Adherence to dietary guidelines and associated factors among rural Australian cancer survivors: a cross-sectional study.

PURPOSE: This study aimed to explore levels of adherence to dietary guidelines, and factors associated with dietary guideline adherence, among rural Australian cancer survivors. METHODS: A cross-sectional study was undertaken. We recruited a convenience sample of adults with cancer who attended the chemotherapy day unit or allied health appointments at a rural hospital in Baw Baw Shire, Victoria, Australia, between August 2017 and December 2021. Dietary guideline adherence was assessed by cross-referencing participants' responses to an adapted version of the Dietary Questionnaire for Epidemiological Studies with dietary recommendations in Australian dietary guidelines. Binary logistic regression was used to assess factors associated with dietary guideline adherence for fruits and whole red meats. RESULTS: There were 107 rural cancer survivors (median age, 67 years). Dietary guideline adherence was highest for alcohol (88%) followed by whole red meats (63%), fruits (56%), processed red meats (24%), cereals/breads/grains (7%), and vegetables (4%). Relative to those aged < 65 years, 65-74-year-olds had 5.7-fold greater odds (adjusted odds ratio (aOR) = 5.74, 95% confidence interval (CI) = 1.91-17.17) of adhering to the dietary guideline for fruits. Relative to those who had completed/ceased treatment, participants who were currently receiving treatment had 78% lower odds (aOR = 0.22, 95% CI = 0.09-0.59) of adhering to the dietary guideline for fruits. CONCLUSION: This study contributes preliminary data on adherence to dietary guidelines and associated factors among rural Australian cancer survivors. Dietary guideline adherence varied across food groups and was mostly low, albeit not markedly worse than Australia's national population for the fruits and vegetables groups. The mostly low adherence in our sample suggests a potential need to increase provision of dietary information, supportive care screening, and, wherever necessary, dietetics referrals, assessments, and interventions among rural cancer survivors. Larger, longitudinal studies of adherence to dietary guidelines and/or tailored, cancer-specific dietary recommendations should be undertaken in future.

Differences in cancer clinical trial activity and trial characteristics at metropolitan and rural trial sites in Victoria, Australia.

OBJECTIVE: Cancer clinical trials (CCTs) provide access to emerging therapies and extra clinical care. We aimed to describe the volume and characteristics of CCTs available across Victoria, Australia, and identify factors associated with rural trial location. METHODS: Quantitative analysis of secondary data from Cancer Council Victoria's Clinical Trials Management Scheme dataset. DESIGN: A cross-sectional study design was used. SETTING: CCTs were available Victoria-wide in 2018. PARTICIPANTS: There were 1669 CCTs and 5909 CCT participants. MAIN OUTCOME MEASURES: Rural CCT location was assessed as a binary variable with categories of 'yes' (modified Monash [MM] categories 2-7) and 'no' (MM category 1). MM categories were determined from postcodes. The highest ('least rural') MM category was used for postcodes with multiple MM categories. RESULTS: Of 1669 CCTs, 168 (10.1%) were conducted in rural areas. Of 5909 CCT participants, 315 (5.3%) participated in rural CCTs. There were 526 CCTs (31.5%) with 1907 (32.3%) newly enrolled participants. Of 1892 newly enrolled participants with postcode data, 488 (25.8%) were rural residents. Of them, 368 (75.4%) participated in metropolitan CCTs. In a multivariable logistic regression analysis for all 1669 CCTs, odds of a rural rather than metropolitan CCT location were significantly (p-value <0.05) lower for early-phase than late-phase trials and non-solid than solid tumour trials but significantly (p-value <0.05) higher for non-industry than industry-sponsored trials. CONCLUSIONS: In Victoria, 10% of CCTs are at rural sites. Most rural-residing CCT participants travel to metropolitan sites, where there are more late-phase, non-solid-tumour and industry-sponsored trials. Approaches to increase the volume and variety of rural CCTs should be considered.

Translation of nonclinical to clinical safety findings for 27 biotherapeutics.

