted alkyne-azide cycloaddition (SPAAC) to form a stable, homogeneous ADC.
Results
The anti-Ror1 antibody SP11285 binds with high affinity to the ROR1 immunoglobulin domain and is cross-reactive to both rodent and monkey ROR1. Unlike other camptothecin analogs, exatecan is resistant to overexpression of Pgp, and therefore has reduced risk of multi-drug resistance. Exatecan also induces immunogenic cell death, thereby providing an avenue for engaging the immune system and enriching the anti-tumor response. STRO-003 has exhibited potent and specific activity in xenograft models for TNBC and lung cancer, and importantly, elicited significant anti-tumor suppression in a panel of NSCLC PDx models, including those with low ROR1 expression. In nonclinical safety studies conducted in cynomolgus monkeys, STRO-003 was tolerated up to 45 mg/kg without signs of hematological toxicity or tissue-specific lesions. By comparison, a similar exatecan-ADC with a cathepsin-sensitive linker was more poorly tolerated and elicited signs of inflammation in the lung.
Conclusions
Our data suggests that STRO-003 is a promising clinical candidate for solid tumor indications and we have initiated IND-enabling studies.
Ethics Approval
All in vivo procedures were conducted in compliance with the guidelines of the Institutional Animal Care and Use Committee (IACUC) at Sutro Biopharma or commissioned contract research organization (CRO).
Abstract Objective Olfactory groove meningiomas (OGM) commonly present with olfactory deficits and compression of the frontal lobes. Given the relationship to dietary behaviors, our objective was to evaluate the relationship between OGMs and postoperative weight loss. Methods Retrospective review of primary resection of meningiomas between 2017 and 2023 at a single institution was conducted. Neurofibromatosis type 2, pregnancy, weight loss medications, or surgeries were excluded. Data collection included preoperative body mass index (preBMI) and postoperative BMI (poBMI) at 3 to 6 and 12 months. Percent BMI change (pcBMI) was calculated by (poBMI − preBMI/preBMI × 100%). IBM SPSS Statistics (Version 27) was used for descriptive statistics and stepwise multiple linear regression. Results Ninety-eight patients met inclusion with a mean age of 57.58 years. Three groups were stratified by location: OGM (n = 15), anterior cranial fossa excluding OGM (ACF; n = 24), and other (OTH; n = 59). Olfactory dysfunction was present in 53.8% of the OGMs. OGM presented with significantly larger lesions (57.25 ± 55.98 mm3) and a higher preBMI (34.58 ± 7.41 kg/m2) than ACF and OTH. A greater pcBMI was seen in OGM at both timepoints (−7.74%, −8.73%). OGM location, tumor volume, and preBMI were found significant on univariate analysis (p < 0.05) and included in multiple linear regression. All regression models were significant (p = 0.001). Location significantly added to the prediction at 3 to 6 and 12 months as well as preBMI at 12 months. In a subanalysis of ACF and OGM, OGM location was significantly associated with negative pcBMI at 3 to 6 and 12 months. Conclusion OGMs are associated with higher preoperative weight and greater weight loss postoperatively compared with other locations.
This study explores Bangladesh's mental health services from an individual- and system-level perspective and provides insights and recommendations for strengthening it's mental health system. We conducted 13 in-depth interviews and 2 focus group discussions. Thirty-one participants were recruited using a combination of purposive and snowball sampling methods. All interviews and group discussions were audio-recorded and transcribed, and key findings were translated from Bengali to English. Data were coded manually and analysed using a thematic and narrative analysis approach. Stakeholders perceived scarcity of service availability at the peripheral level, shortage of professionals, weak referral systems, lack of policy implementation and regulatory mechanisms were significant challenges to the mental health system in Bangladesh. At the population level, low levels of mental health literacy, high societal stigma, and treatment costs were barriers to accessing mental healthcare. Key recommendations included increasing the number of mental health workers and capacity building, strengthening regulatory mechanisms to enhance the quality of care within the health systems, and raising awareness about mental health. Introducing measures that relate to tackling stigma, mental health literacy as well as building the capacity of the health workforce and governance systems will help ensure universal mental health coverage.
Teaching in schools for over 20 years in rural, remote and major centres has provided Stephanie with skills and experiences that she has used in recent consultancy work. During the last eight years, she spent five years as a curriculum consultant. During this time she built relationships with key players to support agencies of change in schools in the Kimberley region of Western Australia. Key focus areas were Literacy and Numeracy and community engagement to improve outcomes for Indigenous students.
In 2010 Largent, Wendler, and Emanuel proposed the "consent substitute model" for emergency research with incapacitated participants. The model provides a means to enroll participants in emergency research without consent, if five conditions are met: 1) the research addresses the patients' urgent medical needs, 2) the risk-benefit ratio is favorable, 3) there are no known conflicts with patients' values or interests, 4) cumulative net risk is minimal, and 5) consent is given as soon as possible. We review national and international ethics laws, regulations, and guidelines to determine 1) whether they accord with the consent substitute model's five conditions and 2) the level of congruence across these documents. We find that only one document meets all five conditions and that there is significant disparity among the documents, particularly between national and international ones. These differences may have stymied international collaboration in emergency research. We recommend that the two international documents used most, the International Council for Harmonization's Guideline for Good Clinical Practice and the World Medical Association's Declaration of Helsinki, are revised to include more specific provisions on emergency medical research.
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