The impact of different censoring methods for analyzing survival using real-world data with linked mortality information: a simulation study.

BACKGROUND: Evaluating outcome reliability is critical in real-world evidence studies. Overall survival is a common outcome in these studies; however, its capture in real-world data (RWD) sources is often incomplete and supplemented with linked mortality information from external sources. Conflicting recommendations exist for censoring overall survival in real-world evidence studies. This simulation study aimed to understand the impact of different censoring methods on estimating median survival and log hazard ratios when external mortality information is partially captured. METHODS: We used Monte Carlo simulation to emulate a non-randomized comparative effectiveness study of two treatments with RWD from electronic health records and linked external mortality data. We simulated the time to death, the time to last database activity, and the time to data cutoff. Death events after the last database activity were attributed to linked external mortality data and randomly set to missing to reflect the sensitivity of contemporary real-world data sources. Two censoring schemes were evaluated: (1) censoring at the last activity date and (2) censoring at the end of data availability (data cutoff) without an observed death. We assessed the performance of each method in estimating median survival and log hazard ratios using bias, coverage, variance, and rejection rate under varying amounts of incomplete mortality information and varying treatment effects, length of follow-up, and sample size. RESULTS: When mortality information was fully captured, median survival estimates were unbiased when censoring at data cutoff and underestimated when censoring at the last activity. When linked mortality information was missing, censoring at the last activity date underestimated the median survival, while censoring at the data cutoff overestimated it. As missing linked mortality information increased, bias decreased when censoring at the last activity date and increased when censoring at data cutoff. CONCLUSIONS: Researchers should consider the completeness of linked external mortality information when choosing how to censor the analysis of overall survival using RWD. Substantial bias in median survival estimates can occur if an inappropriate censoring scheme is selected. We advocate for RWD providers to perform validation studies of their mortality data and publish their findings to inform methodological decisions better.

Upper Gastrointestinal Involvement in Crohn's Disease as an Independent Predictor of New-Onset Strictures: Insights from an Extensive Retrospective Cohort Analysis.

BACKGROUND/AIMS: Crohn's Disease (CD) can affect the entire gastrointestinal tract, including the upper sections (UGI), which is often overlooked, especially in Asian populations. There's a notable gap in research regarding the impact of UGI involvement on the intricate landscape of ensuing complications. This study aims to address this gap. METHODS: Conducting a retrospective study at Chang Gung Memorial Hospital from January 2001 to September 2023, we compared CD patients with UGI (Montreal L4) involvement against non-L4 counterparts, focusing on baseline characteristics, post-diagnosis complications, and overall outcomes. Routine UGI endoscopy was performed around the time of diagnosis in all patients followed in our inflammatory bowel disease (IBD) center, and all CD patients with adequate follow-up were included in this study. RESULTS: The study included 212 CD patients, 111 in the L4 group and 101 in the non-L4 group, with an average follow-up of 40.8 ± 15.1 months. At baseline, individuals in the L4 category demonstrated elevated smoking rates, increased Crohn's Disease Activity Index scores, a higher prevalence of strictures, and a more prevalent usage of biologics and proton pump inhibitors. Moreover, this group was characterized by reduced albumin levels. Upon concluding the follow-up, those with L4 involvement continued to show escalated CDAI scores and hospitalization frequencies, alongside heightened C-reactive protein levels and diminished albumin concentrations. Additionally, the occurrence of UGI involvement, stricturing disease at the time of diagnosis, and a younger age at the onset of CD were pinpointed as independent predictors for the development of new-onset strictures. CONCLUSIONS: CD patients with UGI involvement exhibit elevated disease activity and serve as independent predictors for the development of intestinal strictures. Thorough UGI evaluations at the time of diagnosis, coupled with assertive treatment strategies, are essential for managing these patients effectively.

Using Arterial Pulse and Laser Doppler Analyses to Discriminate between the Cardiovascular Effects of Different Running Levels.

