A phase I open-label, dose-escalation study of NUC-3373, a targeted thymidylate synthase inhibitor, in patients with advanced cancer (NuTide:301).

PURPOSE: 5-fluorouracil (5-FU) is inefficiently converted to the active anti-cancer metabolite, fluorodeoxyuridine-monophosphate (FUDR-MP), is associated with dose-limiting toxicities and challenging administration schedules. NUC-3373 is a phosphoramidate nucleotide analog of fluorodeoxyuridine (FUDR) designed to overcome these limitations and replace fluoropyrimidines such as 5-FU. PATIENTS AND METHODS: NUC-3373 was administered as monotherapy to patients with advanced solid tumors refractory to standard therapy via intravenous infusion either on Days 1, 8, 15 and 22 (Part 1) or on Days 1 and 15 (Part 2) of 28-day cycles until disease progression or unacceptable toxicity. Primary objectives were maximum tolerated dose (MTD) and recommended Phase II dose (RP2D) and schedule of NUC-3373. Secondary objectives included pharmacokinetics (PK), and anti-tumor activity. RESULTS: Fifty-nine patients received weekly NUC-3373 in 9 cohorts in Part 1 (n = 43) and 3 alternate-weekly dosing cohorts in Part 2 (n = 16). They had received a median of 3 prior lines of treatment (range: 0-11) and 74% were exposed to prior fluoropyrimidines. Four experienced dose-limiting toxicities: two Grade (G) 3 transaminitis; one G2 headache; and one G3 transient hypotension. Commonest treatment-related G3 adverse event of raised transaminases occurred in < 10% of patients. NUC-3373 showed a favorable PK profile, with dose-proportionality and a prolonged half-life compared to 5-FU. A best overall response of stable disease was observed, with prolonged progression-free survival. CONCLUSION: NUC-3373 was well-tolerated in a heavily pre-treated solid tumor patient population, including those who had relapsed on prior 5-FU. The MTD and RP2D was defined as 2500 mg/m2 NUC-3373 weekly. NUC-3373 is currently in combination treatment studies. TRIAL REGISTRATION: Clinicaltrials.gov registry number NCT02723240. Trial registered on 8th December 2015. https://clinicaltrials.gov/study/NCT02723240 .

Poor handling of continuous predictors in clinical prediction models using logistic regression: a systematic review.

BACKGROUND AND OBJECTIVES: When developing a clinical prediction model, assuming a linear relationship between the continuous predictors and outcome is not recommended. Incorrect specification of the functional form of continuous predictors could reduce predictive accuracy. We examine how continuous predictors are handled in studies developing a clinical prediction model. METHODS: We searched PubMed for clinical prediction model studies developing a logistic regression model for a binary outcome, published between July 01, 2020, and July 30, 2020. RESULTS: In total, 118 studies were included in the review (18 studies (15%) assessed the linearity assumption or used methods to handle nonlinearity, and 100 studies (85%) did not). Transformation and splines were commonly used to handle nonlinearity, used in 7 (n = 7/18, 39%) and 6 (n = 6/18, 33%) studies, respectively. Categorization was most often used method to handle continuous predictors (n = 67/118, 56.8%) where most studies used dichotomization (n = 40/67, 60%). Only ten models included nonlinear terms in the final model (n = 10/18, 56%). CONCLUSION: Though widely recommended not to categorize continuous predictors or assume a linear relationship between outcome and continuous predictors, most studies categorize continuous predictors, few studies assess the linearity assumption, and even fewer use methodology to account for nonlinearity. Methodological guidance is provided to guide researchers on how to handle continuous predictors when developing a clinical prediction model.

Sample size requirements are not being considered in studies developing prediction models for binary outcomes: a systematic review.

