Nevin Manimala

Cancer Epidemiol Biomarkers Prev. 2021 Apr 7:cebp.1568.2020. doi: 10.1158/1055-9965.EPI-20-1568. Online ahead of print.

ABSTRACT

BACKGROUND: The role of progestogens in colorectal cancer development are poorly characterized. To address this, our group developed a highly sensitive assay to measure concentrations of seven markers of endogenous progestogen metabolism among postmenopausal women.

METHODS: The markers were measured in baseline serum collected from postmenopausal women in a case-cohort study within the Breast and Bone Follow-up to the Fracture Intervention Trial (B~FIT). We followed women not using exogenous hormones at baseline (1992-1993) for up to twelve years: 187 women with incident colorectal cancer diagnosed during follow-up and a subcohort of 495 women selected on strata of age and clinical center. We used adjusted Cox regression models with robust variance to estimate risk for colorectal cancer (hazard ratios [HR], 95% confidence intervals [CI]).

RESULTS: High concentrations of pregnenolone and progesterone were not associated with colorectal cancer (quintile(Q)5 vs. Q1: pregnenolone HR 0.71, CI 0.40-1.25; progesterone HR 1.25, CI 0.71-2.22). A trend of increasing risk was suggested, but statistically imprecise across quintiles of 17-hydroxypregnenolone (Q2 to Q5 HRs 0.75 to 1.44, p-trend 0.06).

CONCLUSIONS: We used sensitive and reliable assays to measure multiple circulating markers of progestogen metabolism. Progestogens were generally unassociated with colorectal cancer risk in postmenopausal women.

IMPACT: Our findings are consistent with most prior research on circulating endogenous sex hormones, which taken together, suggest sex hormones may not be major drivers of colorectal carcinogenesis in postmenopausal women.

PMID:33827983 | DOI:10.1158/1055-9965.EPI-20-1568

Neurology. 2021 Apr 7:10.1212/WNL.0000000000011933. doi: 10.1212/WNL.0000000000011933. Online ahead of print.

ABSTRACT

OBJECTIVE: To investigate the effects of rituximab on retinal atrophy in patients with relapsing-remitting multiple sclerosis (RRMS), we performed serial optical coherence tomography (OCT) scans among a cohort of RRMS patients on rituximab, and compared rates of ganglion cell+inner plexiform layer (GCIPL) atrophy to those observed among age- and sex-matched glatiramer acetate (GA)- and natalizumab-treated RRMS patients, and healthy controls (HCs).

METHODS: In this observational study, patients with RRMS treated with a single disease-modifying therapy, and HCs, were followed with serial OCT for a median duration of 2.8 years. Participants with uncontrolled hypertension, diabetes mellitus, or glaucoma, and eyes with optic neuritis ≤6 months prior to baseline OCT, or during follow-up, were excluded. Statistical analyses were performed using linear mixed-effects regression.

RESULTS: During the overall follow-up period, rates of GCIPL atrophy were -0.28±0.11µm/yr among rituximab-treated RRMS patients (n=35). This was similar to GA-treated (n=49; -0.33±0.05µm/yr; p=0.69) and natalizumab-treated patients (n=88; -0.17±0.10µm/yr; p=0.13), and faster than HCs (n=78; -0.15±0.03µm/yr; p=0.006). Rituximab-treated patients exhibited 0.55±0.23µm/yr faster rates of GCIPL atrophy during the first 12 months of treatment, relative to afterwards (n=25; p=0.02), during which period GCIPL atrophy rates were -0.14±0.13µm/yr.

CONCLUSIONS: Retinal atrophy in RRMS is modulated by rituximab. Greater attenuation of retinal atrophy may occur after 12 months of rituximab treatment, following which time GCIPL atrophy rates are similar to those observed among natalizumab-treated RRMS patients and HCs. Our findings raise the possibility that the neuroprotective therapeutic response with rituximab in RRMS may take up to 12 months, though should be confirmed by larger studies.

CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence on the difference in rate of change of the ganglion cell+inner plexiform layer thickness in patients with RRMS, comparing rituximab to other DMTs.

