Artificial intelligence for predictive biomarker discovery in immuno-oncology: a systematic review.

BACKGROUND: The widespread use of immune checkpoint inhibitors (ICIs) has revolutionised treatment of multiple cancer types. However, selecting patients who may benefit from ICI remains challenging. Artificial intelligence (AI) approaches allow exploitation of high-dimension oncological data in research and development of precision immuno-oncology. MATERIALS AND METHODS: We conducted a systematic literature review of peer-reviewed original articles studying the ICI efficacy prediction in cancer patients across five data modalities: genomics (including genomics, transcriptomics, and epigenomics), radiomics, digital pathology (pathomics), and real-world and multimodality data. RESULTS: A total of 90 studies were included in this systematic review, with 80% published in 2021-2022. Among them, 37 studies included genomic, 20 radiomic, 8 pathomic, 20 real-world, and 5 multimodal data. Standard machine learning (ML) methods were used in 72% of studies, deep learning (DL) methods in 22%, and both in 6%. The most frequently studied cancer type was non-small-cell lung cancer (36%), followed by melanoma (16%), while 25% included pan-cancer studies. No prospective study design incorporated AI-based methodologies from the outset; rather, all implemented AI as a post hoc analysis. Novel biomarkers for ICI in radiomics and pathomics were identified using AI approaches, and molecular biomarkers have expanded past genomics into transcriptomics and epigenomics. Finally, complex algorithms and new types of AI-based markers, such as meta-biomarkers, are emerging by integrating multimodal/multi-omics data. CONCLUSION: AI-based methods have expanded the horizon for biomarker discovery, demonstrating the power of integrating multimodal data from existing datasets to discover new meta-biomarkers. While most of the included studies showed promise for AI-based prediction of benefit from immunotherapy, none provided high-level evidence for immediate practice change. A priori planned prospective trial designs are needed to cover all lifecycle steps of these software biomarkers, from development and validation to integration into clinical practice.

Impact of Exercise and Cognitive Stimulation Therapy on Physical Function, Cognition and Muscle Mass in Pre-Frail Older Adults in the Primary Care Setting: A Cluster Randomized Controlled Trial.

OBJECTIVES: Multicomponent exercise program have shown to improve function and cognition in older adults but studies on pre-frail older adults in the primary care setting are limited. This study aimed i) to evaluate impact of 6 months exercise (Ex) versus complementary effect of 3 months of cognitive stimulation therapy (CST) to 6 months of Ex (Ex+CST) on physical function, muscle mass and cognition versus control group at 3, 6 and 12 months ii) inflammatory biomarkers such as Interleukin-6 (IL-6) and Tumor Necrosis Factor Alpha (TNF-α). DESIGN: Cluster randomised control trial. SETTING AND INTERVENTION: Pre-frail older adults ≥ 65 years attending primary care clinic. Two intervention groups i) Ex 6 months ii) CST 3 months with Ex 6 months. MEASUREMENTS: At 0, 3, 6 and 12 months, questionnaires (on demographics, physical function, cognition, and depression) were administered and physical function assessment (gait speed, short physical performance battery (SPPB) test, handgrip strength, five times sit-to-stand (5x-STS)) was conducted. Muscle mass and its surrogates such as phase angle and body cell mass were measured using bioelectrical impedance analysis machine. Inflammatory biomarkers were measured at 0 and 3 months. RESULTS: Data from 190 participants was analysed at 3 months (111 control, 37 Ex and 41 Ex+CST). At 3 months, significant improvement in cognition was seen only in the Ex+CST group whereas improvements in depression, gait speed, SPPB and 5x-STS were seen in both the Ex and Ex+CST groups. At 6 months, the Ex+CST group improved in cognition and depression whereas improvement in frailty and muscle mass indices were seen in both the interventions groups. At 12 months, both the interventions groups had better perceived health, gait speed and less decline in muscle mass compared with control groups. Both the Ex and Ex+CST had significant association with TNF-α at 3 months (ß -2.71 (95% CI -4.80 - -0.62); p = 0.012 and ß -1.74 (95% CI -3.43 - -0.06); p = 0.043 respectively). CONCLUSION: Combined Ex+CST had significant improvement in cognition whereas the intervention groups improved in depression, physical function, muscle mass, frailty, perceived health and TNF-α levels. With growing evidence of the benefits of multicomponent interventions at primary care level, incorporating it into mainstream care with action plans on long-term sustainability and scalability should be a priority for every country.

