Category: Nevin Manimala

J Clin Oncol. 2023 Apr 27:JCO2202390. doi: 10.1200/JCO.22.02390. Online ahead of print.

ABSTRACT

PURPOSE: It remains unknown whether or not short-term androgen deprivation (STAD) improves survival among men with intermediate-risk prostate cancer (IRPC) treated with dose-escalated radiotherapy (RT).

METHODS: The NRG Oncology/Radiation Therapy Oncology Group 0815 study randomly assigned 1,492 patients with stage T2b-T2c, Gleason score 7, or prostate-specific antigen (PSA) value >10 and ≤20 ng/mL to dose-escalated RT alone (arm 1) or with STAD (arm 2). STAD was 6 months of luteinizing hormone-releasing hormone agonist/antagonist therapy plus antiandrogen. RT modalities were external-beam RT alone to 79.2 Gy or external beam (45 Gy) with brachytherapy boost. The primary end point was overall survival (OS). Secondary end points included prostate cancer-specific mortality (PCSM), non-PCSM, distant metastases (DMs), PSA failure, and rates of salvage therapy.

RESULTS: Median follow-up was 6.3 years. Two hundred nineteen deaths occurred, 119 in arm 1 and 100 in arm 2. Five-year OS estimates were 90% versus 91%, respectively (hazard ratio [HR], 0.85; 95% CI, 0.65 to 1.11]; P = .22). STAD resulted in reduced PSA failure (HR, 0.52; P <.001), DM (HR, 0.25; P <.001), PCSM (HR, 0.10; P = .007), and salvage therapy use (HR, 0.62; P = .025). Other-cause deaths were not significantly different (P = .56). Acute grade ≥3 adverse events (AEs) occurred in 2% of patients in arm 1 and in 12% for arm 2 (P <.001). Cumulative incidence of late grade ≥3 AEs was 14% in arm 1 and 15% in arm 2 (P = .29).

CONCLUSION: STAD did not improve OS rates for men with IRPC treated with dose-escalated RT. Improvements in metastases rates, prostate cancer deaths, and PSA failures should be weighed against the risk of adverse events and the impact of STAD on quality of life.

PMID:37104748 | DOI:10.1200/JCO.22.02390

Pain Med. 2023 Apr 27:pnad049. doi: 10.1093/pm/pnad049. Online ahead of print.

ABSTRACT

OBJECTIVE: To investigate how a behavioral health, artificial intelligence (AI)-powered, digital self-management tool affects the daily functions in adults with chronic back and neck pain.

DESIGN: Eligible subjects were enrolled in a 12-week prospective, multicenter, single-arm, open-label study and instructed to use the digital coach daily. Primary outcome was a change in Patient-Reported Outcomes Measurement Information Systems (PROMIS) scores for pain interference. Secondary outcomes were changes in PROMIS physical function, anxiety, depression, pain intensity scores and pain catastrophizing scale (PCS) scores.

METHODS: Subjects logged daily activities, using PainDrainerTM, and data analyzed by the AI engine. Questionnaire and web-based data were collected at 6 and 12-weeks and compared to subjects’ baseline.

RESULTS: Subjects completed the 6- (n = 41) and 12-week (n = 34) questionnaires. A statistically significant Minimal Important Difference (MID) for pain interference was demonstrated in 57.5% of the subjects. Similarly, MID for physical function was demonstrated in 72.5% of the subjects. A pre- to post-intervention improvement in depression score was also statistically significant, observed in 100% of subjects, as was the improvement in anxiety scores, evident in 81.3% of the subjects. PCS mean scores was also significantly decreased at 12 weeks.

CONCLUSION: Chronic pain self-management, using an AI-powered, digital coach anchored in behavioral health principles significantly improved subjects’ pain interference, physical function, depression, anxiety, and pain catastrophizing over the 12-week study period.

PMID:37104747 | DOI:10.1093/pm/pnad049

Bioinformatics. 2023 Apr 27:btad291. doi: 10.1093/bioinformatics/btad291. Online ahead of print.

