Category: Nevin Manimala

Cancer Genomics Proteomics. 2023 Sep-Oct;20(5):417-432. doi: 10.21873/cgp.20394.

ABSTRACT

BACKGROUND/AIM: Lung cancer remains the main culprit in cancer-related mortality worldwide. Transcript fusions play a critical role in the initiation and progression of multiple cancers. Treatment approaches based on specific targeting of discovered driver events, such as mutations in EGFR, and fusions in NTRK, ROS1, and ALK genes led to profound improvements in clinical outcomes. The formation of chimeric proteins due to genomic rearrangements or at the post-transcriptional level is widespread and plays a critical role in tumor initiation and progression. Yet, the fusion landscape of lung cancer remains underexplored.

MATERIALS AND METHODS: We used the JAFFA pipeline to discover transcript fusions in early-stage non-small cell lung cancer (NSCLC). The set of detected fusions was further analyzed to identify recurrent events, genes with multiple partners and fusions with high predicted oncogenic potential. Finally, we used a generalized linear model (GLM) to establish statistical associations between fusion occurrences and clinicopathological variables. RNA sequencing was used to discover and characterize transcript fusions in 270 NSCLC samples selected from the Glans-Look specimen repository. The samples were obtained during the early stages of disease prior to the initiation of chemo- or radiotherapy.

RESULTS: We identified a set of 792 fusions where 751 were novel, and 33 were recurrent. Four of the 33 recurrent fusions were significantly associated with clinicopathological variables. Several of the fusion partners were represented by well-established oncogenes ERBB4, BRAF, FGFR2, and MET.

CONCLUSION: The data presented in this study allow researchers to identify, select, and validate promising candidates for targeted clinical interventions.

PMID:37643782 | DOI:10.21873/cgp.20394

Inflamm Bowel Dis. 2023 Aug 29:izad145. doi: 10.1093/ibd/izad145. Online ahead of print.

ABSTRACT

BACKGROUND: Inflammatory bowel disease (IBD) is best managed by a multidisciplinary team within a dedicated IBD service. IBD nurses play an important role within this team. We aimed to evaluate the contribution of our comprehensive outpatient IBD nursing service on patient outcomes, quality of care, and healthcare costs.

METHODS: We performed a retrospective review of all IBD nurse encounters with patients over a 12-month period from October 2020 to September 2021 at a tertiary IBD referral center. Each nurse encounter was classified with respect to its clinical context, activities, and outcomes. Descriptive statistics were used to characterize these encounters and an economic analysis was performed to estimate the cost savings to the hospital.

RESULTS: A total of 2537 nurse encounters occurred with 682 patients; 41% of encounters were nurse-initiated contacts with patients and 34% were patient-initiated contacts with the nurse helpline (26% via email, 8% via telephone). Most encounters involved clinical assessments (66%), providing education, counseling or updates (47%), and reviewing investigation results (38%). A gastroenterologist was consulted for advice in 35% of contacts. An estimated 29 emergency department visits, 1925 outpatient clinic visits, and 137 general practitioner visits were avoided. After deducting costs incurred, a net estimated annual saving of up to AUD $570 838 was achieved. Nurses commonly facilitated faster access to investigations (29%), education provision (28%), delivery of biologic services (25%), and medication changes (19%).

CONCLUSIONS: A comprehensive IBD nursing service is associated with improved patient outcomes and quality of care, and reduced healthcare costs. This study supports the expanding role of IBD nurses in a modern multidisciplinary IBD service and the need for greater funding and integration of IBD nurses into IBD services.

PMID:37643766 | DOI:10.1093/ibd/izad145

Transplant Cell Ther. 2023 Aug 27:S2666-6367(23)01505-1. doi: 10.1016/j.jtct.2023.08.023. Online ahead of print.

ABSTRACT

BACKGROUND: Clinical research regarding the impact of pretransplant physical function on transplantation outcomes in older adults is still limited.

METHODS: We retrospectively reviewed the charts of 150 consecutive patients over 55 years of age who underwent their first allogeneic hematopoietic cell transplantation (HCT) at our center between 2010 and 2021. We evaluated the clinical impact of pretransplant physical function, including hand grip strength (HGS), knee extension strength (KES), and distance covered in a six-minute walk test (6MWT), along with other clinical factors on transplantation outcomes such as overall survival (OS), non-relapse mortality (NRM) and cumulative incidence of disease relapse (CIR).