PMID:33827962 | DOI:10.1212/WNL.0000000000011933

Pediatrics. 2021 Apr 7:e20201634. doi: 10.1542/peds.2020-1634. Online ahead of print.

ABSTRACT

BACKGROUND: Clinicians commonly obtain endotracheal aspirate cultures (EACs) in the evaluation of suspected ventilator-associated infections. However, bacterial growth in EACs does not distinguish bacterial colonization from infection and may lead to overtreatment with antibiotics. We describe the development and impact of a clinical decision support algorithm to standardize the use of EACs from ventilated PICU patients.

METHODS: We monitored EAC use using a statistical process control chart. We compared the rate of EACs using Poisson regression and a quasi-experimental interrupted time series model and assessed clinical outcomes 1 year before and after introduction of the algorithm.

RESULTS: In the preintervention year, there were 557 EACs over 5092 ventilator days; after introduction of the algorithm, there were 234 EACs over 3654 ventilator days (an incident rate of 10.9 vs 6.5 per 100 ventilator days). There was a 41% decrease in the monthly rate of EACs (incidence rate ratio [IRR]: 0.59; 95% confidence interval [CI] 0.51-0.67; P < .001). The interrupted time series model revealed a preexisting 2% decline in the monthly culture rate (IRR: 0.98; 95% CI 0.97-1.0; P = .01), immediate 44% drop (IRR: 0.56; 95% CI 0.45-0.70; P = .02), and stable rate in the postintervention year (IRR: 1.03; 95% CI 0.99-1.07; P = .09). In-hospital mortality, hospital length of stay, 7-day readmissions, and All Patients Refined Diagnosis Related Group severity and mortality scores were stable. The estimated direct cost savings was $26 000 per year.

CONCLUSIONS: A clinical decision support algorithm standardizing EAC obtainment from ventilated PICU patients was associated with a sustained decline in the rate of EACs, without changes in mortality, readmissions, or length of stay.

PMID:33827937 | DOI:10.1542/peds.2020-1634

mSphere. 2021 Apr 7;6(2):e01019-20. doi: 10.1128/mSphere.01019-20.

ABSTRACT

Shannon’s entropy is a popular alpha diversity metric because it estimates both richness and evenness in a single equation. However, since its value is dependent on both those parameters, there is theoretically an infinite number of richness/evenness value combinations translating into the same index score. By decoupling both components measured by Shannon’s entropy, two communities having identical indices can be differentiated by mapping richness and evenness coordinates on a scatter plot. In such graphs, confidence ellipses would allow testing significant differences between groups of samples. Multivariate statistical tests such as permutational multivariate analysis of variance (PERMANOVA) can be performed on distance matrices calculated from richness and evenness coordinates and detect statistically significant differences that would have remained unforeseen otherwise. Therefore, plotting richness and evenness on two-dimensional (2D) graphs gives a more thorough understanding of how alpha diversity differs between groups of samples.

PMID:33827912 | DOI:10.1128/mSphere.01019-20

J Immunother Cancer. 2021 Apr;9(4):e002421. doi: 10.1136/jitc-2021-002421.

ABSTRACT

BACKGROUND: Some concomitant medications including antibiotics (ATB) have been reproducibly associated with worse survival following immune checkpoint inhibitors (ICIs) in unselected patients with non-small cell lung cancer (NSCLC) (according to programmed death-ligand 1 (PD-L1) expression and treatment line). Whether such relationship is causative or associative is matter of debate.

METHODS: We present the outcomes analysis according to concomitant baseline medications (prior to ICI initiation) with putative immune-modulatory effects in a large cohort of patients with metastatic NSCLC with a PD-L1 expression ≥50%, receiving first-line pembrolizumab monotherapy. We also evaluated a control cohort of patients with metastatic NSCLC treated with first-line chemotherapy. The interaction between key medications and therapeutic modality (pembrolizumab vs chemotherapy) was validated in pooled multivariable analyses.