ABSTRACT

MOTIVATION: Testing association between multiple phenotypes with a set of genetic variants simultaneously, rather than analyzing one trait at a time, is receiving an increasing attention for its high statistical power and easy explanation on pleiotropic effects. The kernel-based association test (KAT), being free of data dimensions and structures, has proven to be a good alternative method for genetic association analysis with multiple phenotypes. However, KAT suffers from substantial power loss when multiple phenotypes have moderate to strong correlations. To handle this issue, we propose a maximum kernel-based association test (MaxKAT) and suggest using the generalized extreme value distribution to calculate its statistical significance under the null hypothesis.

RESULTS: We show that MaxKAT reduces computational intensity greatly while maintaining high accuracy. Extensive simulations demonstrate that MaxKAT can properly control type I error rates and obtain remarkably higher power than KAT under most of the considered scenarios. Application to a porcine dataset used in biomedical experiments of human disease further illustrates its practical utility.

AVAILABILITY AND IMPLEMENTATION: The R package MaxKAT that implements the proposed method is available on Github https://github.com/WangJJ-xrk/MaxKAT.

PMID:37104737 | DOI:10.1093/bioinformatics/btad291

Am J Public Health. 2023 Apr 27:e1-e8. doi: 10.2105/AJPH.2023.307302. Online ahead of print.

ABSTRACT

The COVID-19 pandemic has revealed the importance of the population-scale effects of both diseases and interventions. Vaccines have had an enormous impact, greatly reducing the suffering caused by COVID-19. Clinical trials have focused on individual-level clinical benefits, however, so the broader effects of the vaccines on preventing infection and transmission, and their overall effect at the community level, remain unclear. These questions can be addressed through alternative designs for vaccine trials, including assessing different endpoints and randomizing at the cluster instead of individual level. Although these designs exist, various factors have limited their use as preauthorization pivotal trials. They face statistical, epidemiological, and logistical limitations as well as regulatory barriers and uncertainty. Addressing these hindrances through research, communication, and policy can improve the evidence base of vaccines, their strategic deployment, and population health, both in the COVID-19 pandemic and in future infectious disease outbreaks. (Am J Public Health. Published online ahead of print April 27, 2023:e1-e8. https://doi.org/10.2105/AJPH.2023.307302).

PMID:37104734 | DOI:10.2105/AJPH.2023.307302

J Clin Oncol. 2023 Apr 27:JCO2201153. doi: 10.1200/JCO.22.01153. Online ahead of print.

ABSTRACT

PURPOSE: Artificial intelligence (AI) algorithms improve breast cancer detection on mammography, but their contribution to long-term risk prediction for advanced and interval cancers is unknown.

METHODS: We identified 2,412 women with invasive breast cancer and 4,995 controls matched on age, race, and date of mammogram, from two US mammography cohorts, who had two-dimensional full-field digital mammograms performed 2-5.5 years before cancer diagnosis. We assessed Breast Imaging Reporting and Data System density, an AI malignancy score (1-10), and volumetric density measures. We used conditional logistic regression to estimate odds ratios (ORs), 95% CIs, adjusted for age and BMI, and C-statistics (AUC) to describe the association of AI score with invasive cancer and its contribution to models with breast density measures. Likelihood ratio tests (LRTs) and bootstrapping methods were used to compare model performance.

RESULTS: On mammograms between 2-5.5 years prior to cancer, a one unit increase in AI score was associated with 20% greater odds of invasive breast cancer (OR, 1.20; 95% CI, 1.17 to 1.22; AUC, 0.63; 95% CI, 0.62 to 0.64) and was similarly predictive of interval (OR, 1.20; 95% CI, 1.13 to 1.27; AUC, 0.63) and advanced cancers (OR, 1.23; 95% CI, 1.16 to 1.31; AUC, 0.64) and in dense (OR, 1.18; 95% CI, 1.15 to 1.22; AUC, 0.66) breasts. AI score improved prediction of all cancer types in models with density measures (P_LRT values < .001); discrimination improved for advanced cancer (ie, AUC for dense volume increased from 0.624 to 0.679, Δ AUC 0.065, P = .01) but did not reach statistical significance for interval cancer.