Human adverse drug reactions (ADRs), and in vivo nonclinical adverse and nonadverse findings, were identified in 27 biotherapeutic programs and placed into organ categories to determine translation. The sensitivity of detecting human ADRs was 30.8% with a positive predictive value (PPV) of 53.3% for nonclinical adverse findings; sensitivity increased to 67.3% and PPV fell to 35.0% when including nonadverse findings. Nonclinical findings were associated with a greater likelihood of a human ADR in that organ category, especially for adverse findings [positive likelihood ratio (LR+) >10 (lower 95% confidence interval [CI] of >5)]. The specificity and negative predictive value (NPV) were very high (>85%). A lack of nonclinical findings in an organ category was associated with a lower likelihood of a human ADR in that organ category. About 40-50% of human ADRs and nonclinical adverse findings, and about 30% of nonclinical nonadverse findings, were attributed to pharmacology. Slightly more than half of the human ADRs with a translating nonclinical finding had findings in animals that could be considered very similar. Overall, 38% of nonclinical findings translated to a human ADR at the organ category level. When nonclinical findings did not translate to humans, the cause was usually higher exposures or longer dosing in animals. All programs with human ADRs attributed to immunogenicity also had nonclinical adverse or nonadverse findings related to immunogenicity. Overall, nonclinical adverse and nonadverse findings were useful in predicting human ADRs, especially at an organ category level, and the majority of human ADRs were predicted by nonclinical toxicity studies.

Prevalence and correlates of advance care planning among Australian hospital inpatients.

The prevalence and factors associated with advance care planning (ACP) documents for Australian public hospital inpatients were determined through cross-sectional study of 123 Victorian hospitals between July 2016 and December 2018. Of the 611 786 included patients, 2.9% had an ACP document. Odds increased significantly in those comorbid, unpartnered, regional and >5 admissions, which supports future ACP conversations and document creation.

Physical activity, obesity, and quality of life among rural Australian cancer survivors: a cross-sectional study.

PURPOSE: We aimed to describe physical activity (PA), obesity, and quality of life (QoL) among rural Australian cancer survivors, assess whether total and item-specific QoL are associated with sufficient PA and obesity, and assess whether PA and obesity interact with respect to QoL. METHODS: In a cross-sectional study, convenience sampling was used to recruit adult cancer survivors via a chemotherapy day unit and allied health professionals at a rural hospital in Baw Baw Shire, Australia. Exclusion criteria were acute malnutrition and end-of-life care. PA and QoL were measured using Godin-Shephard and 7-item Functional Assessment of Cancer Therapy (FACT-G7) questionnaires, respectively. Factors associated with total and item-specific QoL were assessed via linear and logistic regression, respectively. RESULTS: Among 103 rural cancer survivors, the median age was 66 years, 35% were sufficiently physically active, and 41% presented with obesity. Mean/median total QoL scores were 17 on the FACT-G7 scale (0-28; higher scores indicate better QoL). Sufficient PA was associated with better QoL ([Formula: see text]=2.29; 95% confidence interval [CI] = 0.26, 4.33) and more energy (odds ratio [OR] = 4.00, 95% CI = 1.48, 10.78) while obesity was associated with worse QoL ([Formula: see text]=-2.09; 95% CI = -4.17, -0.01) and more pain (OR = 3.88, 95% CI = 1.29, 11.68). The PA-obesity interaction was non-significant (p-value = 0.83). CONCLUSIONS: This is the first known study conducted among rural survivors of any cancer to find sufficient PA and obesity are associated with better and worse QoL, respectively. PA, weight management, and QoL-including energy and pain-should be considered when targeting and tailoring supportive care interventions for rural cancer survivors.

The use of recovery animals in nonclinical safety assessment studies with monoclonal antibodies: further 3Rs opportunities remain.