BACKGROUND: Having an appropriate sample size is important when developing a clinical prediction model. We aimed to review how sample size is considered in studies developing a prediction model for a binary outcome. METHODS: We searched PubMed for studies published between 01/07/2020 and 30/07/2020 and reviewed the sample size calculations used to develop the prediction models. Using the available information, we calculated the minimum sample size that would be needed to estimate overall risk and minimise overfitting in each study and summarised the difference between the calculated and used sample size. RESULTS: A total of 119 studies were included, of which nine studies provided sample size justification (8%). The recommended minimum sample size could be calculated for 94 studies: 73% (95% CI: 63-82%) used sample sizes lower than required to estimate overall risk and minimise overfitting including 26% studies that used sample sizes lower than required to estimate overall risk only. A similar number of studies did not meet the ≥ 10EPV criteria (75%, 95% CI: 66-84%). The median deficit of the number of events used to develop a model was 75 [IQR: 234 lower to 7 higher]) which reduced to 63 if the total available data (before any data splitting) was used [IQR:225 lower to 7 higher]. Studies that met the minimum required sample size had a median c-statistic of 0.84 (IQR:0.80 to 0.9) and studies where the minimum sample size was not met had a median c-statistic of 0.83 (IQR: 0.75 to 0.9). Studies that met the ≥ 10 EPP criteria had a median c-statistic of 0.80 (IQR: 0.73 to 0.84). CONCLUSIONS: Prediction models are often developed with no sample size calculation, as a consequence many are too small to precisely estimate the overall risk. We encourage researchers to justify, perform and report sample size calculations when developing a prediction model.

Impact of COVID-19 pandemic on incidence of long-term conditions in Wales: a population data linkage study using primary and secondary care health records.

BACKGROUND: The COVID-19 pandemic has directly and indirectly had an impact on health service provision owing to surges and sustained pressures on the system. The effects of these pressures on the management of long-term or chronic conditions are not fully understood. AIM: To explore the effects of COVID-19 on the recorded incidence of 17 long-term conditions. DESIGN AND SETTING: This was an observational retrospective population data linkage study on the population of Wales using primary and secondary care data within the Secure Anonymised Information Linkage (SAIL) Databank. METHOD: Monthly rates of new diagnosis between 2000 and 2021 are presented for each long-term condition. Incidence rates post-2020 were compared with expected rates predicted using time series modelling of pre-2020 trends. The proportion of annual incidence is presented by sociodemographic factors: age, sex, social deprivation, ethnicity, frailty, and learning disability. RESULTS: A total of 5 476 012 diagnoses from 2 257 992 individuals are included. Incidence rates from 2020 to 2021 were lower than mean expected rates across all conditions. The largest relative deficit in incidence was in chronic obstructive pulmonary disease corresponding to 343 (95% confidence interval = 230 to 456) undiagnosed patients per 100 000 population, followed by depression, type 2 diabetes, hypertension, anxiety disorders, and asthma. A GP practice of 10 000 patients might have over 400 undiagnosed long-term conditions. No notable differences between sociodemographic profiles of post- and pre-2020 incidences were observed. CONCLUSION: There is a potential backlog of undiagnosed patients with multiple long-term conditions. Resources are required to tackle anticipated workload as part of COVID-19 recovery, particularly in primary care.

Real-world effectiveness of molnupiravir, nirmatrelvir-ritonavir, and sotrovimab on preventing hospital admission among higher-risk patients with COVID-19 in Wales: A retrospective cohort study.

