Quantitative imaging workshop XIX: Utilizing quantitative thoracic imaging to optimize population health final summary

Lung cancer screening involves the use of thoracic CT for both detection and measurements of suspicious lung nodules to guide the screening management. Since lung cancer screening eligibility typically requires age over 50 years along with >20 pack-year tobacco exposure, thoracic CT scans also frequently reveal evidence for pulmonary emphysema as well as coronary artery calcification. These three thoracic diseases are collectively three of the leading causes of premature death across the world. Screening for the major thoracic diseases in this heavily tobacco-exposed cohort is broadening the focus of lung cancer screening to a more comprehensive health evaluation including discussing the relevance of screen-detected findings of the heart and lung parenchyma. The status and implications of these emerging issues were reviewed in a multidisciplinary workshop focused on the process of quantitative imaging in the lung cancer screening setting to guide the evolution of this important new area of public health.     

Current Controversies in Arthroscopic Partial Meniscectomy

Purpose of ReviewGiven the continued controversy among orthopedic surgeons regarding the indications and benefits of arthroscopic partial meniscectomy (APM), this review summarizes the current literature, indications, and outcomes of partial meniscectomy to treat symptomatic meniscal tears.Recent FindingsIn patients with symptomatic meniscal tears, the location and tear pattern play a vital role in clinical management. Tears in the central white-white zone are less amenable to repair due to poor vascularity. Patients may be indicated for APM or non-surgical intervention depending on the tear pattern and symptoms. Non-surgical management for meniscal pathology includes non-steroidal anti-inflammatory drugs (NSAIDs), physical therapy (PT), and intraarticular injections to reduce inflammation and relieve symptoms. There have been several landmark multicenter randomized controlled trials (RCTs) studying the outcomes of APM compared to PT or sham surgery in symptomatic degenerative meniscal tears. These most notably include the 2013 Meniscal Tear in Osteoarthritis Research (MeTeOR) Trial, the 2018 ESCAPE trial, and the sham surgery-controlled Finnish Degenerative Meniscal Lesion Study (FIDELITY), which failed to identify substantial benefits of APM over nonoperative treatment or even placebo surgery.SummaryDespite an abundance of literature exploring outcomes of APM for degenerative meniscus tears, there is little consensus among surgeons about the drivers of good outcomes following APM. It is often difficult to determine if the presenting symptoms are secondary to the meniscus pathology or the degenerative disease in patients with concomitant OA. A central tenet of managing meniscal pathology is to preserve tissue whenever possible. Most RCTs show that exercise therapy may be non-inferior to APM in degenerative tears if repair is not possible. Given this evidence, patients who fail nonoperative treatment should be counseled regarding the risks of APM before proceeding to surgical management.     

Role of anticipation in schizophrenia-related pursuit initiation deficits

Schizophrenia patients exhibit several smooth pursuit abnormalities including poor pursuit initiation. Velocity discrimination is also impaired and is correlated with pursuit initiation performance-suggesting that pursuit deficits are related to impairments in processing velocity information. Studies suggest that pursuit initiation is influenced by prior target motion information and/or expectations and that this is likely caused by expectation-based changes in the perceptual inputs to the pursuit system. We examined whether poor pursuit initiation in schizophrenia results from inaccurate encoding of immediate velocity signals, or whether these deficits reflect a failure to use prior target motion information to "optimize" the response. Twenty-eight patients and 24 controls performed an adapted version of a "remembered pursuit task." Trials consisted of a series of target motions, the first of which occurred unexpectedly, followed by four to seven identical targets each preceded by an auditory cue and a "catch target" in which a cue was given followed by target extinction. Initiation eye velocity in response to unexpected, first targets was similar in the patient and control groups. In contrast, patients showed lower eye velocity in response to repeated, cued targets compared with controls. Patients also showed reduced eye velocity in response to catch targets. Reduction in pursuit latency across repeated targets was less robust in patients. Results suggest that processing of immediate velocity information is unaffected in schizophrenia and that pursuit initiation deficits reflect an inability to accurately generate, store, and/or access "remembered" velocity signals.     