Assessment of reversibility from nonclinical toxicity findings in animals with potential adverse clinical impact is required during pharmaceutical development, but there is flexibility around how and when this is performed and if recovery animals are necessary. For monoclonal antibodies (mAbs) and in accordance with ICH S6(R1) if inclusion of recovery animals is warranted, this need only occur in one study. Data on study designs for first-in-human (FIH)-enabling and later-development toxicity studies were shared from a recent collaboration between the NC3Rs, EPAA, Netherlands Medicines Evaluation Board (MEB) and 14 pharmaceutical companies. This enabled a review of practices on recovery animal use during mAb development and identification of opportunities to reduce research animal use. Recovery animals were included in 68% of FIH-enabling and 69% of later-development studies, often in multiple studies in the same program. Recovery groups were commonly in control plus one test article-dosed group or in all dose groups (45% of studies, each design). Based on the shared data review and conclusions, limiting inclusion of recovery to a single nonclinical toxicology study and species, study design optimisation and use of existing knowledge instead of additional recovery groups provide opportunities to further reduce animal use within mAb development programs.

Re-evaluating the need for chronic toxicity studies with therapeutic monoclonal antibodies, using a weight of evidence approach.

To support registration of monoclonal antibodies (mAbs) for chronic indications, 6-month toxicity studies have historically been conducted. Experience with mAb development has shown a relatively benign and well-understood safety profile for this class, with most toxicity findings anticipated based on pharmacology. We evaluated whether a 6-month toxicity study is necessary to assess the long-term safety of mAbs. Data on First-in-Human (FIH)-enabling and chronic toxicity studies were shared for 142 mAbs submitted by 11 companies. Opportunities to further optimize study designs to reduce animal usage were identified. For 71% of mAbs, no toxicities or no new toxicities were noted in chronic studies compared to FIH-enabling study findings. New toxicities of potential concern for human safety or that changed trial design were identified in 13.5% of cases, with 7% being considered critical and 2% leading to program termination. An iterative, weight-of-evidence model which considers factors that influence the overall risk for a mAb to cause toxicity was developed. This model enables an evidence-based justification, suggesting when 3-month toxicity studies are likely sufficient to support late-stage clinical development and registration for some mAbs.

Novel Methods of Targeting IL-1 Signalling for the Treatment of Breast Cancer Bone Metastasis.

Breast cancer bone metastasis is currently incurable. Evidence suggests that inhibiting IL-1 signalling with the IL1R antagonist, Anakinra, or the IL1ß antibody, Canakinumab, prevents metastasis and almost eliminates breast cancer growth in the bone. However, these drugs increase primary tumour growth. We, therefore, investigated whether targeting other members of the IL-1 pathway (Caspase-1, IL1ß or IRAK1) could reduce bone metastases without increasing tumour growth outside of the bone. Inhibition of IL-1 via MLX01 (IL1ß secretion inhibitor), VRT043198/VX765 (Caspase-1 inhibitor), Pacritinib (IRAK1 inhibitor) or Anakinra (IL1R antagonist) on tumour cell viability, migration and invasion were assessed in mouse mammary E0771 and Py8119 cells in vitro and on primary tumour growth, spontaneous metastasis and metastatic outgrowth in vivo. In vitro, Inhibition of IL-1 signalling by MLX01, VRT043198 and Anakinra reduced migration of E0771 and Py8119 cells and reversed tumour-derived IL1ß induced-increased invasion and migration towards bone cells. In vivo, VX765 and Anakinra significantly reduced spontaneous metastasis and metastatic outgrowth in the bone, whereas MLX01 reduced primary tumour growth and bone metastasis. Pacritinib had no effect on metastasis in vitro or in vivo. Targeting IL-1 signalling with small molecule inhibitors may provide a new therapeutic strategy for breast cancer bone metastasis.

Level and correlates of social support in a community-based sample of Australians who primarily smoke methamphetamine.