RESULTS: 950 and 595 patients were included in the pembrolizumab and chemotherapy cohorts, respectively. Corticosteroid and proton pump inhibitor (PPI) therapy but not ATB therapy was associated with poorer performance status at baseline in both the cohorts. No association with clinical outcomes was found according to baseline statin, aspirin, β-blocker and metformin within the pembrolizumab cohort. On the multivariable analysis, ATB emerged as a strong predictor of worse overall survival (OS) (HR=1.42 (95% CI 1.13 to 1.79); p=0.0024), and progression free survival (PFS) (HR=1.29 (95% CI 1.04 to 1.59); p=0.0192) in the pembrolizumab but not in the chemotherapy cohort. Corticosteroids were associated with shorter PFS (HR=1.69 (95% CI 1.42 to 2.03); p<0.0001), and OS (HR=1.93 (95% CI 1.59 to 2.35); p<0.0001) following pembrolizumab, and shorter PFS (HR=1.30 (95% CI 1.08 to 1.56), p=0.0046) and OS (HR=1.58 (95% CI 1.29 to 1.94), p<0.0001), following chemotherapy. PPIs were associated with worse OS (HR=1.49 (95% CI 1.26 to 1.77); p<0.0001) with pembrolizumab and shorter OS (HR=1.12 (95% CI 1.02 to 1.24), p=0.0139), with chemotherapy. At the pooled analysis, there was a statistically significant interaction with treatment (pembrolizumab vs chemotherapy) for corticosteroids (p=0.0020) and PPIs (p=0.0460) with respect to OS, for corticosteroids (p<0.0001), ATB (p=0.0290), and PPIs (p=0.0487) with respect to PFS, and only corticosteroids (p=0.0033) with respect to objective response rate.

CONCLUSION: In this study, we validate the significant negative impact of ATB on pembrolizumab monotherapy but not chemotherapy outcomes in NSCLC, producing further evidence about their underlying immune-modulatory effect. Even though the magnitude of the impact of corticosteroids and PPIs is significantly different across the cohorts, their effects might be driven by adverse disease features.

PMID:33827906 | DOI:10.1136/jitc-2021-002421

BMJ Open. 2021 Apr 7;11(4):e047121. doi: 10.1136/bmjopen-2020-047121.

ABSTRACT

OBJECTIVES: To develop a prognostic model to identify and quantify risk factors for mortality among patients admitted to the hospital with COVID-19.

DESIGN: Retrospective cohort study. Patients were randomly assigned to either training (80%) or test (20%) sets. The training set was used to fit a multivariable logistic regression. Predictors were ranked using variable importance metrics. Models were assessed by C-indices, Brier scores and calibration plots in the test set.

SETTING: Optum de-identified COVID-19 Electronic Health Record dataset including over 700 hospitals and 7000 clinics in the USA.

PARTICIPANTS: 17 086 patients hospitalised with COVID-19 between 20 February 2020 and 5 June 2020.

MAIN OUTCOME MEASURE: All-cause mortality while hospitalised.

RESULTS: The full model that included information on demographics, comorbidities, laboratory results, and vital signs had good discrimination (C-index=0.87) and was well calibrated, with some overpredictions for the most at-risk patients. Results were similar on the training and test sets, suggesting that there was little overfitting. Age was the most important risk factor. The performance of models that included all demographics and comorbidities (C-index=0.79) was only slightly better than a model that only included age (C-index=0.76). Across the study period, predicted mortality was 1.3% for patients aged 18 years old, 8.9% for 55 years old and 28.7% for 85 years old. Predicted mortality across all ages declined over the study period from 22.4% by March to 14.0% by May.

CONCLUSION: Age was the most important predictor of all-cause mortality, although vital signs and laboratory results added considerable prognostic information, with oxygen saturation, temperature, respiratory rate, lactate dehydrogenase and white cell count being among the most important predictors. Demographic and comorbidity factors did not improve model performance appreciably. The full model had good discrimination and was reasonably well calibrated, suggesting that it may be useful for assessment of prognosis.