RESULTS: There were no differences in OS, NRM, or CIR among the age groups (56-60, 61-65 and 66-70 years). With regard to physical function tests, we divided the study patients into two groups using the median values of HGS, KES and 6MWT (higher and lower groups). Since there were significant differences in HGS and KES between male and female patients, sex-specific threshold values were used. In a univariate analysis, OS tended to be better in the higher-physical function group than in the lower-physical function group (4-year OS, 42.0% vs. 32.0% in HGS, P = 0.14; 44.8% vs. 37.8% in KES, P = 0.17; 46.7% vs. 30.5% in 6MWT, P = 0.099). NRM was significantly lower in the higher-physical function group than in the lower-physical function group (4-year NRM, 25.5% vs. 39.9% in HGS, P = 0.045; 17.7% vs. 38.0% in KES, P = 0.005; 22.5% vs. 43.4% in 6MWT, P = 0.033). There was no significant difference in CIR between the higher- and lower- physical function groups (The 4-year CIR, 34.6% vs. 28.7% in HGS, P = 0.38; 38.5% vs 25.8% in KES, P = 0.20; 33.0% vs 27.0% in 6MWT, P = 0.42). In a multivariate analysis, the higher-KES group (hazard ratio [HR] 0.54 (95% confidence interval [CI], 0.32 – 0.90)) was significantly associated with better OS along with female sex (HR 0.48 [95%CI, 0.26 – 0.89]) and low / intermediate disease risk index (HR 3.59 [95%CI, 2.04 – 6.31]), and higher-KES (HR 0.37 [95%CI, 0.17 – 0.83]) and female sex (HR 0.36 [95%CI, 0.13 – 0.998]) were significantly associated with a reduced risk of NRM. The higher-HGS and higher-6MWT groups tended to be associated with a reduced risk of NRM, but this trend was not statistically significant.

CONCLUSIONS: Pretransplant physical function, particularly the strength of the lower extremities, rather than chronological age is associated with NRM and OS after allogeneic HCT in adults over 55 years of age.

PMID:37643718 | DOI:10.1016/j.jtct.2023.08.023

J Foot Ankle Surg. 2023 Aug 27:S1067-2516(23)00213-2. doi: 10.1053/j.jfas.2023.08.010. Online ahead of print.

ABSTRACT

Minimally invasive (MIS) surgery has gained popularity for hallux valgus correction in the adult population. The advantage of reproducibility of this procedure can aid in lower operating room costs, quicker recovery, and fewer complications. The purpose of this retrospective study was to compare pre-operative versus post-operative foot widths in patients that underwent MIS hallux valgus correction. The average pre-operative foot width was 101.1 ± 5.67 mm and post-operatively the foot width measured at 12-month follow-up was 95.9 ± 4.92 mm, which was statistically significant (p < 0.001). Overall, there was a 5.03±3.71% reduction in foot width, with a statistically significant linear relationship between pre-operative foot width and percent change in width following the procedure (R = -0.46; p = 0.003). Based on our results, we can conclude that MIS bunion surgery can effectively narrow the foot post-operatively, particularly in patients with a wider forefoot, adding cosmetic benefit to the procedure.

PMID:37643686 | DOI:10.1053/j.jfas.2023.08.010

NMR Biomed. 2023 Aug 29:e5026. doi: 10.1002/nbm.5026. Online ahead of print.

ABSTRACT

Blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging (fMRI) is one of the most used imaging techniques to map brain activity or to obtain clinical information about human cortical vasculature, in both healthy and disease conditions. Nevertheless, BOLD fMRI is an indirect measurement of brain functioning triggered by neurovascular coupling. The origin of the BOLD signal is quite complex, and the signal formation thus depends, among other factors, on the topology of the cortical vasculature and the associated hemodynamic changes. To understand the hemodynamic evolution of the BOLD signal response in humans, it is beneficial to have a computational framework available that virtually resembles the human cortical vasculature, and simulates hemodynamic changes and corresponding MRI signal changes via interactions of intrinsic biophysical and magnetic properties of the tissues. To this end, we have developed a mechanistic computational framework that simulates the hemodynamic fingerprint of the BOLD signal based on a statistically defined, three-dimensional, vascular model that approaches the human cortical vascular architecture. The microvasculature is approximated through a Voronoi tessellation method and the macrovasculature is adapted from two-photon microscopy mice data. Using this computational framework, we simulated hemodynamic changes-cerebral blood flow, cerebral blood volume, and blood oxygen saturation-induced by virtual arterial dilation. Then we computed local magnetic field disturbances generated by the vascular topology and the corresponding blood oxygen saturation changes. This mechanistic computational framework also considers the intrinsic biophysical and magnetic properties of nearby tissue, such as water diffusion and relaxation properties, resulting in a dynamic BOLD signal response. The proposed mechanistic computational framework provides an integrated biophysical model that can offer better insights regarding the spatial and temporal properties of the BOLD signal changes.