Little is known about the level and correlates of social support amongst people who use methamphetamine. We aimed to describe, and determine characteristics associated with, social support amongst a community-recruited cohort of Australians who primarily smoked methamphetamine. A cross-sectional study was conducted with data from the Victorian Methamphetamine Cohort Study (VMAX). Adults (aged ≥18 years) who used methamphetamine were recruited from June 2016 to March 2020 across metropolitan and non-metropolitan areas using convenience, snowball, and respondent-driven sampling. Social support was measured using the seven-item Enhancing Recovery In Coronary Heart Disease (ENRICHD) Social Support Inventory (ESSI). Characteristics independently associated with ESSI quartiles were assessed via multivariable partial proportional odds regression. Overall, 718 participants were included for complete-case analysis. Their mean (standard deviation [SD]) age was 34.7 (9.7) years and 62% were male. The mean (SD) and median (lower quartile-upper quartile) ESSI scores were 22.6 (7.6) and 24 (16-29), respectively, on a scale of 8 to 34 where higher scores denote better self-perceived social support. Characteristics independently associated with lower ESSI included past-year homelessness (adjusted odds ratio [aOR] = 0.49, 95% confidence interval [CI] = 0.36-0.66), moderate/severe depression (aOR = 0.60, 95% CI = 0.42-0.86), increasing age relative to <30 years (aOR[30-39] = 0.61, 95% CI = 0.41-0.91; aOR[≥40] = 0.56, 95% CI = 0.35-0.91) and greater than fortnightly methamphetamine use (aOR = 0.69, 95% CI = 0.52-0.91). Characteristics independently associated with higher ESSI were employment (aOR = 1.51, 95% CI = 1.06-2.14) and female gender (aOR = 1.39, 95% CI = 1.00-1.92). Social support services for people who use methamphetamine could be targeted and tailored to subgroups defined by correlates of social support, such as those who experience homelessness, depression or unemployment.

Implementing Optimal Care Pathways for Aboriginal and Torres Strait Islander People With Cancer: A Survey of Rural Health Professionals' Self-Rated Learning Needs.

Objective: In 2018, the Optimal Care Pathway (OCP) for Aboriginal and Torres Strait Islander people with cancer was developed in Australia to improve the cancer care experiences and outcomes of Aboriginal and Torres Strait Islander people. Methods: Our study examined health professionals' learning needs to meet the clinical practice requirements of the new OCP. An electronic questionnaire was distributed to 120 health professionals providing oncology care in two rural areas in Victoria, Australia. Questions included demographics, practice, cancer OCPs and implementation recommendations. Descriptive, chi-square and thematic analyses were undertaken. Results: Fifty-two health professionals from medicine (21%), nursing (37%) and allied health (37%) responded. All OCP sub-categories were selected, with a mean of 23 sub-categories identified as areas requiring additional learning. Aboriginal and Torres Strait Islander Perspectives, Treatment, and End of Life were the categories of higher interest. Care After Initial Treatment and Recovery was the category of lower interest. For respondents without cultural training, sub-categories involving practical tasks were of significant interest. Cultural education, connecting with Aboriginal and Torres Strait Islander services, putting learning into practice and respect emerged as themes. Conclusion: Strategies to address gaps included cultural safety training, person and family centred practice, and partnerships and connections with Aboriginal and Torres Strait Islander people and organisations across primary and tertiary sectors.

Long term survival following a medical emergency team call at an Australian regional hospital.

