Category: Statistics

J Clin Oncol. 2023 Jan 4:JCO2201096. doi: 10.1200/JCO.22.01096. Online ahead of print.

ABSTRACT

PURPOSE: To report clinical and treatment characteristics, remission and failure patterns, and risk factors for local failure (LF) from the EMBRACE-I study.

MATERIALS AND METHODS: EMBRACE-I was a prospective, observational, multicenter cohort study on magnetic resonance imaging-based image-guided adaptive brachytherapy (MR-IGABT) in locally advanced cervical cancer. Treatment consisted of external beam radiotherapy, concurrent chemotherapy, and MR-IGABT. LF was defined as progressive or recurrent disease in the cervix, uterus, parametria, pelvic wall, or vagina. Competing risk analysis was used to estimate local tumor control (LC) and Cox proportional regression models for multivariable analysis and dose-response analysis.

RESULTS: One thousand three hundred eighteen patients with a median follow-up of 52 months were available for this analysis. Eighty-one patients had persistent disease 3 months after end of treatment. Of those, 60 patients achieved LC at 6-9 months without further treatment, whereas 21 patients had progressive disease. In addition, 77 patients developed a local recurrence after complete remission comprising a total number of 98 LFs. LFs were located inside the MR-IGABT target volumes in 90% of patients with LF. In multivariable analysis, histology, minimal dose to 90% of high-risk clinical target volume (CTV_HR), maximum tumor dimension, CTV_HR > 45 cm³, overall treatment time, tumor necrosis on magnetic resonance imaging at diagnosis, uterine corpus infiltration at diagnosis and at MR-IGABT, and mesorectal infiltration at MR-IGABT had significant impact on LF. Dose-response analysis showed that a minimal dose to 90% of 85 Gy to the CTV_HR led to 95% (95% CI, 94 to 97) LC 3 years postintervention for squamous cell in comparison to 86% (95% CI, 81 to 90) for adeno/adenosquamous carcinoma histology.

CONCLUSION: The present study demonstrates the safety and validity of the GYN GEC-ESTRO/ICRU-89 target concept and provides large-scale evidence for dose prescription and new risk factors for LF in MR-IGABT in locally advanced cervical cancer.

PMID:36599120 | DOI:10.1200/JCO.22.01096

Dis Colon Rectum. 2023 Jan 4. doi: 10.1097/DCR.0000000000002623. Online ahead of print.

ABSTRACT

BACKGROUND: Anal cancer is associated with high-risk human papillomavirus infection and oncoprotein expression. We have identified several protease inhibitors, used to treat HIV, that decrease oncogene expression.

OBJECTIVE: The aim of this project is to determine whether the protease inhibitor, Saquinavir, results in a treatment response in anal cancer spheroids.

DESIGN: K14E6/E7 transgenic mice (n=5), which express HPV16 oncoproteins E6 and E7 in their epithelium, were treated topically at the anus with carcinogen, 7,12 dimethylbenz[a]anthracene, to promote anal tumor growth. Tumors were excised and digested, and cells were plated. The tumor cells form 3D multicellular aggregates, known as spheroids.

SETTINGS: This study was performed in an American Association for Accreditation of Laboratory Animal Care approved facility.

INTERVENTIONS: Spheroids were placed in treatment groups: no treatment, vehicle (dimethyl sulfoxide), and 15 μM Saquinavir. Spheroids were imaged immediately prior to treatment and 24-hours post-treatment.

MAIN OUTCOME MEASURES: Spheroid diameters were measured using ImageJ and mean percent reduction was calculated for each spheroid to determine treatment effect on spheroid growth. Analysis of variance using pairwise comparisons were performed with Fisher’s protected least significant difference tests.

RESULTS: No treatment (n=119 spheroids) and vehicle (n=126 spheroids) groups demonstrated an increase in spheroid diameter over the treatment period. In contrast, spheroids treated with Saquinavir (n=151 spheroids), demonstrated a statistically significant percent reduction compared to no treatment (p value < 0.0001) and vehicle (p value = 0.002) groups.

LIMITATIONS: A limitation of this data is that some human error is likely present given that images were analyzed by three different scientists.

CONCLUSIONS: Saquinavir leads to a statistically significant percent reduction in mice anal tumor spheroid growth ex-vivo when compared to control groups. Protease inhibitor therapy may be an effective treatment or adjuvant therapy to the Nigro protocol to promote anal cancer tumor regression. See Video Abstract at http://links.lww.com/DCR/C82.