OBJECTIVE: To compare the effectiveness of molnupiravir, nirmatrelvir-ritonavir, and sotrovimab with no treatment in preventing hospital admission or death in higher-risk patients infected with SARS-CoV-2 in the community. DESIGN: Retrospective cohort study of non-hospitalized adult patients with COVID-19 using the Secure Anonymised Information Linkage (SAIL) Databank. SETTING: A real-world cohort study was conducted within the SAIL Databank (a secure trusted research environment containing anonymised, individual, population-scale electronic health record (EHR) data) for the population of Wales, UK. PARTICIPANTS: Adult patients with COVID-19 in the community, at higher risk of hospitalization and death, testing positive for SARS-CoV-2 between 16th December 2021 and 22nd April 2022. INTERVENTIONS: Molnupiravir, nirmatrelvir-ritonavir, and sotrovimab given in the community by local health boards and the National Antiviral Service in Wales. MAIN OUTCOME MEASURES: All-cause admission to hospital or death within 28 days of a positive test for SARS-CoV-2. STATISTICAL ANALYSIS: Cox proportional hazard model with treatment status (treated/untreated) as a time-dependent covariate and adjusted for age, sex, number of comorbidities, Welsh Index of Multiple Deprivation, and vaccination status. Secondary subgroup analyses were by treatment type, number of comorbidities, and before and on or after 20th February 2022, when omicron BA.1 and omicron BA.2 were the dominant subvariants in Wales. RESULTS: Between 16th December 2021 and 22nd April 2022, 7013 higher-risk patients were eligible for inclusion in the study. Of these, 2040 received treatment with molnupiravir (359, 17.6%), nirmatrelvir-ritonavir (602, 29.5%), or sotrovimab (1079, 52.9%). Patients in the treatment group were younger (mean age 53 vs 57 years), had fewer comorbidities, and a higher proportion had received four or more doses of the COVID-19 vaccine (36.3% vs 17.6%). Within 28 days of a positive test, 628 (9.0%) patients were admitted to hospital or died (84 treated and 544 untreated). The primary analysis indicated a lower risk of hospitalization or death at any point within 28 days in treated participants compared to those not receiving treatment. The adjusted hazard rate was 35% (95% CI: 18-49%) lower in treated than untreated participants. There was no indication of the superiority of one treatment over another and no evidence of a reduction in risk of hospitalization or death within 28 days for patients with no or only one comorbidity. In patients treated with sotrovimab, the event rates before and on or after 20th February 2022 were similar (5.0% vs 4.9%) with no significant difference in the hazard ratios for sotrovimab between the time periods. CONCLUSIONS: In higher-risk adult patients in the community with COVID-19, those who received treatment with molnupiravir, nirmatrelvir-ritonavir, or sotrovimab were at lower risk of hospitalization or death than those not receiving treatment.

Effect of the COVID-19 pandemic on incidence of long-term conditions in Welsh residents: a population linkage study.

BACKGROUND: The COVID-19 pandemic had direct and indirect effects on health. Indirect effects on long term medical conditions (LTCs) are unclear. We examined trends in recorded incidences of LTCs and quantified differences between expected rates and observed rates from 2020 onwards. METHODS: This is a population data linkage study using primary and secondary care data within the Secure Anonymised Information Linkage Databank. We included data of Welsh residents diagnosed with any of 17 identified LTCs for the first time between Jan 1, 2000, and Dec 31, 2021. LTC's include mental health conditions, respiratory diseases, and heart conditions among others, generally chosen in line with the Quality and Outcomes Framework. The primary outcome was incidence rates (monthly number of new cases per 100 000 population). For each LTC, we did interrupted time series analysis of incidence rates from 2015 to 2021. Expected rates from between Jan 1, 2020, to Dec 31, 2021, were predicted using overall trends and seasonal patterns from the preceding 5 years and compared with observed rates. FINDINGS: We included 5 476 012 diagnoses from 2 257 992 individuals diagnosed with at least one LTC between Jan 1, 2000, to Dec 31, 2021. Across multiple long-term conditions, there was an abrupt reduction in observed incidence of new diagnoses from March to April 2020, followed by a general increase in incidence towards prepandemic rates. The conditions with the largest percentage difference between the observed and expected incidence rates in 2020 and 2021 were chronic obstructive pulmonary disease (38·4% lower than expected), depression (28·3% lower), hypertension (25·5% lower), and anxiety disorders (24·9% lower). The condition with the largest absolute difference between observed and expected incidence rates was anxiety disorders, with 830 per 100 000 less in 2020 and 2021 compared with observed rates. INTERPRETATION: The reduction in incidence rates of LTCs suggests an underreporting of LTCs, especially during 2020 and early 2021. The emergence of these yet undiagnosed cases could result in a surge of new patients in the near future. FUNDING: This work was supported by the Wales COVID-19 Evidence Centre, funded by Health and Care Research Wales.

Hierarchy and Reliability of the Preschool Language Scales-Fifth Edition: Mokken Scale Analysis.