Objective: To investigate the long term survival of medical emergency team (MET) patients at an Australian regional hospital and describe associated patient and MET call characteristics. Design: Retrospective cohort study. Data linkage to the statewide death registry was performed to allow for long term survival analysis, including multivariable Cox proportional hazards regression and production of Kaplan-Meier survival curves. Setting: A large Australian regional hospital. Participants: Adult patients who received a MET call from 1 July 2012 to 3 March 2020. Main outcome measures: Survival to 30, 90 and 180 days; one year; and 5-years after index MET call. Results: The study included 6499 eligible patients. The cohort median age was 71 years, and 52.4% of the patients were female. Surgical (39.6%) and medical (36.9%) patients comprised most of the cohort. Thirty-day survival was 86.5% one-year survival was 66.1%. Among patients aged < 75 years, factors independently associated with significantly higher long term mortality included age (hazard ratio [HR], 3.26 [95% CI, 2.63-4.06]; for patients aged 65-74 v 18-54 years), male sex (HR, 0.71 [95% CI, 0.61-0.83]; for females) and pre-existing limitation of medical therapy (HR, 2.76; 95% CI, 2.28-3.35). Among patients aged ≥ 75 years, factors independently associated with significantly higher long term mortality included age (HR, 1.46 [95% CI, 1.29-1.65]; for patients aged ≥ 85 years), male sex (HR, 0.74 [95% CI, 0.66-0.83]; for females), and altered MET criteria (HR, 1.33; 95% CI, 1.03-1.71). Conclusions: Long term survival probabilities of MET call patients are affected by factors including age, sex, and limitation of medical therapy status. These data may be useful for clinicians conducting end-of-life discussions with patients.

Functional outcomes following an in-hospital cardiac arrest: A retrospective cohort study.

BACKGROUND/PURPOSE: Whilst much is known about the survival outcomes of patients that suffer an in-hospital cardiac arrest (IHCA) in Australia very little is known about the functional outcomes of survivors. This study aimed to describe the functional outcomes of a cohort of patients that suffered an in-hospital cardiac arrest (IHCA) and survived to hospital discharge in a regional Australian hospital. METHODS: This is a single-centre retrospective observational cohort study conducted in a regional Australian hospital. All adult patients that had an IHCA in the study hospital between 1 Jan 2017 and 31 Dec 2019 and survived to hospital discharge were included in the study. Functional outcomes were reported using the Modified Rankin Scale (mRS), a six-point scale for which increasing scores represent increasing disability. Scores were assigned through a retrospective review of medical notes. RESULTS: Overall, 102 adult patients had an IHCA during the study period, of whom 50 survived to hospital discharge. The median age of survivors was 68 years, and a third had a shockable initial arrest rhythm. Of survivors, 47 were able to be assigned both mRS scores. At discharge, 81% of patients achieved a favourable functional outcome (mRS 0-3 or equivalent function at discharge equal to admission). CONCLUSIONS: Most survivors to hospital discharge following an IHCA have a favourable functional outcome and are discharged home. Although these results are promising, larger studies across multiple hospitals are required to further inform what is known about functional outcomes in Australian IHCA survivors.

Rural community-based nurses' self-reported knowledge and skills in the provision of psychosocial care to palliative and end-of-life clients and carers.

OBJECTIVE: This study examined rural community-based nurses' self-reported knowledge and skills in the provision of psychosocial care to rural residing palliative and end-of-life clients and carers. We further sought to determine correlates of knowledge gaps to inform workforce education and planning. METHOD: Nurses from a rural area of Victoria, Australia, were invited to complete an electronic questionnaire rating their knowledge against 6 national palliative care standards and 10 screening and assessment tools. A 5-point scale of (1) No experience to (5) Can teach others was used to rate knowledge. Results were classified into three categories: practice gaps, areas of consolidation, and strengths. Descriptive and logistical regression was used to analyze data. RESULTS: A total of 122 of 165 nurses (response rate = 74%) completed the survey. Of these nurses, 87% were Registered Nurses, 43% had ≥10 years' experience in palliative care, and 40% had palliative care training. The majority of practices across the standards and screening and assessment tools were rated as knowledge strengths (N = 55/67, 82%). Gaps and areas of consolidation were in the use of client and carer assessment tools, the care of specific populations such as children, supporting carers with appropriate referrals, resources, and grief, and facilitating the processes of reporting a death to the coroner. Lack of formal training and lower years of experience were found to be associated with practice gaps. SIGNIFICANCE OF RESULTS: Our study found rural nurses were confident in their knowledge and skills in the majority of psychosocial care. As generalist nurses make up the majority of the rural nursing workforce, further research should be undertaken on what educational strategies are needed to support and upskill rural community-based nurses to undertake formal training in palliative care.