TCR sequencing: applications in immuno-oncology research.

•T-cell receptor (TCR) interaction with major histocompatibility complex-antigen complexes leads to antitumour responses.•TCR sequencing analysis allows characterisation of T cells that recognise tumour neoantigens.•T-cell clonal revival and clonal replacement potentially underpin immunotherapy responses.

Association of Pain and Impact of Dual-Task Exercise on Function, Cognition and Quality of Life.

PURPOSE: This study aimed to assess the factors associated with pain and evaluate the impact of dual-task exercise on pain improvement, quality of life (QOL), cognition and function in older adults. PATIENTS AND METHODS: This study is a secondary data analysis of the HAPPY (Healthy Ageing Promotion Program for You) study. At risk older adults ≥ 60 years old were enrolled in a community dual-task exercise program. Assessments for frailty, sarcopenia, falls, quality of life (QOL) and perceived health, depression, cognition and physical function were performed at baseline and 3 months. Pain intensity was derived from EQ-5D and stratified into no pain, slight pain and moderate to extreme pain. RESULTS: Out of 296 participants, 37.2% had slight pain and 11.1% had moderate to severe pain. Both slight and moderate to extreme pain compared with no pain group were significantly associated with lower perceived health (68.2,63.6 vs 76.0) and QOL index (0.70,0.59 vs 0.93); moderate to extreme pain was also significantly associated with depression, low mental vitality, frailty, sarcopenia and poorer physical performance. After 3 months of dual-task exercise, pain improved in 70.8% of the moderate to extreme pain group and 50.8% of slight pain group. Significant improvement in perceived health, QOL, physical function and cognition were also observed. CONCLUSION: Proactive efforts are required to screen for pain and manage frailty, sarcopenia and depression. Dual-task exercise proved safe and possibly effective in reducing pain and improving QOL, physical and cognitive function in older adults. Prospective randomized studies are needed to validate the effectiveness of dual-task vs single-task exercise, including impact of reversal of frailty and sarcopenia in pain management.

Community characteristics modify the relationship between obesity prevention efforts and dietary intake in children: the Healthy Communities Study.

BACKGROUND: The influence of community characteristics on the effectiveness of childhood obesity prevention efforts is not well understood. OBJECTIVE: Examine the interaction of community characteristics with the relationship between community programmes and policies (CPPs) and dietary intake. METHODS: An observational study of 5138 children in grades K-8 in 130 US communities was conducted in 2013-2015. Key informant interviews identified and characterized CPPs. CPP scores were generated for the number of target behaviours (CPP-Behav) and the number of behaviour change strategies (CPP-Strat) addressed by all CPPs and CPPs with nutrition goals over the prior 6 years in each community. Dietary intake was assessed by dietary screener and included intake of sugar from sugar-sweetened beverages; energy-dense foods; fruits and vegetables; whole grains; and fibre. Multivariate statistical models assessed the interactions between US region, urbanicity, community-level income, and community-level race/ethnicity and CPP scores in relation to dietary intake. RESULTS: CPP-Strat was positively associated with healthier dietary intakes in the Northeast and West, and in high Hispanic communities; the reverse was true in the South, and in high African-American and low-income communities. The CPP-Behav was positively associated with healthier dietary intakes in the South and rural areas, and the reverse was true in the West. CONCLUSION: The relationships between CPP index scores and dietary intake were most strongly influenced by region and urbanicity and to a lesser extent by community-level race/ethnicity and income. Findings suggest that different considerations may be needed for childhood obesity prevention efforts in communities with different characteristics.

Associations of community programs and policies with children's dietary intakes: the Healthy Communities Study.