Purpose This study examined the psychometric properties of the Preschool Language Scales-Fifth Edition (PLS-5 English) among preschool children from low-socioeconomic status (SES) families. Method The PLS-5 was administered individually to 169 3- to 4-year-old children enrolled in Head Start programs. We carried out a Mokken scale analysis (MSA), which is a nonparametric item response theory analysis, to examine the hierarchy among items and the reliability of test scores of the PLS-5 Auditory Comprehension (AC) and Expressive Communication (EC) scales. Results The PLS-5 EC items retained a moderate Mokken scale with the inclusion of all the items. On the other hand, the PLS-5 AC items formed a moderate Mokken scale only with the exclusion of five unscalable items. The latent class reliability coefficients for the AC and the EC scale scores were both above .90. Several items that violated the invariant item ordering assumption were found for both scales. Conclusions MSA can be used to examine the relationship between the latent language ability and the probability of passing an item with ordinal responses. Results indicate that for preschool children from low-SES families, it is appropriate to use the PLS-5 EC scale scores for comparing individuals' expressive language abilities; however, researchers and speech-language pathologists should be cautious when using the PLS-5 AC scale scores to evaluate individuals' receptive language abilities. Other implications of the MSA results are further discussed.

Mitochondrial Inhibitor Atovaquone Increases Tumor Oxygenation and Inhibits Hypoxic Gene Expression in Patients with Non-Small Cell Lung Cancer.

PURPOSE: Tumor hypoxia fuels an aggressive tumor phenotype and confers resistance to anticancer treatments. We conducted a clinical trial to determine whether the antimalarial drug atovaquone, a known mitochondrial inhibitor, reduces hypoxia in non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients with NSCLC scheduled for surgery were recruited sequentially into two cohorts: cohort 1 received oral atovaquone at the standard clinical dose of 750 mg twice daily, while cohort 2 did not. Primary imaging endpoint was change in tumor hypoxic volume (HV) measured by hypoxia PET-CT. Intercohort comparison of hypoxia gene expression signatures using RNA sequencing from resected tumors was performed. RESULTS: Thirty patients were evaluable for hypoxia PET-CT analysis, 15 per cohort. Median treatment duration was 12 days. Eleven (73.3%) atovaquone-treated patients had meaningful HV reduction, with median change -28% [95% confidence interval (CI), -58.2 to -4.4]. In contrast, median change in untreated patients was +15.5% (95% CI, -6.5 to 35.5). Linear regression estimated the expected mean HV was 55% (95% CI, 24%-74%) lower in cohort 1 compared with cohort 2 (P = 0.004), adjusting for cohort, tumor volume, and baseline HV. A key pharmacodynamics endpoint was reduction in hypoxia-regulated genes, which were significantly downregulated in atovaquone-treated tumors. Data from multiple additional measures of tumor hypoxia and perfusion are presented. No atovaquone-related adverse events were reported. CONCLUSIONS: This is the first clinical evidence that targeting tumor mitochondrial metabolism can reduce hypoxia and produce relevant antitumor effects at the mRNA level. Repurposing atovaquone for this purpose may improve treatment outcomes for NSCLC.

Symptom Burden and Unmet Needs in Malignant Pleural Mesothelioma: Exploratory Analyses From the RESPECT-Meso Study.