Quantitative microcapillary electrophoresis immunoassay (mCE IA) for end-to-end analysis of pertactin within in-process samples and Quadracel® vaccine.

Protein concentration is an important attribute in the production of subunit or component-based vaccine antigens. Rigorous monitoring of protein concentration is required to identify potential areas for yield improvement. The current GMP method for quantitation is the plate-based ELISA which requires numerous hands-on steps and has low sensitivity in comparison to new microfluidic systems. To address this issue, a sensitive automated microCapillary Electrophoresis ImmunoAssay (mCE IA) method was developed to accurately separate and quantitate pertactin (PRN), an important antigen of the modern acellular Pertussis (aP) vaccine. PRN is reported to be a low-yielding antigen; thus, it is critical to observe its concentration throughout its manufacturing process. First, a primary antibody for PRN was identified to establish suitable immunoprobing conditions for detection of PRN over a wide linear dynamic range that spans 3 orders of magnitude. Next, the pre-adsorbed PRN Drug Substance (DS) was used as a reference standard to quantitate PRN samples against a calibration curve with adequate accuracy and precision. Four representative samples including three in-process steps and final adjuvanted drug product: Quadracel®, were examined to demonstrate the capability of mCE IA to quantitate PRN with high sensitivity and specificity. The matrices of the selected samples contain additional components (e.g. other proteins, growth factors, cell culture media, residual ammonium sulfate, and aluminum adjuvant) often making the quantitation of PRN challenging. The specificity and method linearity were demonstrated by spiking pre-adsorbed PRN DS into the four representative samples. In addition, it was shown that reportable concentrations of PRN for nine downstream process steps as analyzed by our method is comparable to concentrations obtained with ELISA. Most importantly, this study demonstrated that our method's quantitative accuracy is independent of matrix components, as each sample undergoes extensive dilution. This allows for seamless end-to-end analysis of PRN from fermenter harvest, through to complex downstream process samples to adjuvanted drug products. Finally, for the first time the developed and qualified mCE IA method was shown to quantify PRN throughout the entire manufacturing process to provide rapid feedback for process optimizations allowing for accurate yield and step-loss calculations.

Block of TREK and TRESK K2P channels by lamotrigine and two derivatives sipatrigine and CEN-092.

TREK and TRESK K2P channels are widely expressed in the nervous system, particularly in sensory neurons, where they regulate neuronal excitability. In this study, using whole-cell patch-clamp electrophysiology, we characterise the inhibitory effect of the anticonvulsant lamotrigine and two derivatives, sipatrigine and 3,5-diamino-6-(3,5-bistrifluoromethylphenyl)-1,2,4-triazine (CEN-092) on these channels. Sipatrigine was found to be a more effective inhibitor than lamotrigine of TREK-1, TREK-2 and TRESK channels. Sipatrigine was slightly more potent on TREK-1 channels (EC50 = 16 µM) than TRESK (EC50 = 34 µM) whereas lamotrigine was equally effective on TREK-1 and TRESK. Sipatrigine was less effective on a short isoform of TREK-2, suggesting the N terminus of the channel is important for both inhibition and subsequent over-recovery. Inhibition of TREK-1 and TREK-2 channels by sipatrigine was reduced by mutation of a leucine residue associated with the norfluoxetine binding site on these channels (L289A and L320A on TREK-1 and TREK-2, respectively) but these did not affect inhibition by lamotrigine. Inhibition of TRESK by sipatrigine and lamotrigine was attenuated by mutation of bulky phenylalanine residues (F145A and F352A) in the inner pore helix. However, phosphorylation mutations did not alter the effect of sipatrigine. CEN-092 was a more effective inhibitor of TRESK channels than TREK-1 channels. It is concluded that lamotrigine, sipatrigine and CEN-092 are all inhibitors of TREK and TRESK channels but do not greatly discriminate between them. The actions of these compounds may contribute to their current and potential use in the treatment of pain and depression.