BACKGROUND AND AIMS: Running can induce advantageous cardiovascular effects such as improved arterial stiffness and blood-supply perfusion. However, the differences between the vascular and blood-flow perfusion conditions under different levels of endurance-running performance remains unclear. The present study aimed to assess the vascular and blood-flow perfusion conditions among 3 groups (44 male volunteers) according to the time taken to run 3 km: Level 1, Level 2, and Level 3. METHODS: The radial blood pressure waveform (BPW), finger photoplethygraphy (PPG), and skin-surface laser-Doppler flowmetry (LDF) signals of the subjects were measured. Frequency-domain analysis was applied to BPW and PPG signals; time- and frequency-domain analyses were applied to LDF signals. RESULTS: Pulse waveform and LDF indices differed significantly among the three groups. These could be used to evaluate the advantageous cardiovascular effects provided by long-term endurance-running training, such as vessel relaxation (pulse waveform indices), improvement in blood supply perfusion (LDF indices), and changes in cardiovascular regulation activities (pulse and LDF variability indices). Using the relative changes in pulse-effect indices, we achieved almost perfect discrimination between Level 3 and Level 2 (AUC = 0.878). Furthermore, the present pulse waveform analysis could also be used to discriminate between the Level-1 and Level-2 groups. CONCLUSIONS: The present findings contribute to the development of a noninvasive, easy-to-use, and objective evaluation technique for the cardiovascular benefits of prolonged endurance-running training.

The effect of giving verbal feedback during neck stabilisation exercise as an addition to physical therapy in patients with chronic neck pain: A randomised controlled trial.

OBJECTIVES: To study the addition of feedback-guided neck strength home exercise to physical therapy as an enhanced rehabilitation programme in the treatment of patients with chronic neck pain. DESIGN: A prospective randomised controlled trial. SETTING: Rehabilitation department of an academic hospital. SUBJECTS: Patients with chronic neck pain. INTERVENTIONS: The patients in both groups received supervised physical therapy sessions 3 times a week for 12 weeks. Patients in Group A (N = 38) used the neck strengthening exerciser device for 20 min daily at home for 6 weeks and patients in Group B (N = 20) performed 20 min of daily regular neck exercise at home for 6 weeks. OUTCOME MEASURES: Neck disability index, pain visual analogue scale, active range of motion of the neck, Patient Global Assessment and patient evaluation of treatment effect. All subjects were assessed at baseline as well as at 6- and 12-week follow-ups. RESULTS: At the 6-week follow-up, Group A exhibited significantly greater improvements (P < 0.05) in pain Visual Analogue Scale (Group A: 2.97 ± 1.57; Group B: 4.20 ± 1.82), neck disability index (Group A: 13.95 ± 8.07; Group B: 20.07 ± 9.14) and active cervical extension (Group A: 65.26 ± 12.76; Group B: 51.45 ± 11.78). At 12-week follow-up, Group A also exhibited significantly greater active cervical extension (Group A: 67.74 ± 11.94; Group B: 53.85 ± 14.09; P < 0.05). CONCLUSION: Adding neck strengthening exerciser home training to physical therapy was demonstrated to be more effective than physical therapy alone for patients with chronic neck pain.

Alpelisib plus fulvestrant in PIK3CA-mutated, hormone receptor-positive advanced breast cancer after a CDK4/6 inhibitor (BYLieve): one cohort of a phase 2, multicentre, open-label, non-comparative study.

BACKGROUND: Alpelisib, a PI3Kα-selective inhibitor and degrader, plus fulvestrant showed efficacy in hormone receptor-positive, HER2-negative, PIK3CA-mutated advanced breast cancer in SOLAR-1; limited data are available in the post-cyclin-dependent kinase 4/6 inhibitor setting. BYLieve aimed to assess alpelisib plus endocrine therapy in this setting in three cohorts defined by immediate previous treatment; here, we report results from cohort A. METHODS: This ongoing, phase 2, multicentre, open-label, non-comparative study enrolled patients with hormone receptor-positive, HER2-negative, advanced breast cancer with tumour PIK3CA mutation, following progression on or after previous therapy, including CDK4/6 inhibitors, from 114 study locations (cancer centres, medical centres, university hospitals, and hospitals) in 18 countries worldwide. Participants aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 2 or less, with no more than two previous anticancer treatments and no more than one previous chemotherapy regimen, were enrolled in three cohorts. In cohort A, patients must have had progression on or after a CDK4/6 inhibitor plus an aromatase inhibitor as the immediate previous treatment. Patients received oral alpelisib 300 mg/day (continuously) plus fulvestrant 500 mg intramuscularly on day 1 of each 28-day cycle and on day 15 of cycle 1. The primary endpoint was the proportion of patients alive without disease progression at 6 months per local assessment using Response Evaluation Criteria in Solid Tumors, version 1.1, in patients with a centrally confirmed PIK3CA mutation. This trial is registered with ClinicalTrials.gov, NCT03056755. FINDINGS: Between Aug 14, 2017, and Dec 17, 2019 (data cutoff), 127 patients with at least 6 months' follow-up were enrolled into cohort A. 121 patients had a centrally confirmed PIK3CA mutation. At data cutoff, median follow-up was 11·7 months (IQR 8·5-15·9). 61 (50·4%; 95% CI 41·2-59·6) of 121 patients were alive without disease progression at 6 months. The most frequent grade 3 or worse adverse events were hyperglycaemia (36 [28%] of 127 patients), rash (12 [9%]), and rash maculopapular (12 [9%]). Serious adverse events occurred in 33 (26%) of 127 patients. No treatment-related deaths were reported. INTERPRETATION: BYLieve showed activity of alpelisib plus fulvestrant with manageable toxicity in patients with PIK3CA-mutated, hormone receptor-positive, HER2-negative advanced breast cancer, after progression on a CDK4/6 inhibitor plus an aromatase inhibitor. FUNDING: Novartis Pharmaceuticals.