BACKGROUND: The impact of community-based obesity prevention efforts on child nutrition has not been adequately studied. OBJECTIVE: Examine relationships between number, type and intensity of community programs and policies (CPPs) and child nutrition. METHODS: An observational study of 5138 children (grades K-8) in 130 U.S. communities was conducted in 2013-2015. CPPs were identified by 10-14 key informant interviews per community. CPPs were characterized based on: count, intensity, number of different strategies used and number of different behaviours targeted. Scores for the prior 6 years were calculated separately for CPPs that addressed primarily nutrition, primarily physical activity (PA) or total combined. Child intakes were calculated from a dietary screener and dietary behaviours were based on survey responses. Multi-level statistical models assessed associations between CPP indices and nutrition measures, adjusting for child and community-level covariates. RESULTS: Implementing more types of strategies across all CPPs was related to lower intakes of total added sugar (when CPPs addressed primarily PA), sugar-sweetened beverages (for nutrition and PA CPPs) and energy-dense foods of minimal nutritional value (for total CPPs). Addressing more behaviours was related to higher intakes of fruit and vegetables (for nutrition and total CPPs) and fibre (total CPPs). Higher count and intensity (PA and total CPPs) were related to more consumption of lower fat compared with higher fat milk. A higher count (PA CPPs) was related to fewer energy-dense foods and whole grains. No other relationships were significant at P < 0.05. CONCLUSION: Multiple characteristics of CPPs to prevent obesity appear important to improve children's diets.

Objectives of community policies and programs associated with more healthful dietary intakes among children: findings from the Healthy Communities Study.

BACKGROUND: Rational planning of community policies and programs (CPPs) to prevent obesity requires an understanding of CPP objectives associated with dietary behaviours. OBJECTIVE: The objective of the study is to identify objectives of CPPs associated with healthful dietary behaviours. METHODS: An observational study identified 4026 nutrition CPPs occurring in 130 communities in the prior 6 years. Dietary intakes of fruits and vegetables, added sugar and sugar-sweetened beverages, among others, were reported among 5138 children 4-15 years of age from the communities, using a Dietary Screener Questionnaire with children age 9 years and older (parent assisted) or parent proxies for younger children. CPPs were documented through key informant interviews and characterized by their intensity, count, and objectives including target dietary behaviour and food environment change strategy. Associations between dietary intakes and CPP objectives were assessed using hierarchical statistical models. RESULTS: CPPs with the highest intensity scores that targeted fast food or fat intake or provided smaller portions were associated with greater fruit and vegetable intake (0.21, 0.19, 0.23 cup equivalents/day respectively with p values <0.01, 0.04, 0.03). CPPs with the highest intensity scores that restricted the availability of less healthful foods were associated with lower child intakes of total added sugar (-1.08 tsp/day, p < 0.01) and sugar from sugar-sweetened beverages (-1.63 tsp/day, p = 0.04). Similar associations were observed between CPP count and dietary outcomes. No other significant associations were found between CPP target behaviours or environmental strategies and dietary intakes/behaviours. CONCLUSION: CPPs that targeted decreases in intakes of less healthful foods and/or aimed to modify the availability of less healthful foods and portions were associated with healthier child dietary behaviours.

Measuring the intensity of community programs and policies for preventing childhood obesity in a diverse sample of US communities: the Healthy Communities Study.

INTRODUCTION: Efforts to address the critical public health problem of childhood obesity are occurring across the USA; however, little is known about how to characterize the intensity of these efforts. OBJECTIVES: The purposes of this study are to describe the intensity of community programs and policies (CPPs) to address childhood obesity in 130 US communities and to examine the extent to which observed CPPs targeted multiple behaviours and employed a comprehensive array of strategies. METHODS: To document CPPs occurring over a 10-year period, key informants were interviewed using a semi-structured interview protocol. Staff coded CPPs for key characteristics related to intensity, including reach, duration and strategy. Three types of CPP scores were calculated for intensity of CPPs, targeting of CPPs towards multiple behaviours and strategies used. RESULTS: Nine thousand six hundred eighty-one CPPs were identified. On average, communities had 74 different CPPs in place (standard deviation 30), with variation in documented CPPs (range 25-295). Most communities experienced a steady, modest increase in intensity scores over 10 years. CPP targeting scores suggested that communities expanded the focus of their efforts over time to include more behaviours and strategies. CONCLUSIONS: Findings of this large-scale study indicate that great variation exists across communities in the intensity and focus of community interventions being implemented to address childhood obesity.