Factors Associated With Quality of Life Among People Living With a Stoma in Nonmetropolitan Areas.

BACKGROUND: Interruption of gastrointestinal continuity through surgical formation of a stoma can be lifesaving. However, it is also typically associated with reduced quality of life (QoL). Although past research has investigated QoL among people living with a stoma, no known studies have investigated stoma-related QoL, specifically among nonmetropolitan residents who may experience distinct health issues compared with their metropolitan counterparts. OBJECTIVES: The aim of the study was to investigate the level of and factors associated with QoL among people living with a stoma in nonmetropolitan Australia. METHODS: In a cross-sectional survey, 678 adults with colostomy, ileostomy, and/or urostomy and with membership in a regional Victorian stoma association were given the City of Hope Quality of Life Questionnaire for a Patient With an Ostomy (QOL-O). Total QoL score was calculated and described before categorization into quintiles. Patient factors associated with quintiles of QoL were assessed using univariable and multivariable proportional odds ordinal logistic regression, with a 95% confidence interval excluding 1.00 denoting statistical significance. RESULTS: Overall, 311 regional ostomy association members (46%) responded to any QOL-O questions; 285 members responded to >80% of QOL-O questions and contributed data to the study. Their median age was 73 years, and 60% were male. The median total QoL score was 6.9 on a scale of 0-10, where a higher number indicates better QoL. Factors independently associated with better QoL in the multivariable model were working full/part time, no poststoma clothing change, poststoma sexual activity, and older age. Factors independently associated with worse QoL were poststoma depression and a stoma location issue. DISCUSSION: People living with a stoma in nonmetropolitan Australia reported moderate-to-high QoL. Better QoL was identified in those who worked, had no poststoma clothing change, were sexually active poststoma, and were older. Worse QoL was seen in those who had poststoma depression and stoma location issues. Healthcare providers could influence stoma-related QoL by identifying risk factors and tailoring interventions toward individuals in nonmetropolitan settings.

A data visualisation method for assessing exposure misclassification in case-crossover studies: the example of tricyclic antidepressants and the risk of hip fracture in older people.

BACKGROUND: The case-crossover design is suited to medication safety studies but is vulnerable to exposure misclassification. Using the example of tricyclic antidepressants and the risk of hip fracture, we present a data visualisation tool for observing exposure misclassification in case-crossover studies. METHODS: A case-crossover study was conducted using Australian Government Department of Veterans' Affairs claims data. Beneficiaries aged over 65 years who were hospitalised for hip fracture between 2009 and 2012 were included. The case window was defined as 1-50 days pre fracture. Control window one and control window two were defined as 101-150 and 151-200 days pre fracture, respectively. Patients were stratified by whether exposure status changed when control window two was specified instead of control window one. To visualise potential misclassification, each subject's tricyclic antidepressant dispensings were plotted over the 200 days pre fracture. RESULTS: The study population comprised 8828 patients with a median age of 88 years. Of these subjects, 348 contributed data to the analyses with either control window. The data visualisation suggested that 14% of subjects were potentially misclassified with control window one while 45% were misclassified with control window two. The odds ratio for the association between tricyclic antidepressants and hip fracture was 1.18 (95% confidence interval = 0.91-1.52) using control window one, whereas risk was significantly increased (odds ratio = 1.43, 95% confidence interval = 1.11-1.83) using control window two. CONCLUSIONS: Exposure misclassification was less likely to be present with control window one than with an earlier control window, control window two. When specifying different control windows in a case-crossover study, data visualisation can help to assess the extent to which exposure misclassification may contribute to variable results.

Oesophageal cancer treatment patterns, timeliness of care and outcomes in the Loddon Mallee region of Victoria: A retrospective cohort study.