Effectiveness of Alpelisib + Fulvestrant Compared with Real-World Standard Treatment Among Patients with HR+, HER2-, PIK3CA-Mutated Breast Cancer.

BACKGROUND: The BYLieve trial (NCT03056755) confirmed efficacy and safety of alpelisib with fulvestrant for hormone receptor-positive (HR+), human epidermal growth factor receptor-2-negative (HER2-), PIK3CA-mutated advanced breast cancer (ABC), after cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) with an aromatase inhibitor (AI) as immediate prior therapy. Further analyses were performed to compare efficacy from BYLieve with effectiveness of standard treatment in the real-world setting. MATERIALS AND METHODS: Patients who progressed on a CDK4/6i plus AI and were treated with alpelisib with fulvestrant in BYLieve were matched with a real-world patient cohort who received standard-of-care from a deidentified clinico-genomics database (CGDB). Primary and secondary endpoints were to compare progression-free survival (PFS), estimated by the Kaplan-Meier method, and the proportion of patients remaining progression-free at 6 months, respectively, between the two cohorts. RESULTS: A total of 855 patients with PIK3CA-mutant disease who had prior CDK4/6i plus hormone therapy were selected from the CGDB; further matching to 120 patients from BYLieve selected 95 patients without exposure to HER2-targeting agents, clinical study drug, or alpelisib. In unadjusted and postmatching results, primary and secondary endpoints favored treatment with alpelisib with fulvestrant in BYLieve more than standard treatments in the real-world cohort. Postadjustment, median PFS for patients treated with alpelisib in BYLieve was 7.3 versus 3.7 months in the real-world cohort, and 6-month PFS was 54.6% versus 40.1%, respectively. CONCLUSION: Matched/weighted analysis comparing BYLieve with the real-world setting further supports the clinical benefit of alpelisib with fulvestrant for treatment of HR+, HER2-, PIK3CA-mutant ABC after CDK4/6i treatment. IMPLICATIONS FOR PRACTICE: Approximately 40% of patients with hormone receptor-positive (HR+), human epidermal growth factor receptor-2-negative (HER2-) advanced breast cancer (ABC) have PIK3CA-mutated tumors, which have been associated with endocrine therapy resistance. Alpelisib, an α-selective phosphatidylinositol-3-kinase inhibitor, demonstrated significantly improved progression-free survival in SOLAR-1 and demonstrated clinical efficacy in BYLieve when combined with fulvestrant. Data are limited in comparing the efficacy of alpelisib combined with fulvestrant with effectiveness of standard therapy after CDK4/6i treatment. Using real-world data, this is the first analysis comparing alpelisib combined with fulvestrant with standard treatments for HR+, HER2-, PIK3CA-mutant ABC in the post-CDK4/6i setting.

Comparison of the corticosteroid injection and hyaluronate in the treatment of chronic subacromial bursitis: A randomized controlled trial.