One-year result of XEN45 implant for glaucoma: efficacy, safety, and postoperative management.

PurposeTo report the efficacy, safety profile, and postoperative management of XEN45 implant at 12-month follow-up.Patients and methodsThis was a retrospective, non-randomised interventional case series involving patients who underwent XEN45 implantation by a single, experienced glaucoma specialist in a tertiary centre. Primary outcome measures were the intraocular pressure (IOP) and the number of medications at 1-year follow-up visit. Two IOP criteria were chosen to measure success: IOP ≤21 mm Hg and ≥20% reduction from baseline (criteria one); and IOP ≤15 mm Hg and ≥30% reduction from baseline (criteria two).ResultsAll 39 eyes completed 1-year follow-up. The mean preoperative IOP was 24.9±7.8 mm Hg on three drops, which reduced to 14.5±3.4 mm Hg at month 12 (P<0.005) on 0.7 drops (P<0.005). On the basis of criteria one, the cumulative probability of success at 1 year was 87.0% without medication and 92.0% with medication. On the basis of criteria two, cumulative probability of success was 62.0% without medication and 64.0% with medication. Bleb intervention with a median of 2 (range 1-4) was required for 51.3% of eyes. Implant was obstructed by iris tissue in three eyes (7.7%); one eye (2.6%) developed hyphaema; eight eyes (20.5%) had numerical hypotony (IOP≤5 mm Hg) at day 1, of which all spontaneously resolved by week 4 apart from one eye.ConclusionsThe XEN45 implant proved to be an effective treatment with a good safety profile at 1-year follow-up period. The high rate of postoperative bleb intervention does not make XEN45 a 'fit-and-forget' procedure and therefore the procedure should ideally be performed by surgeons experienced in bleb management.

Twelve-year analysis of microbial keratitis trends at a UK tertiary hospital.

PurposeTo investigate the frequencies, trends, and in vitro drug susceptibilities of the causative pathogens in microbial keratitis in Manchester Royal Eye Hospital.Patients and methodsCorneal scrape results recorded by the microbiology service between 2004 and 2015 were extracted from an established database. A total of 4229 corneal scrape specimens were identified from an established database. First-line antibiotic treatment in our centre during the study period was ofloxacin and second line was cefuroxime and gentamicin.ResultsMean age was 45.9±21.0. A total of 1379 samples (32.6%) were culture positive. One hundred forty-eight (10.7%) specimens cultured multiple organisms. Of the 1539 organisms identified, 63.3% were Gram-positive bacteria, 27.3% Gram-negative bacteria, 7.1% fungi, and 2.3% Acanthamoebae. A decreasing trend in Gram-positive isolates was found together with a stable trend in Gram negatives and an increasing trend in Acanthamoeba and fungi. There appeared to be a significant increasing trend of Moraxella infection (P=0.001). In all, 83.1 and 90.8% of Gram-positive and -negative isolates tested were susceptible to ofloxacin, respectively. Cefuroxime covered 86.6% of Gram-positive and 61.4% of Gram-negative isolates, whereas gentamicin covered 88.8 and 96.5% of Gram-positive and -negative isolates, respectively.ConclusionWe found a change in the type of Gram-negative organisms isolated over time, with the Moraxella species on the rise. Reassuringly, no significant increase in resistance was observed in vitro for any of the commonly used antibiotics. Ofloxacin remains a good first-line antibiotic treatment but duo-therapy does have broader coverage and should be considered in non-responsive cases.

Manchester iStent study: 3-year results and cost analysis.