A comparison of amphetamine- and methamphetamine-induced locomotor activity in rats: evidence for qualitative differences in behavior

Rationale Methamphetamine (METH) is typically characterized as a more potent psychostimulant than amphetamine (AMPH), but few studies have directly compared the effects of these drugs at low, behaviorally activating doses that tend not to produce focused stereotypy. Objectives The objective of the study was to compare the effects of AMPH or METH treatment on locomotor activity in an open-field arena, focusing on their ability to produce conditioned locomotor activity, sensitization, and cross-sensitization. Materials and methods Adult male rats were given AMPH or METH (0.5 or 1.0 mg/kg) for 5 days, with half of the rats presented with discrete, salient stimuli (S+) during the postinjection period. After a 3-day withdrawal, they were given three different injections on successive days: a saline challenge to assess conditioned responding, a drug challenge to assess sensitization, and a cross-sensitization test to the same dose of the drug with which they were not pretreated. Results Except in certain conditions, AMPH and METH were equipotent at activating locomotor activity. The exceptions included when rats were presented with S+ on acute and drug challenge days and in tests of cross-sensitization. There were no consistent differences in the magnitude of sensitization produced by AMPH or METH, and both drugs produced similar amounts of conditioned locomotion after a saline injection. Conclusions We have found specific conditions where METH is more potent than AMPH, but this study and others that used higher doses of these drugs are not consistent with the generalized characterization of METH as a more potent psychostimulant.     

Old ideals and new realities: the changing context of young people's partnerships in Cebu,Philippines

The Philippines has experienced rapid sociodemographic changes in recent years, with implications for young people. This study combines quantitative and qualitative data from Metro Cebu to assess the timing and predictors of young people's partnerships, as well as the context in which these partnerships are occurring. The majority of young people (54%) had premarital sex, though this pattern varied by gender. Wealthier, urban young men, and women with less education and lower reported religiosity, were more likely to have premarital sex. Engagement in risk behaviours was predictive of premarital sex for both males and females. The qualitative data contextualise the circumstances under which young people engage in sex and form partnerships and illustrate how sociocultural norms contribute to gender differences in partnership patterns. Given the ‘new’ realities of young Filipinos' lives, targeted efforts to support the transition to adulthood are needed to avert potentially adverse life events.     

Direct and quantitative evaluation of the human CYP3A4 contribution (fm) to drug clearance using the in vitro SILENSOMES model

1.?Among the different in vitro studies recommended by the regulatory agencies, no gold-standard model can easily and directly measure the quantitative CYP450 contributions to drug biotransformation. In this article, we propose an original strategy, called Silensomes^TM, to produce human liver microsomes silenced for one specific CYP450, thanks to specific mechanism-based inhibitors (MBI).

2.?Using azamulin as a specific CYP3A4 MBI, we demonstrated the proof of concept that CYP3A4 can be totally, specifically (even against 3A5) and permanently (at least for six years) inhibited by our process. Thus, comparing clearance in control and CYP3A4-Silensomes^TM, CYP3A4 contributions were determined for 11 CYP3A4 substrates which correlated with known in vivo contributions and revealed accuracy with less than 10% error. In comparison, contributions determined using recombinant human CYP450 (rhCYP450s) were less accurate (more than 10% error for 30% of the tested CYP3A4 substrates).

3.?This easy and ready-to-use in vitro method combines the advantages of existing models (specificity of rhCYP450s and representativeness of HLM) without their drawbacks. The same strategy could be used to silence other major CYP450s one-by-one to provide a complete direct CYP450 quantitative phenotyping kit.     

Online 1H‐MRS measurements of time‐varying lactate production in an animal model of glioma during administration of an anti‐tumoral drug

The aims of this study were to implement a magnetic resonance spectroscopy (MRS) protocol for the online profiling of subnanomolar quantities of metabolites sampled from the extracellular fluid using implanted microdialysis and to apply this protocol in glioma‐bearing rats for the quantification of lactate concentration and the measurement of time‐varying lactate concentration during drug administration. MRS acquisitions on the brain microdialysate were performed using a home‐built, proton‐tuned, microsolenoid with an active volume of 2 μL. The microcoil was placed at the outlet of the microdialysis probe inside a preclinical magnetic resonance imaging (MRI) scanner. C6‐bearing rats were implanted with microdialysis probes perfused with artificial cerebrospinal fluid solution and the lactate dehydrogenase (LDH) inhibitor oxamate. Microcoil magnetic resonance spectra were continuously updated using a single‐pulse sequence. Localized in vivo spectra and high‐resolution spectra on the dialysate were also acquired. The limit of detection and limit of quantification per unit time of the lactate methyl peak were determined as 0.37 nmol/√min and 1.23 nmol/√min, respectively. Signal‐to‐noise ratios (SNRs) of the lactate methyl peak above 120 were obtained from brain tumor microdialysate in an acquisition time of 4 min. On average, the lactate methyl peak amplitude measured in vivo using the nuclear magnetic resonance (NMR) microcoil was 193 ± 46% higher in tumor dialysate relative to healthy brain dialysate. A similar ratio was obtained from high‐resolution NMR spectra performed on the collected dialysate. Following oxamate addition in the perfusate, a monotonic decrease in the lactate peaks was observed in all animals with an average time constant of 4.6 min. In the absence of overlapping NMR peaks, robust profiling of extracellular lactate can be obtained online using a dedicated sensitive NMR microcoil. MRS measurements of the dynamic changes in lactate production induced by anti‐tumoral drugs can be assessed accurately with temporal resolutions on the order of minutes. The MRS protocol can be readily transferred to the clinical environment with the use of suitable clinical microdialysis probes.     