OBJECTIVE: Malignant Pleural Mesothelioma (MPM) has a poor prognosis and high symptom burden. RESPECT-Meso was a multicenter randomized study examining the role of early specialist palliative care (SPC) on quality of life (QoL) with MPM. This is a post-hoc exploratory analysis of the symptom burden and unmet needs identified from RESPECT-Meso participants. METHODS: Exploratory analysis from 174 participants using the General Health Status (GHS) measure (from the EORTC QLQ-C30 QoL questionnaire) and 87 participants using validated assessment questionnaires in those randomized to SPC. Eligibility for the study included confirmed MPM with diagnosis <6 weeks prior, performance score (PS) 0 or 1, no significant physical or psychological comorbidity. Cox proportional hazards models were derived to examine for relationships with survival. Free text was assessed using content analysis, looking for common themes and words. RESULTS: Participants were predominantly male (79.9%), mean age 72.8 years, PS was 0 in 38%, 78% of MPM was epithelioid. At least 3 symptoms were reported in 69.8% of participants, including fatigue (81%), dyspnea (73.3%), pain (61.2%), weight loss (59.3%). Anxiety was reported by 54.7% of participants, 52.3% low mood and 48.8% anhedonia symptoms. After multivariable adjustment, only pain remained statistically significant with a hazard ratio (HR) 2.9 (95% CI 1.3-6.7; p = 0.01). For each 1 unit increase in GHS score, the HR for death was 0.987 (0.978-0.996; p = 0.006), indicating a worse reported QoL is related to shorter survival. Unmet needs were common: 25.9% wanted more information about their condition, 24.7% about their care and 21.2% about their treatment. 79.1% were concerned about the effect of their illness on family. CONCLUSION: There is a high symptom burden in mesothelioma despite good baseline performance status. A worse QoL is associated with a worse survival. Unmet needs are common, perhaps highlighting a need for improved communication and information sharing.

Language Skills, Behaviour Problems, and Classroom Emotional Support among Preschool Children from Low-income Families.

The purpose of this study was to examine the relationship between language skills and behavioural problems and the potential moderating role of the quality of classroom emotional support in this relationship among 242 preschool children from low-income families. The Preschool Language Scale-5 was administered individually to each child. The quality of classroom emotional support was measured using the Emotional Support domain of the Classroom Assessment Scoring System for Pre-Kindergarten. Teachers and parents completed the Child Behaviour Checklist for Ages 1½-5. Results indicated the inverse relationship between language skills and behaviour problems varied by the level of classroom emotional support provided by teachers. Specifically, children with lower language skills exhibited higher levels of behaviour problems in classrooms where teachers provided lower levels of emotional support. Findings from this study have important implications for enhancing teachers' emotional support aimed at children with lower language skills and for future research.

Early specialist palliative care on quality of life for malignant pleural mesothelioma: a randomised controlled trial.

PURPOSE: Malignant pleural mesothelioma (MPM) has a high symptom burden and poor survival. Evidence from other cancer types suggests some benefit in health-related quality of life (HRQoL) with early specialist palliative care (SPC) integrated with oncological services, but the certainty of evidence is low. METHODS: We performed a multicentre, randomised, parallel group controlled trial comparing early referral to SPC versus standard care across 19 hospital sites in the UK and one large site in Western Australia. Participants had newly diagnosed MPM; main carers were additionally recruited. INTERVENTION: review by SPC within 3 weeks of allocation and every 4 weeks throughout the study. HRQoL was assessed at baseline and every 4 weeks with the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30. PRIMARY OUTCOME: change in EORTC C30 Global Health Status 12 weeks after randomisation. RESULTS: Between April 2014 and October 2016, 174 participants were randomised. There was no significant between group difference in HRQoL score at 12 weeks (mean difference 1.8 (95% CI -4.9 to 8.5; p=0.59)). HRQoL did not differ at 24 weeks (mean difference -2.0 (95% CI -8.6 to 4.6; p=0.54)). There was no difference in depression/anxiety scores at 12 weeks or 24 weeks. In carers, there was no difference in HRQoL or mood at 12 weeks or 24 weeks, although there was a consistent preference for care, favouring the intervention arm. CONCLUSION: There is no role for routine referral to SPC soon after diagnosis of MPM for patients who are cared for in centres with good access to SPC when required. TRIAL REGISTRATION NUMBER: ISRCTN18955704.

Nutritional intervention and neurodevelopmental outcome in infants with suspected cerebral palsy: the Dolphin infant double-blind randomized controlled trial.