PurposeTo evaluate the safety, efficacy, and the cost of combined phacoemulsification and single iStent insertion in open angle glaucoma (OAG) at 3-years follow-up.MethodsThis was a prospective, uncontrolled, interventional case series. All subjects underwent single iStent implantation combined with cataract surgery by a single surgeon and were followed up over 3 years. Primary outcome measures were the reduction in intraocular pressure (IOP) and number of glaucoma drops at 1, 2, and 3 years. The costs of the procedure vs the cost of continuation of glaucoma drops were calculated and compared in patients who completed 3-years follow-up.ResultsForty-one patients were included in the study and thirty-six patients completed 3-years follow-up. Mean pre-op IOP was 21.2 mm Hg on 2.1 medications. Mean IOP was reduced to 15.9 mm Hg on 0.5 drops, 16.1 mm Hg on 1.0 drops, and 17.1 mm Hg (P<0.001) on 1.3 drops (P<0.001) at 1, 2, and 3 years, respectively. The overall cost of combined cataract surgery and iStent was estimated to be £829.32 more in total than conservative management with brand name eye drops over 3 years (£7.70 per patient per year) and £14 176.9 more if generic drops were used. (£131.3 per patient per year).ConclusionsCombined phaco-iStent proved to be a safe and effective way of managing patients with OAG over our 3-year follow-up period. The cost-effectiveness of the procedure may vary depending on whether brand name or generic eye drops are used.

Anterior segment OCT imaging in mucopolysaccharidoses type I, II, and VI.

PURPOSE: To describe the anterior segment optical coherence tomography (AS-OCT) characteristics of patients with ocular manifestations of mucopolysaccharidoses type I (Hurler), II (Hunter), and VI (Maroteaux-Lamy). METHODS: Prospective, observational study of nine consecutive patients with variants of mucopolysaccharidosis (MPS) attending the Paediatric Ophthalmology service at Manchester Royal Eye Hospital, UK. All patients underwent Visante AS-OCT imaging as part of their ophthalmic assessment. RESULTS: Ocular involvement tended to be symmetrical. Angle-to-angle distance was significantly lower in MPS VI than in MPS I (P=0.04). Anterior chamber depth, angle opening distance, trabecular-iris space area, and scleral spur angle tended to be lower in MPS VI than in MPS I, but did not reach statistical significance. Corneal thickness in the central 0-2 mm zone was greater in MPS VI than in MPS I, approaching but not attaining statistical significance (P=0.07). The 2-5 and 5-7 mm zones were significantly thicker in MPS VI than MPS I (P=0.04, P=0.04). There was no difference in corneal thickness between MPS I and MPS VI in the peripheral 7-10 mm zone (P=0.57). Measurements of the patient with MPS II resembled the mean values of the MPS I group. CONCLUSION: AS-OCT is valuable in quantifying anterior segment pathology in MPS. It suggests more crowded anterior segments and greater corneal thickness in patients with MPS VI than MPS I. AS-OCT is useful in evaluating the risk and mechanism of glaucoma in MPS patients, and may improve our assessment of the efficacy of systemic treatment.

Severity of airflow limitation, co-morbidities and management of chronic obstructive pulmonary disease patients acutely admitted to hospital.

OBJECTIVE: To assess the disease spectrum, severity of airflow limitation, admission pattern, co-morbidities, and management of patients admitted for acute exacerbations of chronic obstructive pulmonary disease. DESIGN: Case series. SETTING: An acute regional hospital in Hong Kong. PATIENTS: Adult subjects admitted during January 2010 to December 2010 with the principal discharge diagnosis of chronic obstructive pulmonary disease. RESULTS: In all, the records of 253 patients with physician-diagnosed chronic obstructive pulmonary disease were analysed. The majority were old (mean age, 78 years). The median number of admissions per patient for this condition in 2010 was two. About two thirds (64%) had had spirometry at least once. Mean forced expiratory volume in one second predicted was 55%. Almost 90% had moderate-to-very severe airflow limitation by spirometry. Overall, long-acting bronchodilators (beta agonists and/or antimuscarinics) were being prescribed for only 21% of the patients. CONCLUSION: Most of the patients admitted to hospital for acute exacerbations of chronic obstructive pulmonary disease were old, had multiple co-morbidities, and the majority had moderate-to-severe airflow limitation by spirometry. Almost half of them (around 46%) had two or more admissions in 2010. Adherence to the latest treatment guidelines seemed inadequate, there being a low prescription rate of long-acting bronchodilators. Chronic obstructive pulmonary disease patients warranting emergency admissions are at risk of future exacerbations and mortality. Management by a designated multidisciplinary team is recommended.