CONCLUSION: AI imaging algorithms coupled with breast density independently contribute to long-term risk prediction of invasive breast cancers, in particular, advanced cancer.

PMID:37104728 | DOI:10.1200/JCO.22.01153

J Chem Inf Model. 2023 Apr 27. doi: 10.1021/acs.jcim.3c00187. Online ahead of print.

ABSTRACT

In this work, we show that the apparent pK_a measured by standard titration experiments is an insufficient measure of acidity or basicity of organic functional groups in multiprotic compounds─a frequent aspect of lead optimization in pharmaceutical research. We show that the use of the apparent pK_a in this context may result in costly mistakes. To properly represent the group’s true acidity/basicity, we propose pK₅₀─a single-proton midpoint measure derived from a statistical thermodynamics treatment of multiprotic ionization. We show that pK₅₀, which may be directly measured in specialized NMR titration experiments, is superior in tracking the functional group’s acidity/basicity across congeneric series of related compounds and converges to the well familiar ionization constant in the monoprotic case.

PMID:37104727 | DOI:10.1021/acs.jcim.3c00187

J Clin Oncol. 2023 Apr 27:JCO2202389. doi: 10.1200/JCO.22.02389. Online ahead of print.

ABSTRACT

PURPOSE: To report patient-reported outcomes (PROs) of a phase III trial evaluating total androgen suppression (TAS) combined with dose-escalated radiation therapy (RT) for patients with intermediate-risk prostate cancer.

METHODS: Patients with intermediate-risk prostate cancer were randomly assigned to dose-escalated RT alone (arm 1) or RT plus TAS (arm 2) consisting of luteinizing hormone-releasing hormone agonist/antagonist with oral antiandrogen for 6 months. The primary PRO was the validated Expanded Prostate Cancer Index Composite (EPIC-50). Secondary PROs included Patient-Reported Outcome Measurement Information System (PROMIS)-fatigue and EuroQOL five-dimensions scale questionnaire (EQ-5D). PRO change scores, calculated for each patient as the follow-up score minus baseline score (at the end of RT and at 6, 12, and 60 months), were compared between treatment arms using a two-sample t test. An effect size of 0.50 standard deviation was considered clinically meaningful.

RESULTS: For the primary PRO instrument (EPIC), the completion rates were ≥86% through the first year of follow-up and 70%-75% at 5 years. For the EPIC hormonal and sexual domains, there were clinically meaningful (P < .0001) deficits in the RT + TAS arm. However, there were no clinically meaningful differences by 1 year between arms. There were also no clinically meaningful differences at any time points between arms for PROMIS-fatigue, EQ-5D, and EPIC bowel/urinary scores.

CONCLUSION: Compared with dose-escalated RT alone, adding TAS demonstrated clinically meaningful declines only in EPIC hormonal and sexual domains. However, even these PRO differences were transient, and there were no clinically meaningful differences between arms by 1 year.

PMID:37104723 | DOI:10.1200/JCO.22.02389

J Am Chem Soc. 2023 Apr 27. doi: 10.1021/jacs.3c01095. Online ahead of print.

ABSTRACT

Conformational changes underpin function and encode complex biomolecular mechanisms. Gaining atomic-level detail of how such changes occur has the potential to reveal these mechanisms and is of critical importance in identifying drug targets, facilitating rational drug design, and enabling bioengineering applications. While the past two decades have brought Markov state model techniques to the point where practitioners can regularly use them to glimpse the long-time dynamics of slow conformations in complex systems, many systems are still beyond their reach. In this Perspective, we discuss how including memory (i.e., non-Markovian effects) can reduce the computational cost to predict the long-time dynamics in these complex systems by orders of magnitude and with greater accuracy and resolution than state-of-the-art Markov state models. We illustrate how memory lies at the heart of successful and promising techniques, ranging from the Fokker-Planck and generalized Langevin equations to deep-learning recurrent neural networks and generalized master equations. We delineate how these techniques work, identify insights that they can offer in biomolecular systems, and discuss their advantages and disadvantages in practical settings. We show how generalized master equations can enable the investigation of, for example, the gate-opening process in RNA polymerase II and demonstrate how our recent advances tame the deleterious influence of statistical underconvergence of the molecular dynamics simulations used to parameterize these techniques. This represents a significant leap forward that will enable our memory-based techniques to interrogate systems that are currently beyond the reach of even the best Markov state models. We conclude by discussing some current challenges and future prospects for how exploiting memory will open the door to many exciting opportunities.