OBJECTIVE: To analyse the effectiveness of corticosteroid (CS) and hyaluronic acid (HA) subacromial - subdeltoid (SASD) injection compared with normal saline (NS) in patients with chronic subacromial bursitis (CSB). DESIGN: A prospective three-arm double-blinded randomised controlled trial. SETTING: Rehabilitation department of two teaching hospitals. SUBJECTS: Patients with CSB (N = 186) divided into CS (N = 68), HA (N = 60), and NS (N = 58) groups. INTERVENTIONS: Three SASD injections under ultrasound guidance: group A, 20 mg of triamcinolone; group B, 2.5 mL of HA; and group C, 2.5 mL of NS. OUTCOME MEASURES: The primary outcome measures were the pain visual analogue scale (VAS) score at eight weeks. The secondary outcomes were scores on the Shoulder Pain and Disability Index (SPADI) and Shoulder Disability Questionnaire. RESULTS: At eight weeks, the pain VAS scores during activity were 2.56 ± 2.29, 3.65 ± 2.50, and 4.71 ± 2.83 in the CS, HA, and NS groups, respectively (CS vs NS, P < 0.001; HA vs NS, P = 0.013; CS vs HA, P = 0.010). SPADI scores were 40.83 ± 21.75, 36.92 ± 22.78, and 33.35 ± 23.38 in the CS, HA, and NS groups, respectively (CS vs NS, P < 0.001; HA vs NS, P = 0.197; CS vs HA, P = 0.004). CONCLUSION: Ultrasound-guided corticosteroid injection into the subacromial - subdeltoid bursa was proven to be effective and superior to hyaluronic acid and normal saline injection for treating CSB. Hyaluronic acid injection was only marginally more effective than normal saline injection.Trial Registration: ClinicalTrials.gov: NCT02702206.

Strain and Temperature Sensitivities Along with Mechanical Properties of CNT Buckypaper Sensors.

In this work, buckypaper composed of multi-walled carbon nanotubes (MWCNT) was prepared through a vacuum filtration process. The effect of MWCNT aspect ratio on the buckypaper performance was investigated. The freestanding and highly flexible buckypaper can be used as a sensor to attach on a complex surface monitoring the strain and temperature at the critical area. The mechanical properties of the buckypaper were examined using the tensile and nanoindentation tests. The strain and temperature sensitivities of the buckypaper were evaluated through the four-point bending and thermal chamber tests, respectively. In addition, the microstructure and thermal stability of the buckypaper were studied by scanning electron microscopy (SEM) and thermogravimetric analyzer (TGA), respectively. Experimental results showed that the mechanical properties such as Young's modulus, tensile strength, fracture strain, and hardness of the buckypaper made of high aspect ratio MWCNTs were significantly superior to the buckypaper consisted of low aspect ratio MWCNTs, while the strain and temperature sensitivities of the buckypaper composed of low aspect ratio MWCNTs were better than that of the buckypaper made of high aspect ratio MWCNTs.

Optimizing the Sensor Placement for Foot Plantar Center of Pressure without Prior Knowledge Using Deep Reinforcement Learning.

We study the foot plantar sensor placement by a deep reinforcement learning algorithm without using any prior knowledge of the foot anatomical area. To apply a reinforcement learning algorithm, we propose a sensor placement environment and reward system that aims to optimize fitting the center of pressure (COP) trajectory during the self-selected speed running task. In this environment, the agent considers placing eight sensors within a 7 × 20 grid coordinate system, and then the final pattern becomes the result of sensor placement. Our results show that this method (1) can generate a sensor placement, which has a low mean square error in fitting ground truth COP trajectory, and (2) robustly discovers the optimal sensor placement in a large number of combinations, which is more than 116 quadrillion. This method is also feasible for solving different tasks, regardless of the self-selected speed running task.

The Use of Wearable Sensors for the Movement Assessment on Muscle Contraction Sequences in Post-Stroke Patients during Sit-to-Stand.

Electromyography (EMG) sensors have been used to study the sequence of muscle contractions during sit-to-stand (STS) in post-stroke patients. However, the majority of the studies used wired sensors with a limited number of placements. Using the latest improved wearable technology with 16 sensors, the current study was a thorough investigation to evaluate the contraction sequences of eight key muscles on the trunk and bilateral limbs during STS in post-stroke patients, as it became feasible. Multiple wearable sensors for the detection of muscle contraction sequences showed that the post-stroke patients performed STS with abnormal firing sequences, not only in the primary mover on the sagittal plane during raising, but also in the tibialis anterior, which may affect anticipatory postural adjustment in the gluteus medius, which may affect balance control. The abnormal tibialis anterior contraction until the early ascending phase and the delayed firing of the gluteus muscles highlight the importance of whole-kinetic-chain monitoring of contraction sequences using wearable sensors. The findings can be helpful for the design of therapeutic exercises.

Contemporary Incidence and Outcomes of Prostate Cancer Lymph Node Metastases.