PMID:33827848 | DOI:10.1136/bmjopen-2020-047121

BMJ Open. 2021 Apr 7;11(4):e046226. doi: 10.1136/bmjopen-2020-046226.

ABSTRACT

OBJECTIVE: This study aims to advance understanding of globally valid versus country-specific quality dimensions and indicators, as perceived by relevant stakeholders. It specifically addresses patient-level indicators for cataract surgery.

DESIGN: A mixed-methods case study comparing Singapore and The Netherlands SETTING: Singapore (2017-2019) and The Netherlands (2014-2015).

PARTICIPANTS: Stakeholder representatives of cataract care in Singapore and The Netherlands.

INTERVENTION: Based on the previously identified complete set of stakeholders in The Netherlands, we identified stakeholders of cataract care in Singapore. Stakeholder representatives then established a multi-stakeholder perspective on the quality of cataract care using a concept mapping approach. This yielded a multidimensional cluster map based on multivariate statistical analyses. Consensus-based quality dimensions were subsequently defined during a plenary session. Thereafter, Singaporean dimensions were matched with dimensions obtained in The Netherlands to identify commonalities and differences.

MAIN OUTCOME MEASURE: Health-services quality dimensions of cataract care.

RESULTS: 19 Singaporean stakeholders representing patients, general practitioners, ophthalmologists, nurses, care providers, researchers and clinical auditors defined health-services quality of cataract care using the following eight dimensions: clinical outcome, patient outcomes, surgical process, surgical safety, patient experience, access, cost and standards of care. Compared with the Dutch results, 61% of the indicators were allocated to dimensions of comparable names and compositions. Considerable differences also existed in the composition of some dimensions and the importance attached to indicators.

CONCLUSIONS AND RELEVANCE: This study on cataract care in Singapore and The Netherlands shows that cataract care quality measurement instruments can share a common international core. At the same time, it emphasises the importance of taking a country-specific multi-stakeholder approach to quality definition and measurement. Complementing an international core set with country-specific measures is required to ensure that the included dimensions and indicators adequately capture the country-specific quality views.

PMID:33827846 | DOI:10.1136/bmjopen-2020-046226

BMJ Open. 2021 Apr 7;11(4):e044854. doi: 10.1136/bmjopen-2020-044854.

ABSTRACT

OBJECTIVE: Survival gains in teenagers and young adults (TYA) are reported to be lower than children and adults for some cancers. Place of care is implicated, influencing access to specialist TYA professionals and research.Consequently, age-appropriate specialist cancer care is advocated for TYA although systematic investigation of associated outcomes is lacking. In England, age-appropriate care is delivered through 13 Principal Treatment Centres (TYA-PTC). BRIGHTLIGHT is the national evaluation of TYA cancer services to examine outcomes associated with differing places and levels of care. We aimed to examine the association between exposure to TYA-PTC care, survival and documentation of clinical processes of care.

DESIGN: Prospective cohort study.

SETTING: 109 National Health Service (NHS) hospitals across England.

PARTICIPANTS: 1114 TYA, aged 13-24, newly diagnosed with cancer between 2012 and 2014.

INTERVENTION: Participants were assigned a TYA-PTC category dependent on the proportion of care delivered in a TYA-PTC in the first year after diagnosis: all care in a TYA-PTC (ALL-TYA-PTC, n=270), no care in a TYA-PTC (NO-TYA-PTC, n=359), and some care in a TYA-PTC with additional care in a children’s/adult unit (SOME-TYA-PTC, n=419).

PRIMARY OUTCOME: Data were collected on documented processes indicative of age-appropriate care using clinical report forms, and survival through linkage to NHS databases.

RESULTS: TYA receiving NO-TYA-PTC care were less likely to have documentation of molecular diagnosis, be reviewed by a children’s or TYA multidisciplinary team, be assessed by supportive care services or have a fertility discussion. There was no significant difference in survival according to category of care. There was weak evidence that the association between care category and survival differed by age (p=0.08) with higher HRs for those over 19 receiving ALL or SOME-TYA-PTC compared with NO-TYA-PTC.