PMID:36599112 | DOI:10.1097/DCR.0000000000002623

Am J Speech Lang Pathol. 2023 Jan 4:1-15. doi: 10.1044/2022_AJSLP-22-00086. Online ahead of print.

ABSTRACT

INTRODUCTION: The prevalence of traumatic brain injury (TBI) in the criminal justice system (CJS) is well known. Furthermore, the impact of TBI on communication has been well documented; however, no study has explored the communication challenges of those with TBI in the CJS or considered their implications within CJS contexts. Moreover, no study has examined the possible differences in communication between those with TBI and CJS history and those with TBI but no CJS history.

PURPOSE: This cross-sectional pilot study provides a preliminary exploration of the cognitive-communication challenges in a sample of adults with histories of TBI and CJS involvement compared with a sample of adults with histories of TBI but no CJS involvement.

METHOD: Eight individuals with histories of TBI and CJS involvement were recruited through community agencies. The La Trobe Communication Questionnaire (LCQ) was administered to collect self-reported data on perceived cognitive-communication abilities, including social communication behaviors. Findings were examined and then compared with a previously studied sample of 160 individuals with TBI. Logistic regressions were calculated to determine whether response scores on the LCQ would be predictive of group membership (i.e., TBI + CJS or TBI only).

RESULTS: A range of cognitive-communication challenges were reported by both groups. A logistic regression analysis demonstrated a reasonable inference that LCQ responses may predict group membership and support the potential for statistically significant and meaningful results to justify future studies.

CONCLUSIONS: These challenges have the potential to negatively impact the success of communication interactions within the CJS and illustrate a need for speech-language pathology services for individuals with TBI in the CJS. The nature and magnitude of between-group differences merits further investigation with larger samples to explore whether any specific cognitive-communication challenge is unique to, or predictive of, CJS involvement for purposes of targeted assessment and intervention.

PMID:36599105 | DOI:10.1044/2022_AJSLP-22-00086

Multivariate Behav Res. 2023 Jan 4:1-26. doi: 10.1080/00273171.2022.2158776. Online ahead of print.

ABSTRACT

The impact of missing data on statistical inference varies depending on several factors such as the proportion of missingness, missing-data mechanism, and method employed to handle missing values. While these topics have been extensively studied, most recommendations have been made assuming that all missing values are from the same missing-data mechanism. In reality, it is very likely that a mixture of missing-data mechanisms is responsible for missing values in a dataset and even within the same pattern of missingness. Although a mixture of missing-data mechanisms and causes within a dataset is a likely scenario, the performance of popular missing-data methods under these circumstances is unknown. This study provides a realistic evaluation of methods for handling missing data in this setting using Monte Carlo simulation in the context of regression. This study also seeks to identify acceptable proportions of missing values that violate the missing-data mechanism assumed by the method used to handle missing values. Results indicate that multiple imputation (MI) performs better than other principled or ad-hoc methods. Different missing-data methods are also compared via the analysis of a real dataset in which mixtures of missingness mechanisms are created. Recommendations are provided for the use of different methods in practice.

PMID:36599049 | DOI:10.1080/00273171.2022.2158776

Multivariate Behav Res. 2023 Jan 4:1-12. doi: 10.1080/00273171.2022.2155930. Online ahead of print.

ABSTRACT

The cross-sectional correlation is frequently used to summarize psychological data, and can be considered the basis for many statistical techniques. However, the work of Peter Molenaar on ergodicity has raised concerns about the meaning and utility of this measure, especially when the interest is in discovering general laws that apply to (all) individuals. Through using Cattell’s databox and adopting a multilevel perspective, this paper provides a closer look at the cross-sectional correlation, with the goal to better understand its meaning when ergodicity is absent. An analytical expression is presented that shows the cross-sectional correlation is a function of the between-person correlation (based on person-specific means), and the within-person correlation (based on individuals’ temporal deviations from their person-specific means). Two curiosities related to this expression of the cross-sectional correlation are elaborated on, that is: a) the difference between the within-person correlation and the (average) person-specific correlation; and b) the unexpected scenarios that can arise because the cross-sectional correlation is a weighted sum rather than a weighted average of the between-person and within-person correlations. Seven specific examples are presented to illustrate various ways in which these two curiosities may combine; R code is provided, which allows researchers to investigate additional scenarios.