PURPOSE: The incidence of localized prostate cancer has decreased with shifts in prostate cancer screening. While recent population based studies demonstrated a stable incidence of locoregional prostate cancer, they categorized organ confined, extraprostatic and lymph node positive disease together. However, to our knowledge the contemporary incidence of prostate cancer with pelvic lymph node metastases remains unknown. MATERIALS AND METHODS: We used SEER (Surveillance, Epidemiology and End Results) data from 2004 to 2014 to identify men diagnosed with prostate cancer. We analyzed trends in the age standardized prostate cancer incidence by stage. The impact of disease extent on mortality was assessed by adjusted Cox proportional hazard analysis. RESULTS: During the study period the annual incidence of nonmetastatic prostate cancer decreased from 5,119.1 to 2,931.9 per million men (IR 0.57, 95% CI 0.56-0.58, p <0.01) while the incidence of pelvic lymph node metastases increased from 54.1 to 79.5 per million men (IR 1.47, 95% CI 1.33-1.62, p <0.01). The incidence of distant metastases in men 75 years old or older reached a nadir in 2011 compared to 2004 (IR 0.81, 95% CI 0.74-0.90, p <0.01) and it increased in 2012 compared to 2011 (IR 1.13, 95% CI 1.02-1.24, p <0.05). The risk of cancer specific mortality significantly increased in men diagnosed with pelvic lymph node metastases (HR 4.5, 95% CI 4.2-4.9, p <0.01) and distant metastases (HR 21.9, 95% CI 21.2-22.7, p <0.01) compared to men with nonmetastatic disease. CONCLUSIONS: The incidence of pelvic lymph node metastases is increasing coincident with a decline in the detection of localized disease. Whether this portends an increase in the burden of advanced disease or simply reflects decreased lead time remains unclear. However, this should be monitored closely as the increase in N1 disease reflects an increase in incurable prostate cancer at diagnosis.

The Design and Application of Simplified Insole-Based Prototypes with Plantar Pressure Measurement for Fast Screening of Flat-Foot.

This study aimed to find the correlation between conventional Arch Index (AI) measurements and our prototype of a simplified insole-based plantar pressure measurement system and to find out the effective plantar pressure sensor position. Twenty-one subjects participated in this study, which was divided into two groups: 10 subjects with flatfoot and 11 subjects with normal foot. Five force sensitive resistance sensors were used on this prototype using Arduino as the data acquisition device. Two types of trials, namely static and dynamic, were conducted to validate our system against the ink-type AI measurement as a golden standard. The results showed that in the static trial, there was a high linear correlation with the medial arch sensor configuration, while in the dynamic trial, there was a high linear correlation in the medial arch sensor configuration and sensor 5 configuration. This study showed that both static and dynamic tests using the self-developed device could effectively determine most of the flatfoot subjects and suggests that in the future, it can be applied in clinical applications because of its advantages when compared to the expensive-high tech graphic input board and conventional tools, like ink-type based measurements.

Multiple-Wearable-Sensor-Based Gait Classification and Analysis in Patients with Neurological Disorders.

The aim of this study was to conduct a comprehensive analysis of the placement of multiple wearable sensors for the purpose of analyzing and classifying the gaits of patients with neurological disorders. Seven inertial measurement unit (IMU) sensors were placed at seven locations: the lower back (L5) and both sides of the thigh, distal tibia (shank), and foot. The 20 subjects selected to participate in this study were separated into two groups: stroke patients (11) and patients with neurological disorders other than stroke (brain concussion, spinal injury, or brain hemorrhage) (9). The temporal parameters of gait were calculated using a wearable device, and various features and sensor configurations were examined to establish the ideal accuracy for classifying different groups. A comparison of the various methods and features for classifying the three groups revealed that a combination of time domain and gait temporal feature-based classification with the Multilayer Perceptron (MLP) algorithm outperformed the other methods of feature-based classification. The classification results of different sensor placements revealed that the sensor placed on the shank achieved higher accuracy than the other sensor placements (L5, foot, and thigh). The placement-based classification of the shank sensor achieved 89.13% testing accuracy with the Decision Tree (DT) classifier algorithm. The results of this study indicate that the wearable IMU device is capable of differentiating between the gait patterns of healthy patients, patients with stroke, and patients with other neurological disorders. Moreover, the most favorable results were reported for the classification that used the combination of time domain and gait temporal features as the model input and the shank location for sensor placement.

Indications, Utilization and Complications Following Prostate Biopsy: New York State Analysis.