AIM: To investigate whether docosahexaenoic acid (DHA), choline, and uridine-5-monophosphate (UMP) supplementation improves neurodevelopmental outcome in infants with suspected cerebral palsy (CP) versus a comparison group of children. METHOD: Infants aged 1 to 18 months with suspected CP were recruited from UK child development centres. Participants received daily treatment or control supplementation for 2 years (double-blind randomized control design). Stratification was by age, sex, predominant pattern of motor involvement (four limbs or other), and visual impairment (or not). The primary outcome was the cognitive composite score of the Bayley Scales of Infant and Toddler Development, Third Edition (CCS-Bayley-III). Secondary outcomes included language composite and motor composite scores of the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III). RESULTS: Forty infants were recruited; 35 began supplementation, 29 completed 1 to 2 years' supplementation. The treatment group CCS-Bayley-III was non-significantly higher than the comparison group (mean 77.7 [SD 19.2] and 72.2 [SD 19.8] respectively, mean modelled difference 4.4 [-2.8, 11.6]). The treatment group language scores, but not motor scores, were non-significantly higher than for the comparison group. INTERPRETATION: Most families found supplementation feasible. No statistically significant differences in neurodevelopmental outcome between the treatment and comparison groups were identified. Further investigation of neurodevelopmental outcome after supplementation with DHA, choline, and UMP of infants with suspected CP is warranted. WHAT THIS PAPER ADDS: This was the first trial of phosphatidylcholine precursor supplementation in infants with suspected cerebral palsy (CP). Families of infants with suspected CP found 2-year nutritional supplementation feasible. There was no statistically significant neurodevelopmental advantage for the treatment group versus the comparison group. However, treatment group cognitive and language advantage were of clinically meaningful magnitude.

Language performance of low-income African American and European American preschool children on the PPVT-III.

PURPOSE: The performance of low-income African American preschoolers (36 to 52 months old) on the Peabody Picture Vocabulary Test--Third Edition (PPVT-III; L. M. Dunn & L. M. Dunn, 1997) was examined to provide a norm for assessing the performance of this population and to explore the link between socioeconomic status (SES) and language scores on the PPVT-III. METHOD: Four hundred and eighty-two African American and 52 European American children in a comparison group were individually administered the PPVT-III. RESULTS: On average, African American children performed approximately 1.5 SD below the expected mean based on national norms. Using standard cutoff scores, the PPVT-III identified more children as having language delays than did other measures of language abilities. Socioeconomic factors were related to PPVT-III scores, indicating that the degree of disadvantage within children with low SES was related to language abilities. Maternal education level, marital status, and the number of children in the household were uniquely associated with children's performance on the PPVT-III. CLINICAL IMPLICATIONS: The importance of supporting language development in preschool children from low-income families is discussed.

Problem behaviors of low-income children with language delays: an observation study.

Children from low-income families are at increased risk for significant behavioral and language problems. Early identification of these problems is essential for effective intervention. The purpose of the present study was to use multiple behavioral assessments to examine the behavioral profiles of sixty 3- and 4-year-old children from low-income families enrolled in Head Start programs and to compare the behavior characteristics of 32 children with language delays with those of 28 children with typical language development. Teachers completed the Child Behavior Checklist/Caregiver-Teacher Report Form/2-5 (CTRF; T. M. Achenbach, 1997) and the Social Skills Rating System (SSRS; F. M. Gresham and S. N. Elliott, 1990), and children were observed in the classrooms during structured and unstructured activities. Children with language delays exhibited more problem behaviors and poorer social skills on some of the observational measures than did children with typical language development, as predicted, but not on all.

The performance of low-income, African American children on the Preschool Language Scale-3.

This study examined the performance of 701 low-income African American preschoolers (36 to 52 months old) on the Preschool Language Scale-3 (PLS-3, I. L. Zimmerman, V. G. Steiner, & R. E. Pond, 1992). On average, African American children performed about 1 SD below the expected means for their ages on both the Expressive Communication and Auditory Comprehension subscales. Independent sample t tests showed no significant differences between African American children and a comparison sample of 50 European American children. Item analysis was used to examine the potentially problematic items of the PLS-3 for each age cohort of children. We found that 6 items appeared to be particularly difficult for the African American sample. The findings suggest that the PLS-3 is generally an informative language test for African American preschoolers; however, scores should be interpreted with caution.