PMID:37643645 | DOI:10.1002/nbm.5026

J R Soc Interface. 2023 Aug;20(205):20230310. doi: 10.1098/rsif.2023.0310. Epub 2023 Aug 30.

ABSTRACT

Despite widespread claims of power laws across the natural and social sciences, evidence in data is often equivocal. Modern data and statistical methods reject even classic power laws such as Pareto’s law of wealth and the Gutenberg-Richter law for earthquake magnitudes. We show that the maximum-likelihood estimators and Kolmogorov-Smirnov (K-S) statistics in widespread use are unexpectedly sensitive to ubiquitous errors in data such as measurement noise, quantization noise, heaping and censorship of small values. This sensitivity causes spurious rejection of power laws and biases parameter estimates even in arbitrarily large samples, which explains inconsistencies between theory and data. We show that logarithmic binning by powers of λ > 1 attenuates these errors in a manner analogous to noise averaging in normal statistics and that λ thereby tunes a trade-off between accuracy and precision in estimation. Binning also removes potentially misleading within-scale information while preserving information about the shape of a distribution over powers of λ, and we show that some amount of binning can improve sensitivity and specificity of K-S tests without any cost, while more extreme binning tunes a trade-off between sensitivity and specificity. We therefore advocate logarithmic binning as a simple essential step in power-law inference.

PMID:37643642 | DOI:10.1098/rsif.2023.0310

Pain Med. 2023 Aug 29:pnad119. doi: 10.1093/pm/pnad119. Online ahead of print.

ABSTRACT

BACKGROUND: Orthopedic patients report pain as their main symptom complaint. Subjective pain experience is correlated with self-reported psychological state such as distress.

PURPOSE: This study tests whether scores from a measure of mindful attention are associated with subjective pain levels and if psychological distress scores function as a mediation path.

METHODS: During routine visits to a single orthopedic clinic in East Los Angeles, 525 patients were recruited to participate in the study. Participants reported on measures of pain (Universal Pain Assessment Tool, UPAT), mindful attention (Five-Facet Mindfulness Questionnaire, FFMQ) and psychological distress (Depression, Anxiety, and Stress Scale, DASS). We used Pearson correlation to examine relationships between FFMQ and UPAT scores, and mediation analyses to test indirect effects of DASS scores as a mediation path.

RESULTS: The average age of the sample was 54 years (range 18-98), 61% were male, and 64% were non-Hispanic White individuals. The locations of injury were shoulder (72%), elbow (21%) and clavicle or wrist (7%). 91% reported mild or greater pain in the past two weeks (M = 4.2 ± 2.5, range 0-10) and 49% reported mild or more severe distress symptoms (DASS: 13.0 ± 11.5). FFMQ scores inversely predicted UPAT scores (β = 0.-22, p < 0.01) mediated through DASS scores. DASS subscale scores for depression (β=-0.10, p = 0.02) and stress (β=-0.08, p = 0.04) but not anxiety (β=-0.03, p = 0.33) produced significant indirect effects. FFMQ acting-with-awareness and non-judging subscales had the largest effect on depression and stress DASS subscale scores.

CONCLUSIONS: We find statistical support to suggest distress-particularly depressed mood and stress-mediates the association between mindful attention and pain intensity among orthopedic patients. A disposition of mindful attention may counter distress ailments that exacerbate subjective pain, and this has possible implications for mindfulness training interventions offered to orthopedic patients.

PMID:37643631 | DOI:10.1093/pm/pnad119

Stat Med. 2023 Aug 29. doi: 10.1002/sim.9887. Online ahead of print.