PURPOSE: Uptake of active surveillance and changes in prostate cancer care may affect the utilization of and complications following prostate needle biopsy. We characterized recent trends and risk factors for prostate needle biopsy complications using a statewide, all-payer cohort. MATERIALS AND METHODS: We used SPARCS (New York Statewide Planning and Research Cooperative System) to identify prostate needle biopsies performed between 2011 and 2014 via the transrectal and the transperineal approach (9,472 and 421 patients, respectively). We characterized trends in utilization and complications using Poisson regression and the Cochrane-Armitage test. We applied logistic regression to examine predictors of complications within 30 days of prostate needle biopsy. RESULTS: Ambulatory use of prostate needle biopsy decreased with time (p <0.01). The most common indication for prostate needle biopsy was elevated prostate specific antigen in 53.2% of patients, followed by active surveillance for cancer in 26.7%, abnormal digital rectal examination in 2.6% and atypia in 1.6%. The prostate needle biopsy associated infection rate increased from 2.6% to 3.5% during the study period (p = 0.02). Among the 777 repeat prostate needle biopsies, the complication rate was comparable to that of initial prostate needle biopsy. Preprocedural rectal swab was done in less than 1% of prostate needle biopsies. On multivariable analysis, patient race, procedure year, diabetes (OR 1.92, 95% CI 1.29-2.86, p <0.01), transrectal approach (OR 3.48, 95% CI 1.27-9.54, p = 0.02) and recent hospitalization (OR 2.03, 95% CI 1.43-2.89, p <0.01) were significantly associated with infection. The median total charge for infectious complications was $4,129 (IQR 711-19,185). CONCLUSIONS: Across New York State, infectious complications after prostate needle biopsy have increased over time. With higher complications using the transrectal approach and minimal utilization of targeted antibiotic prophylaxis, further efforts should focus on the evaluation and implementation of these strategies to reduce post-prostate needle biopsy complications nationally.

CK2 activity is required for the interaction of FGF14 with voltage-gated sodium channels and neuronal excitability.

Recent data shows that fibroblast growth factor 14 (FGF14) binds to and controls the function of the voltage-gated sodium (Nav) channel with phenotypic outcomes on neuronal excitability. Mutations in the FGF14 gene in humans have been associated with brain disorders that are partially recapitulated in Fgf14(-/-) mice. Thus, signaling pathways that modulate the FGF14:Nav channel interaction may be important therapeutic targets. Bioluminescence-based screening of small molecule modulators of the FGF14:Nav1.6 complex identified 4,5,6,7 -: tetrabromobenzotriazole (TBB), a potent casein kinase 2 (CK2) inhibitor, as a strong suppressor of FGF14:Nav1.6 interaction. Inhibition of CK2 through TBB reduces the interaction of FGF14 with Nav1.6 and Nav1.2 channels. Mass spectrometry confirmed direct phosphorylation of FGF14 by CK2 at S228 and S230, and mutation to alanine at these sites modified FGF14 modulation of Nav1.6-mediated currents. In 1 d in vitro hippocampal neurons, TBB induced a reduction in FGF14 expression, a decrease in transient Na(+) current amplitude, and a hyperpolarizing shift in the voltage dependence of Nav channel steady-state inactivation. In mature neurons, TBB reduces the axodendritic polarity of FGF14. In cornu ammonis area 1 hippocampal slices from wild-type mice, TBB impairs neuronal excitability by increasing action potential threshold and lowering firing frequency. Importantly, these changes in excitability are recapitulated in Fgf14(-/-) mice, and deletion of Fgf14 occludes TBB-dependent phenotypes observed in wild-type mice. These results suggest that a CK2-FGF14 axis may regulate Nav channels and neuronal excitability.-Hsu, W.-C. J., Scala, F., Nenov, M. N., Wildburger, N. C., Elferink, H., Singh, A. K., Chesson, C. B., Buzhdygan, T., Sohail, M., Shavkunov, A. S., Panova, N. I., Nilsson, C. L., Rudra, J. S., Lichti, C. F., Laezza, F. CK2 activity is required for the interaction of FGF14 with voltage-gated sodium channels and neuronal excitability.

Predictors of acupuncture use among children and adolescents with cancer.