PMID:36599045 | DOI:10.1080/00273171.2022.2155930

Clin J Pain. 2023 Jan 2. doi: 10.1097/AJP.0000000000001092. Online ahead of print.

ABSTRACT

OBJECTIVE: The purpose of this systematic review is to assess the effectiveness and safety of conservative interventions compared to other interventions, placebo/sham interventions, or no intervention on disability, pain, function, quality of life, and psychological impact in adults with cervical radiculopathy (CR).

METHODS: We searched MEDLINE, CENTRAL, CINAHL, Embase, and PsycINFO from inception to June 15, 2022 to identify studies that were RCTs, had at least one conservative treatment arm, and diagnosed participants with CR through confirmatory clinical examination and/or diagnostic tests. Studies were appraised using the Cochrane Risk of Bias 2 tool and the quality of the evidence was rated using the GRADE approach.

RESULTS: Of the 2,561 records identified, 59 trials met our inclusion criteria (n=4108 participants). Due to clinical and statistical heterogeneity, the findings were synthesized narratively. There is very-low certainty evidence supporting the use of acupuncture, Prednisolone, cervical manipulation, and low-level laser therapy for pain and disability in the immediate to short-term, and thoracic manipulation and low-level laser therapy for improvements in cervical range of motion (ROM) in the immediate term. There is low to very-low certainty evidence for multimodal interventions, providing inconclusive evidence for pain, disability, and ROM. There is inconclusive evidence for pain reduction following conservative management compared to surgery, rated as very-low certainty.

DISCUSSION: There is a lack of high-quality evidence, limiting our ability to make any meaningful conclusions. As the number of people with CR is expected to increase, there is an urgent need for future research to help address these gaps.

PMID:36599029 | DOI:10.1097/AJP.0000000000001092

Sci Transl Med. 2023 Jan 4;15(677):eadc9606. doi: 10.1126/scitranslmed.adc9606. Epub 2023 Jan 4.

ABSTRACT

Degenerative mitral valve (MV) regurgitation (MR) is a highly prevalent heart disease that requires surgery in severe cases. Here, we show that a decrease in the activity of the serotonin transporter (SERT) accelerates MV remodeling and progression to MR. Through studies of a population of patients with MR, we show that selective serotonin reuptake inhibitor (SSRI) use and SERT promoter polymorphism 5-HTTLPR LL genotype were associated with MV surgery at younger age. Functional characterization of 122 human MV samples, in conjunction with in vivo studies in SERT^-/- mice and wild-type mice treated with the SSRI fluoxetine, showed that diminished SERT activity in MV interstitial cells (MVICs) contributed to the pathophysiology of MR through enhanced serotonin receptor (HTR) signaling. SERT activity was decreased in LL MVICs partially because of diminished membrane localization of SERT. In mice, fluoxetine treatment or SERT knockdown resulted in thickened MV leaflets. Similarly, silencing of SERT in normal human MVICs led to up-regulation of transforming growth factor β1 (TGFβ1) and collagen (COL1A1) in the presence of serotonin. In addition, treatment of MVICs with fluoxetine not only directly inhibited SERT activity but also decreased SERT expression and increased HTR2B expression. Fluoxetine treatment and LL genotype were also associated with increased COL1A1 expression in the presence of serotonin in MVICs, and these effects were attenuated by HTR2B inhibition. These results suggest that assessment of both 5-HTTLPR genotype and SERT-inhibiting treatments may be useful tools to risk-stratify patients with MV disease to estimate the likelihood of rapid disease progression.

PMID:36599005 | DOI:10.1126/scitranslmed.adc9606

J Pediatr Hematol Oncol. 2023 Jan 1;45(1):e26-e30. doi: 10.1097/MPH.0000000000002575. Epub 2022 Oct 20.