INTRODUCTION: Few studies have investigated oesophageal cancer care in regional areas. This study aimed to describe treatment patterns for oesophageal cancer in a regional area, and to identify factors associated with radiotherapy utilisation, timeliness of care, and death. METHODS: In a retrospective cohort study, medical records were reviewed to source data on all patients diagnosed with and/or treated for oesophageal cancer at two regional Victorian hospitals over July 2015-June 2018. Cox proportional hazards regression was employed to identify factors associated with time from diagnosis to death while binary logistic regression was used to identify factors associated with radiotherapy utilisation and treatment within 28 days of diagnosis - a time frame derived from the relevant optimal care pathway. RESULTS: Of 95 patients, 72% had radiotherapy, 32% received any treatment within 28 days, and 78% died over a median time of nine months. Odds of not receiving radiotherapy were decreased (odds ratio [OR] = 0.26, 95% confidence interval [CI] = 0.08-0.87) for histology other than adenocarcinoma. Odds of timely care were increased for any palliative radiotherapy (OR = 3.47, 95% CI = 1.15-10.5) and decreased for older age (OR = 0.95, 95% CI = 0.91.0.999). Hazard of death was elevated for stage IV disease (hazard ratio [HR] = 2.73, 95% CI = 1.64-4.54) and reduced for radical intent (HR = 0.27, 95% CI = 0.15-0.48). CONCLUSION: Nearly three-quarters of regional oesophageal cancer patients had radiotherapy while approximately one-third received any treatment within the recommended 28 days. Any palliative radiotherapy and younger age were associated with timely treatment. Future studies could further investigate factors related to timely oesophageal cancer care.

Classic and evolving approaches to evaluating cross reactivity of mAb and mAb-like molecules - A survey of industry 2008-2019.

Monoclonal antibodies (mAbs) and mAb derivatives have become mainstay pharmaceutical modalites. A critical assessment is to ascertain the specificity of these molecules prior to human clinical trials. The primary technique for determining specificity has been the immunohistochemistry (IHC)-based "Tissue Cross-Reactivity" (TCR) assay, where the candidate molecule is applied to > 30 tissues to look for unexpected staining. In the last few years, however, non-IHC array-based platforms have emerged that allow for screening 75-80% of the human membrane proteome, indicating a viable alternative and/or addition to the IHC methods. The preclinical sciences subcommittee of the Biotechnology Innovation Organization (BIO), "BioSafe", conducted a survey of 26 BIO member companies to understand current sponsor experience with the IHC and array techniques. In the last ten years, respondents noted they have conducted more than 650 IHC TCR assays, largely on full length mAbs, with varying impacts on programs. Protein/cell arrays have been utilized by almost half of the companies and sponsors are gaining familiarity and comfort with the platform. Initial experience with recent versions of these arrays has been largely positive. While most sponsors are not prepared to eliminate the IHC TCR assay, growing experience with these alternatives allows them to confidently choose other approaches with or without TCR assays.

Strategies and Recommendations for Using a Data-Driven and Risk-Based Approach in the Selection of First-in-Human Starting Dose: An International Consortium for Innovation and Quality in Pharmaceutical Development (IQ) Assessment.

Various approaches to first-in-human (FIH) starting dose selection for new molecular entities (NMEs) are designed to minimize risk to trial subjects. One approach uses the minimum anticipated biological effect level (MABEL), which is a conservative method intended to maximize subject safety and designed primarily for NMEs having high perceived safety risks. However, there is concern that the MABEL approach is being inappropriately used for lower risk molecules with negative impacts on drug development and time to patient access. In addition, ambiguity exists in how MABEL is defined and the methods used to determine it. The International Consortium for Innovation and Quality in Pharmaceutical Development convened a working group to understand current use of MABEL and its impact on FIH starting dose selection, and to make recommendations for FIH dose selection going forward. An industry-wide survey suggested the achieved or estimated maximum tolerated dose, efficacious dose, or recommended phase II dose was > 100-fold higher than the MABEL-based starting dose for approximately one third of NMEs, including trials in patients. A decision tree and key risk factor table were developed to provide a consistent, data driven-based, and risk-based approach for selecting FIH starting doses.