CONCLUSION: TYA-PTC care was associated with better documentation of clinical processes associated with age-appropriate care but not improved survival.

PMID:33827838 | DOI:10.1136/bmjopen-2020-044854

BMJ Open. 2021 Apr 7;11(4):e044669. doi: 10.1136/bmjopen-2020-044669.

ABSTRACT

INTRODUCTION: Intervention in the preschool period is currently recommended for autism spectrum disorder. Therapies delivered by parents are particularly suitable for young children. Preschool Autism Communication Trial (PACT) is a parent-mediated therapy that has shown a significant and sustained impact on autism symptom reduction. However, access to such evidence-based therapies for families is limited due to autism centres located in large urban areas. Using videoconferencing to deliver PACT training to parents may improve accessibility for families living in underserved areas.

METHODS AND ANALYSIS: This single-blind randomised controlled trial, involving six sites in France, will investigate the efficacy of a telehealth, videoconferencing-based, parent-mediated PACT therapy on autism symptoms, over a 12-month period. It will compare PACT plus treatment as usual (TAU) against TAU only in a cohort of 238 toddlers (119 per group) aged 18-36 months at inclusion and living with their families more than 40 min away from the specialist centres for autism. Primary outcome will include change of overall autism score on the Autism Diagnostic Observation Scale (ADOS) at 12 months. Secondary outcomes will measure change in child skills, child functioning, impact on parents (stress, health, priorities) and implementation characteristics. Repeated measures analyses will be used to test the effect of PACT intervention on the overall ADOS module 1 score over the 12-month study period. Linear mixed models will be used with time, treatment allocation and the interaction between treatment and time as fixed effects and individual variation as random effect.

ETHICS AND DISSEMINATION: This protocol (V.5, date: 25 October 2019) is approved by the French National Review Board (reference no 2018-A02516-49). The results will be disseminated via peer-reviewed journals TRIAL REGISTRATION NUMBER: NCT04244721.

PMID:33827837 | DOI:10.1136/bmjopen-2020-044669

BMJ Open. 2021 Apr 7;11(4):e043364. doi: 10.1136/bmjopen-2020-043364.

ABSTRACT

OBJECTIVE: To establish the acceptability and feasibility of delivering the Active Communication Education (ACE) programme to increase quality of life through improving communication and hearing aid use in the UK National Health Service.

DESIGN: Randomised controlled, open feasibility trial with embedded economic and process evaluations.

SETTING: Audiology departments in two hospitals in two UK cities.

PARTICIPANTS: Twelve hearing aid users aged 18 years or over who reported moderate or less than moderate benefit from their new hearing aid.

INTERVENTIONS: Consenting participants (along with a significant other) were to be randomised by a remote, centralised randomisation service in groups to ACE plus treatment-as-usual (intervention group) or treatment-as-usual only (control group).

PRIMARY OUTCOME MEASURES: The primary outcomes were related to feasibility: recruitment, retention, treatment adherence and acceptability to participants and fidelity of treatment delivery.

SECONDARY OUTCOME MEASURES: International Outcomes Inventory for Hearing Aids, Self-Assessment of Communication, EQ-5D-5L and Short-Form 36. Blinding of the participants and facilitator was not possible.

RESULTS: Twelve hearing aid users and six significant others consented to take part. Eight hearing aid users were randomised: four to the intervention group; and four to treatment-as-usual only. Four significant others participated alongside the randomised participants. Recruitment to the study was very low and centres only screened 466 hearing aid users over the 15-month recruitment period, compared with the approximately 3500 anticipated. Only one ACE group and one control group were formed. ACE could be delivered and appeared acceptable to participants. We were unable to robustly assess attrition and attendance rates due to the low sample size.

CONCLUSIONS: While ACE appeared acceptable to hearing aid users and feasible to deliver, it was not feasible to identify and recruit participants struggling with their hearing aids at the 3-month posthearing aid fitting point.

TRIAL REGISTRATION NUMBER: ISRCTN28090877.

PMID:33827834 | DOI:10.1136/bmjopen-2020-043364