ABSTRACT

Children with cancer often present with general and nonspecific symptoms leading to initial diagnostic workup inclusive of clinical imaging. Various sequences of magnetic resonance imaging (MRI) are becoming more available for diagnostic imaging. However, there is currently a dearth of literature quantifying the sensitivity and specificity of whole-body MRI in identifying pediatric malignancy. In this study, a retrospective analysis was performed of pediatric whole-body MRI inclusive of short tau inversion recovery sequence conducted at an academic pediatric medical center from 2013 to 2018. Kappa statistics were used to evaluate the diagnostic agreement between MRI results and the gold standard diagnostic study of the respective final diagnosis. Sensitivity, specificity, false-positive, and false-negative estimates were provided with joint 90% confidence regions. One hundred forty-two patients received a whole-body MRI during the study period. The sensitivity of whole-body MRI in detecting malignancy was found to be 93.8% with a specificity of 93.4%. The positive and negative predictive values were determined to be 65.2% and 99.1%, respectively. Our findings suggest that whole-body MRI may be of value as an initial diagnostic tool for pediatric malignancy. Larger multicenter collaboration will be needed to further support these data.

PMID:36598963 | DOI:10.1097/MPH.0000000000002575

J Pediatr Hematol Oncol. 2023 Jan 1;45(1):25-28. doi: 10.1097/MPH.0000000000002600. Epub 2022 Nov 24.

ABSTRACT

PURPOSE: Central venous lines (CVL) in children with acute lymphoblastic leukemia (ALL) provide comfortable administration of intensive chemotherapy and blood sampling. The optimal time for the insertion of CVL in patients with ALL during induction therapy is controversial. This study aimed to investigate the frequency of CVL-related complications in children with ALL concerning the time of CVL insertion.

PATIENTS AND METHODS: We reviewed the records of 52 pediatric ALL patients with CVL. CVL placement before or on treatment day 15 was defined as “early insertion”, and after treatment day 15 was defined as “late insertion”. Demographics, preoperative blood counts, type of central line, time of CVL placement, CVL-related complications, and blood counts during complications were all noted. All the data were collected from those with the first catheter use.

RESULTS: CVL was placed ≤15 days in 26 patients (50%) and after 15 days in 26 patients (50%). Regarding the infection rates, no statistical difference was found between early and late CVL-inserted groups (P=n.s.). Five patients developed thrombosis, and risk was found to be similar between early and late CVL-inserted groups (P=n.s.). Catheter-related mechanical complications were recorded in 7 patients (3 in early and 4 in late CVL-inserted group, (P=n.s.).

CONCLUSION: The present study showed no relation between the timing of CVL placement during induction therapy and the occurrence of infection and thrombosis. Our results suggest that CVL can be placed safely at the time of diagnosis or early induction treatment to provide a comfortable administration of chemotherapy and decrease painful blood samplings.

PMID:36598960 | DOI:10.1097/MPH.0000000000002600

Proc Natl Acad Sci U S A. 2023 Jan 10;120(2):e2123182120. doi: 10.1073/pnas.2123182120. Epub 2023 Jan 4.

ABSTRACT

Early-life experience enduringly sculpts thalamocortical (TC) axons and sensory processing. Here, we identify the very first synaptic targets that initiate critical period plasticity, heralded by altered cortical oscillations. Monocular deprivation (MD) acutely induced a transient (<3 h) peak in EEG γ-power (~40 Hz) specifically within the visual cortex, but only when the critical period was open (juvenile mice or adults after dark-rearing, Lynx1-deletion, or diazepam-rescued GAD65-deficiency). Rapid TC input loss onto parvalbumin-expressing (PV) inhibitory interneurons (but not onto nearby pyramidal cells) was observed within hours of MD in a TC slice preserving the visual pathway – again once critical periods opened. Computational TC modeling of the emergent γ-rhythm in response to MD delineated a cortical interneuronal gamma (ING) rhythm in networks of PV-cells bearing gap junctions at the start of the critical period. The ING rhythm effectively dissociated thalamic input from cortical spiking, leading to rapid loss of previously strong TC-to-PV connections through standard spike-timing-dependent plasticity rules. As a consequence, previously silent TC-to-PV connections could strengthen on a slower timescale, capturing the gradually increasing γ-frequency and eventual fade-out over time. Thus, ING enables cortical dynamics to transition from being dominated by the strongest TC input to one that senses the statistics of population TC input after MD. Taken together, our findings reveal the initial synaptic events underlying critical period plasticity and suggest that the fleeting ING accompanying a brief sensory perturbation may serve as a robust readout of TC network state with which to probe developmental trajectories.

PMID:36598942 | DOI:10.1073/pnas.2123182120