PMID:37104720 | DOI:10.1021/jacs.3c01095

Clin J Pain. 2023 Apr 24. doi: 10.1097/AJP.0000000000001116. Online ahead of print.

ABSTRACT

OBJECTIVE: Determine the relative effectiveness and safety profiles of percutaneous and minimally invasive interventions for chronic low back pain.

METHODS: A systematic search was performed for randomized controlled trials (RCTs) published in the past 20 years reporting on radiofrequency (RF) ablation of the basivertebral, disc annulus and facet nerve structures, steroid injection of the disc, facet joint and medial branch, biologic therapies, and multifidus muscle stimulation. Outcomes evaluated included Visual Analog Scale (VAS) pain scores, Oswestry Disability Index (ODI) scores, quality of life (SF-36 and EQ-5D) scores and serious adverse event (SAE) rates. Basivertebral nerve (BVN) ablation was chosen as the subject of comparison to all other therapies using a random-effects meta-analysis.

RESULTS: Twenty-seven studies were included. BVN ablation was found to provide significant improvements in VAS and ODI scores for 6-, 12- and 24-months follow-up (P≤0.05). Biologic therapy and multifidus muscle stimulation were the only two treatments with both VAS and ODI outcomes not significantly different from BVN ablation at 6-, 12- and 24-months follow-up. All outcomes found to be statistically significant represented inferior results to those of BVN ablation. Insufficient data precluded meaningful comparisons of SF-36 and EQ-5D scores. The SAE rates for all therapies and all reported time points were not significantly different from BVN ablation except for biologic therapy and multifidus muscle stimulation at 6-months follow- up.

CONCLUSIONS: BVN ablation, biologic therapy and multifidus stimulation all provide significant, durable improvements in both pain and disability compared to other interventions, which provided only short-term pain relief. Studies on BVN ablation reported no SAEs, a significantly better result than for studies of biologic therapy and multifidus stimulation.

PMID:37104694 | DOI:10.1097/AJP.0000000000001116

J Infus Nurs. 2023 May-Jun 01;46(3):149-156. doi: 10.1097/NAN.0000000000000503.

ABSTRACT

Caregiver/patient fall injury risks increase when medical tubing drapes on floors. The objective of this research was to examine the value of a novel carriage system that organizes and elevates medical and intravenous (IV) tubing. Using a prospective, multicenter, cohort design, value of the IV carriage system was assessed using a valid, reliable survey that provided the total score and scores of 3 involvement factors: personal relevance, attitude, and importance. The survey was scored on a 0-100 scale, and questions about tubing elevation, patient mobility, and ease of use were rated on 0-10 scales. Participants were adult and pediatric inpatient caregivers (n = 131). In adult intensive care environments (n = 61), carriage system value scores were higher in the quaternary care site compared to 4 enterprise adult intensive care sites (median [Q1, Q3]: 90.0 [69.2, 97.5] vs 72.5 [52.5, 78.3], respectively; P = .008). Compared to nurses working in adult environments (n = 58), pediatric nurses (n = 40) had higher value scores (median [Q1, Q3]: 89.2 [68.3, 97.5] vs 97.5 [85.8, 100.0], respectively; P = .007). High median score ratings (9-10) were given for tubing elevation, patient mobility, and ease of use. In conclusion, the IV carriage system was valued by nurses as an important tool in clinical practice.

PMID:37104690 | DOI:10.1097/NAN.0000000000000503