BACKGROUND: Evidence for the application of acupuncture in pediatric oncology is limited. We investigated the acceptance of acupuncture and factors associated with its use among children and adolescents with cancer. METHODS: Ninety acupuncture-naïve children receiving cancer treatment at Columbia University Medical Center (CUMC) provided consent/assent for participation. Participants could choose to receive or refuse integrative services offered at CUMC. Symptoms were collected for a 6-month period with the Memorial Symptom Assessment Scale (MSAS). Acute and delayed adverse events among participants who received acupuncture were recorded. RESULTS: Fifty-four percent of the participants elected to receive acupuncture. In total, 252 acupuncture sessions were administered with a median of four sessions per patient (range 1-13 sessions). Pain (56%), nausea (51%), lack of energy (50%), and irritability (43%) were the most frequently reported symptoms in the whole cohort. Determinants of acupuncture use included older age and ethnicity. Acupuncture was more likely than other integrative modalities to be used for gastrointestinal and constitutional symptoms including drowsiness (odds ratio [OR], 3.34; 95% confidence interval [CI], 1.98-5.66; P < 0.0001), lack of energy (OR, 3.23; 95% CI, 1.78-5.87; P = 0.0001), and pain (OR, 2.63; 95% CI, 1.46-4.72; P = 0.001). Adverse events were reported by 3% of the participants. There was no increased incidence of adverse events in children with thrombocytopenia (P = 0.189) or neutropenia (P = 0.497). CONCLUSION: Our results highlight the potential use of acupuncture as a safe, adjunctive therapy for symptom management within existing supportive care regimens in pediatric oncology and potential areas to focus research initiatives.

Quantitative proteomics reveals protein-protein interactions with fibroblast growth factor 12 as a component of the voltage-gated sodium channel 1.2 (nav1.2) macromolecular complex in Mammalian brain.

Voltage-gated sodium channels (Nav1.1-Nav1.9) are responsible for the initiation and propagation of action potentials in neurons, controlling firing patterns, synaptic transmission and plasticity of the brain circuit. Yet, it is the protein-protein interactions of the macromolecular complex that exert diverse modulatory actions on the channel, dictating its ultimate functional outcome. Despite the fundamental role of Nav channels in the brain, information on its proteome is still lacking. Here we used affinity purification from crude membrane extracts of whole brain followed by quantitative high-resolution mass spectrometry to resolve the identity of Nav1.2 protein interactors. Of the identified putative protein interactors, fibroblast growth factor 12 (FGF12), a member of the nonsecreted intracellular FGF family, exhibited 30-fold enrichment in Nav1.2 purifications compared with other identified proteins. Using confocal microscopy, we visualized native FGF12 in the brain tissue and confirmed that FGF12 forms a complex with Nav1.2 channels at the axonal initial segment, the subcellular specialized domain of neurons required for action potential initiation. Co-immunoprecipitation studies in a heterologous expression system validate Nav1.2 and FGF12 as interactors, whereas patch-clamp electrophysiology reveals that FGF12 acts synergistically with CaMKII, a known kinase regulator of Nav channels, to modulate Nav1.2-encoded currents. In the presence of CaMKII inhibitors we found that FGF12 produces a bidirectional shift in the voltage-dependence of activation (more depolarized) and the steady-state inactivation (more hyperpolarized) of Nav1.2, increasing the channel availability. Although providing the first characterization of the Nav1.2 CNS proteome, we identify FGF12 as a new functionally relevant interactor. Our studies will provide invaluable information to parse out the molecular determinant underlying neuronal excitability and plasticity, and extending the relevance of iFGFs signaling in the normal and diseased brain.

Use, complications, and costs of stereotactic body radiotherapy for localized prostate cancer.

BACKGROUND: Stereotactic body radiotherapy (SBRT) for localized prostate cancer has potential advantages over traditional radiotherapies. Herein, the authors compared national trends in use, complications, and costs of SBRT with those of traditional radiotherapies. METHODS: The authors identified men who underwent SBRT, intensity-modulated radiotherapy (IMRT), brachytherapy, and proton beam therapy as primary treatment of prostate cancer between 2004 and 2011 from Surveillance, Epidemiology, and End Results Program (SEER)-Medicare linked data. Temporal trend of therapy use was assessed using the Cochran-Armitage test. Two-year outcomes were compared using the chi-square test. Median treatment costs were compared using the Kruskal-Wallis test. RESULTS: A total of 542 men received SBRT, 9647 received brachytherapy, 23,408 received IMRT, and 800 men were treated with proton beam therapy. There was a significant increase in the use of SBRT and proton beam therapy (P<.001), whereas brachytherapy use decreased (P<.001). A higher percentage of patients treated with SBRT and brachytherapy had low-grade cancer (Gleason score ≤ 6 vs ≥ 7) compared with individuals treated with IMRT and proton beam therapy (54.0% and 64.2% vs 35.2% and 49.6%, respectively; P<.001). SBRT compared with brachytherapy and IMRT was associated with equivalent gastrointestinal toxicity but more erectile dysfunction at 2-year follow-up (P<.001). SBRT was associated with more urinary incontinence compared with IMRT and proton beam therapy but less compared with brachytherapy (P<.001, respectively). The median cost of SBRT was $27,145 compared with $17,183 for brachytherapy, $37,090 for IMRT, and $54,706 for proton beam therapy (P<.001). CONCLUSIONS: The use of SBRT and proton beam therapy for localized prostate cancer has increased over time. Despite men of lower disease stage undergoing SBRT, SBRT was found to be associated with greater toxicity but lower health care costs compared with IMRT and proton beam therapy. Cancer 2016;122:2496-504. © 2016 American Cancer Society.