Metabolomic prostate cancer fields in HRMAS MRS‐profiled histologically benign tissue vary with cancer status and distance from cancer

In this article, we review the state of the field of high resolution magic angle spinning MRS (HRMAS MRS)‐based cancer metabolomics since its beginning in 2004; discuss the concept of cancer metabolomic fields, where metabolomic profiles measured from histologically benign tissues reflect patient cancer status; and report our HRMAS MRS metabolomic results, which characterize metabolomic fields in prostatectomy‐removed cancerous prostates. Three‐dimensional mapping of cancer lesions throughout each prostate enabled multiple benign tissue samples per organ to be classified based on distance from and extent of the closest cancer lesion as well as the Gleason score (GS) of the entire prostate. Cross‐validated partial least squares‐discriminant analysis separations were achieved between cancer and benign tissue, and between cancer tissue from prostates with high (≥4 + 3) and low (≤3 + 4) GS. Metabolomic field effects enabled histologically benign tissue adjacent to cancer to distinguish the GS and extent of the cancer lesion itself. Benign samples close to either low GS cancer or extensive cancer lesions could be distinguished from those far from cancer. Furthermore, a successfully cross‐validated multivariate model for three benign tissue groups with varying distances from cancer lesions within one prostate indicates the scale of prostate cancer metabolomic fields. While these findings could, at present, be potentially useful in the prostate cancer clinic for analysis of biopsy or surgical specimens to complement current diagnostics, the confirmation of metabolomic fields should encourage further examination of cancer fields and can also enhance understanding of the metabolomic characteristics of cancer in myriad organ systems. Our results together with the success of HRMAS MRS‐based cancer metabolomics presented in our literature review demonstrate the potential of cancer metabolomics to provide supplementary information for cancer diagnosis, staging, and patient prognostication.     

Validity of heart rate measurements by the Garmin Forerunner 225 at different walking intensities

The accuracy of wrist worn heart rate monitors based on photoplethysmography (PPG) is not fully clinically accepted. Therefore, we aimed to validate heart rate measurements of a commercially available PPG heart rate monitor, i.e. the Garmin Forerunner^® 225. Twelve healthy volunteers (six women; mean age: 28 years) performed a treadmill protocol consisting of: five minutes sitting, five minutes standing, 10 minutes walking at 4 km/h, 10 minutes walking at a gradient of 5% and intensity of 4–6 metabolic equivalents (METs), 10 minutes walking at a gradient of 8% and intensity of seven METs or more. Walking speeds were individually determined. Walking bouts were separated by a standardised five minute rest period. Heart rate was measured as the average of the last three minutes standing and of each walking bout. A three lead patch-based electrocardiogram (ECG; Zensor^®) was used as criterion method. Statistical analyses included Pearson’s correlation (r), paired t-tests, root mean squared error (RMSE) and Bland?Altman plots. The mean values per three minutes of every condition did not differ significantly between the Garmin Forerunner^® 225 and the Zensor^®. RMSE was 3.01 beats per minute (bpm) or 2.89%. The Bland–Altman bias was 1.57 bpm. Limits of agreement (LoA) were wide, ranging from 32.53 to 29.40 bpm. However, Pearson’s r ranged from 0.650 to 0.868 suggesting moderate to strong validity. Generally, mean heart rates, r values, RMSE and the Bland–Altman bias indicated good overall agreement in this sample of healthy adults, but wide LoA are making it difficult to trust individual measurements.