ABSTRACT

Response-dependent sampling is routinely used as an enrichment strategy in the design of family studies investigating the heritable nature of disease. In addition to the response of primary interest, investigators often wish to investigate the association between biomarkers and secondary responses related to possible comorbidities. Statistical analysis regarding genetic biomarkers and their association with the secondary outcome must address the biased sampling scheme involving the primary response. In this article, we develop composite likelihoods and two-stage estimation procedures for such secondary analyses in which the within-family dependence structure for the primary and secondary outcomes is modeled via a Gaussian copula. The dependence among responses within family members is modeled based on kinship coefficients. Auxiliary data from independent individuals are exploited by augmenting the composite likelihoods to increase precision of marginal parameter estimates and enhance the efficiency of estimators of the dependence parameters. Simulation studies are carried out to evaluate the finite sample performance of the proposed method, and an application to a motivating family study in psoriatic arthritis is given for illustration.

PMID:37643587 | DOI:10.1002/sim.9887

Clin Biomech (Bristol, Avon). 2023 Aug 23;109:106077. doi: 10.1016/j.clinbiomech.2023.106077. Online ahead of print.

ABSTRACT

BACKGROUND: Observational gait analysis is frequently used by clinicians to subjectively assess straight walking but is not often used to examine turning. Interlimb comparisons of phase- specific turning biomechanics in people with unilateral lower limb amputation has not previously been documented.

METHODS: A retrospective examination of gait kinematics and kinetics from five participants with unilateral transtibial amputation was performed. Data were collected during 90° step and spin turns capturing three distinct turning steps. Gait metrics of interest included: total turn time, stance time, peak knee flexion angle during Pre-Swing and Initial Swing gait phases, peak hip flexion and extension, ground reaction impulse, and whole body angular momentum. Statistical comparisons were made based on turn type between sound and prosthetic limbs.

FINDINGS: During the three turn steps (approach, apex, depart), participants spent significantly more time (P < 0.01) on their sound limb compared to their prosthetic limb regardless of turn type. Additionally, the prosthetic limb hip and knee exhibited more flexion (P < 0.05) during the apex step of turns, and whole body angular momentum was higher when the sound limb was used during the apex step of a turn (P < 0.05).

INTERPRETATION: This descriptive study offers the first phase-specific quantification of turning biomechanics in people with lower limb amputation. Results indicate that people with unilateral transtibial amputation spend more time on and experience higher impulses through their sound compared to their prosthetic limb during 90° turns, and that the prosthetic limb is performing differently than the sound limb, potentially increasing risks of injury or falls.

PMID:37643570 | DOI:10.1016/j.clinbiomech.2023.106077

Vet Parasitol. 2023 Aug 25;322:110008. doi: 10.1016/j.vetpar.2023.110008. Online ahead of print.

ABSTRACT

Parasitic diseases are considered to be a cause of oxidative stress which leads to oxidative damage of various molecules including DNA. This can result in mutations, replication errors, and genome instability. Therefore, aim of this study was to measure DNA damage induced by Dirofilaria immitis in the single cells such as dogs’ leukocytes using the comet assay. Also, we monitored the effects of antiparasitic treatment on mitigation of sensitivity to DNA damage in leukocytes treated with H₂O₂ using the in vivo and ex vivo comet assay. The whole blood samples from 34 dogs from Serbia were used, both males and females, from one to 13 years old, both pure and mixed-breeds. A rapid immunochromatographic test (Antigen Rapid Heartworm Ag 2.0 Test Kit, Bionote, Minnesota, USA) was used for the detection of D. immitis antigens. The modified Knott’s test and PCR were used in the aim of detecting D. immitis microfilariae in dogs’ blood, and evaluating the number of circulating microfilariae during the treatment. The genotoxicity evaluation showed that D. immitis infection resulted in DNA damage in naturally infected dogs, with the highest DNA damage occurring in the group of dogs with severe clinical signs. Treatment with ivermectin and doxycycline decreased DNA damage in leukocytes of dogs in all groups, as the intensity of infection decreased due to applied therapy. Ex vivo comet assay results showed that leukocytes exhibited decreased sensitivity to H₂O₂-induced DNA damage during treatment. The results of the modified Knott’s test and PCR in our study showed that treatment with ivermectin and doxycycline was successful in decreasing the average number of microfilariae during the time and at the end eliminating them from the dogs’ blood.

PMID:37643566 | DOI:10.1016/j.vetpar.2023.110008