An expedited stroke triage pathway: the key to shortening the door-to-needle time in delivery of thrombolysis.

OBJECTIVES: To assess time management of stroke thrombolysis triage and functional outcomes in patients receiving recombinant tissue plasminogen activator for hyperacute stroke, and identify bottlenecks in delivery of the treatment. DESIGN: Prospective study. SETTING: A university teaching hospital in Hong Kong. PATIENTS: Patients with suspected hyperacute stroke referred to the stroke thrombolysis team during October 2008 to September 2009. MAIN OUTCOME MEASURES: Time performance records including door-to-stroke team, door-to-needle, and onset-to-thrombolysis times. Functional outcomes by modified Rankin Scale score at 3 months, and thrombolysis-related complications including haemorrhagic transformations and mortality. RESULTS: During the 12-month period, 95 thrombolysis calls were received; recombinant tissue plasminogen activator was given intravenously to 17 (18%) of the patients and intra-arterially to 11 (12%). The mean (standard deviation) door-to-stroke team and the door-to-needle times for intravenous recombinant tissue plasminogen activator patients were 33 (25) and 80 (25) minutes, respectively; both were about 20 minutes longer than that recommended by the National Institute of Neurological Disorders and Stroke. The mean National Institute of Health Stroke Scale score for patients received intravenous recombinant tissue plasminogen activator was 16 (standard deviation, 7). The mean (standard deviation) onset-to-treatment time was 144 (42) minutes. Nine (53%) patients who received intravenous recombinant tissue plasminogen activator achieved favourable outcomes at 3 months, with a modified Rankin Scale score of 0 to 1. Symptomatic haemorrhage and mortality occurred in one (6%) patient. CONCLUSION: A dedicated stroke triage pathway is essential to ensure efficient and safe delivery of thrombolysis therapy. Improvements in door-to-stroke team time through integration with emergency medicine staff and neuroradiologists may improve thrombolysis eligibility.

Utilizing an electronic health record system to improve vaccination coverage in children.

BACKGROUND: Electronic Health Records (EHR) are widely believed to improve quality of care and effectiveness of service delivery. Use of EHR to improve childhood immunization rates has not been fully explored in an ambulatory setting. OBJECTIVE: To describe a pediatric practice's use of Electronic Health Records (EHR) in improving childhood immunization. METHODS: A multi-faceted EHR-based quality improvement initiative used electronic templates with pre-loaded immunization records, automatic diagnosis coding, and EHR alerts of missing or delayed vaccinations. An electronic patient tracking system was created to identify patients with missing vaccines. Barcode scanning technology was introduced to aid speed and accuracy of documentation of administered vaccines. Electronic reporting to a local health department immunization registry facilitated ordering of vaccines. RESULTS: Immunization completion rates captured in monthly patient reports showed a rise in the percentage of children receiving the recommended series of vaccination (65% to 76%) (p<0.000). Barcode technology reduced the time of immunization documentation (86 seconds to 26 seconds) (p<0.000). Use of barcode scanning showed increased accuracy of documentation of vaccine lot numbers (from 95% to 100%) (p<0.000). CONCLUSION: EHR-based quality improvement interventions were successfully implemented at a community health center. EHR systems have versatility in their ability to track patients in need of vaccines, identify patients who are delayed, facilitate ordering and coding of multiple vaccines and promote interdisciplinary communication among personnel involved in the vaccination process. EHR systems can be used to improve childhood vaccination rates.