Immediate and long-term efficacy of laterally-wedged insoles on persons with bilateral medial knee osteoarthritis during walking.

BACKGROUND: The current study aimed to investigate the immediate and long-term effects of laterally-wedged (LW) insoles on the knee loadings, the knee abductor moment (KAM) in particular, and the compensatory changes at other lower limb joints in patients with bilateral medial knee osteoarthritis during level walking with and without LW insoles. METHODS: Older adults with bilateral medial knee OA (age 66 ± 5.3 years; height 156 ± 4.9 cm; mass 60 ± 5.1 kg; leg length 83.72 ± 3.64 cm) were studied using computerized gait analysis initially (Baseline) and 6 weeks after using LW insoles (Follow-up) during barefoot walking and walking with LW insoles (7° of lateral inclination, with medial arch support). The three-dimensional angles and internal moments at the lower limb joints, as well as the ground reaction forces, were obtained using a motion analysis system and two forceplates. Key features of all the variables were compared using paired t tests for immediate effects (barefoot vs. LW) and for long-term effects (Baseline vs. Follow-up). The symptomatic severity (WOMAC Index) was also evaluated (Baseline vs. Follow-up). RESULTS: The KAM with LW insoles at Baseline was significantly reduced when compared to the barefoot condition (p < 0.05), suggesting that the LW insoles were effective in reducing unfavorable loadings at the knee immediately upon wearing the insoles. After 6 weeks of wearing LW insoles (Follow-up), no significant changes were found in most of the biomechanical variables, including KAM (p > 0.05), when compared to Baseline with LW insoles. However, a specific gait adaptation with reduced knee loading was revealed when walking without LW insoles, i.e., for the barefoot condition (p < 0.05). CONCLUSIONS: After long-term use of LW insoles, the pain and physical function were improved with decreased peak KAM. A specific gait adaptation with reduced KAM was also found when walking without LW insoles. These results indicate a positive long-term effect in persons with bilateral medial knee OA, both as an orthosis to assist walking, and as a treatment intervention to facilitate gait adaptations in favor of reduced KAM.

Genome-wide analysis of DNA copy number alterations and loss of heterozygosity in intracranial germ cell tumors.

BACKGROUNDS: Intracranial germ cell tumors (GCTs) are rare and heterogeneous with very little is known about their pathogenesis and underlying genetic abnormalities. PROCEDURES: In order to identify candidate genes and pathways which are involved in the pathogenesis of these tumors, we have profiled 62 intracranial GCTs for DNA copy number alterations (CNAs) and loss of heterozygosity (LOH) by using single nucleotide polymorphism (SNP) array and quantitative real time PCR (qPCR). RESULTS: Initially 27 cases of tumor tissues with matched blood samples were fully analyzed by SNP microarray and qPCR. Statistical analysis using the genomic identification of significant targets in cancer (GISTIC) tool identified 10 regions of significant copy number gain and 11 regions of significant copy number loss. While overall pattern of genomic aberration was similar between germinoma and nongerminomatous germ cell tumors (NGGCTs), a few subtype-specific peak regions were identified. Analysis by SNP array and qPCR was replicated using an independent cohort of 35 cases. CONCLUSIONS: Frequent aberrations of CCND2 (12p13) and RB1 (13q14) suggest that Cyclin/CDK-RB-E2F pathway might play a critical role in the pathogenesis of intracranial GCTs. Frequent gain of PRDM14 (8q13) implies that transcriptional regulation of primordial germ cell specification might be an important factor in the development of this tumor.