Causal network localization of brain stimulation targets for trait anxiety.

Transcranial magnetic stimulation (TMS) and deep brain stimulation (DBS) can treat some neuropsychiatric disorders, but there is no consensus approach for identifying new targets. We localized causal circuit-based targets for anxiety that converged across multiple natural experiments. Lesions (n=451) and TMS sites (n=111) that modify anxiety mapped to a common normative brain circuit (r=0.68, p=0.01). In an independent dataset (n=300), individualized TMS site connectivity to this circuit predicted anxiety change (p=0.02). Subthalamic DBS sites overlapping the circuit caused more anxiety (n=74, p=0.006), thus demonstrating a network-level effect, as the circuit was derived without any subthalamic sites. The circuit was specific to trait versus state anxiety in datasets that measured both (p=0.003). Broadly, this illustrates a pathway for discovering novel circuit-based targets across neuropsychiatric disorders.

The evolution of neuromodulation for chronic stroke: From neuroplasticity mechanisms to brain-computer interfaces.

Stroke is one of the most common and debilitating neurological conditions worldwide. Those who survive experience motor, sensory, speech, vision, and/or cognitive deficits that severely limit remaining quality of life. While rehabilitation programs can help improve patients' symptoms, recovery is often limited, and patients frequently continue to experience impairments in functional status. In this review, invasive neuromodulation techniques to augment the effects of conventional rehabilitation methods are described, including vagus nerve stimulation (VNS), deep brain stimulation (DBS) and brain-computer interfaces (BCIs). In addition, the evidence base for each of these techniques, pivotal trials, and future directions are explored. Finally, emerging technologies such as functional near-infrared spectroscopy (fNIRS) and the shift to artificial intelligence-enabled implants and wearables are examined. While the field of implantable devices for chronic stroke recovery is still in a nascent stage, the data reviewed are suggestive of immense potential for reducing the impact and impairment from this globally prevalent disorder.

Pairing taVNS and CIMT is feasible and may improve upper extremity function in infants.

In this study we combined non-invasive transcutaneous auricular vagal nerve stimulation (taVNS) with 40 h of constraint induced movement therapy (CIMT) in infants. All infants completed the full intervention with no adverse events. Therapists were able to maintain high treatment fidelity and reported high ratings for ease of use and child tolerance. Preliminary results show promising gains on motor outcomes: Mean QUEST increase 19.17 (minimal clinically important difference, MCID 4.89); Mean GMFM increase 13.33 (MCID 1%-3%). Infants also exceeded expectations on Goal Attainment Scores (+1). Early data is promising that taVNS paired with intensive motor CIMT is feasible, reliable, and safe in young infants with hemiplegia, and may help harness activity-dependent plasticity to enhance functional movement.

Is an uncomplicated postoperative recovery following total pelvic exenteration a more important prognostic factor than achieving R0 in the first 2 years?

AIM: Total pelvic exenteration (TPE) can achieve an R0 resection in locally advanced and recurrent rectal cancer (LARC and RRC) and remains the only curative option. The resultant high morbidity creates prolonged complex recoveries, rendering patients unfit for adjuvant chemotherapy. This study aims to evaluate the impact of this on overall survival (OS) and disease-free survival (DFS) as it has not been studied previously. METHOD: This is a retrospective single-centre study from 2017 to 2021 evaluating patients with LARC or RRC who underwent a curative TPE. Demographics, oncological history, perioperative data [using Clavien-Dindo (CD) scoring], disease recurrence and mortality were analysed using multivariate Cox regression to assess the impact of variables on DFS and OS. RESULTS: A total of 120 patients were included with a median follow-up of 3 years. 28% of patients received adjuvant chemotherapy, 27.5% had surgical follow-up and 44% missed systemic treatment. Missed treatment was predominantly due to prolonged recovery or poor performance status (59%). Patients who missed adjuvant chemotherapy experienced significantly higher CD scores (p = 0.0031), reintervention rates (p=0.0056) and further related surgeriesp (p = 0.0314). Missing adjuvant chemotherpy is a significant factor for poorer survival, with almost a three times higher mortality (p=0.0096, hazard ratio 2.7). R status was not a significant factor for OS following multivariate analysis (p = 0.336), indicating that another factor has an impact on survival within the first 2 years. CONCLUSIONS: In the initial 2 years after exenteration, an uncomplicated postoperative recovery allows for the delivery of adjuvant chemotherapy, prolonging survival. R0/R1 status was not the main prognostic factor. Longer follow-up and further multivariate analysis may influence decisions about aggressive R0 resection balanced against the patient being fit for chemotherapy postoperatively.

Improved naming in patients with Broca's aphasia with tDCS.

BACKGROUND: Language impairment (aphasia) is a common neurological deficit after strokes. For individuals with chronic aphasia (beyond 6 months after the stroke), language improvements with speech therapy (ST) are often limited. Transcranial direct current stimulation (tDCS) is a promising approach to complement language recovery but interindividual variability in treatment response is common after tDCS, suggesting a possible relationship between tDCS and type of linguistic impairment (aphasia type). METHODS: This current study is a subgroup analysis of a randomised controlled phase II futility design clinical trial on tDCS in chronic post-stroke aphasia. All participants received ST coupled with tDCS (n=31) vs sham tDCS (n=39). Confrontation naming was tested at baseline, and 1, 4, and 24 weeks post-treatment. RESULTS: Broca's aphasia was associated with maximal adjunctive benefit of tDCS, with an average improvement of 10 additional named items with tDCS+ST compared with ST alone at 4 weeks post-treatment. In comparison, tDCS was not associated with significant benefits for other aphasia types F(1)=4.23, p=0.04. Among participants with Broca's aphasia, preservation of the perilesional posterior inferior temporal cortex was associated with higher treatment benefit (R=0.35, p=0.03). CONCLUSIONS: These results indicate that adjuvant tDCS can enhance ST to treat naming in Broca's aphasia, and this may guide intervention approaches in future studies.

A preliminary randomized controlled trial of repetitive transcranial magnetic stimulation applied to the left dorsolateral prefrontal cortex in treatment seeking participants with cannabis use disorder.

BACKGROUND: Cannabis use disorder (CUD) is a common and consequential disorder. When applied to the dorsolateral prefrontal cortex (DLPFC), repetitive transcranial magnetic stimulation (rTMS) reduces craving across substance use disorders and may have therapeutic clinical effects when applied in serial-sessions. The present study sought to preliminarily determine whether serial-sessions of rTMS applied to the DLPFC had a therapeutic effect in CUD. METHODS: This study was a two-site, phase-2, double-blind, randomized-controlled-trial. Seventy-two treatment-seeking participants (37.5% Women, mean age 30.2±9.9SD) with ≥moderate-CUD were randomized to active or sham rTMS (Beam-F3, 10Hz, 20-total-sessions, two-sessions-per-visit, two-visits-per-week, with cannabis cues) while undergoing a three-session motivational enhancement therapy intervention. The primary outcome was the change in craving between pre- and post- treatment (Marijuana Craving Questionnaire Short-Form-MCQ-SF). Secondary outcomes included the number of weeks of abstinence and the number of days-per-week of cannabis use during 4-weeks of follow-up. RESULTS: There were no significant differences in craving between conditions. Participants who received active-rTMS reported numerically, but not significantly, more weeks of abstinence in the follow-up period than those who received sham-rTMS (15.5%-Active; 9.3%-Sham; rate ratio = 1.66 [95% CI: 0.84, 3.28]; p=0.14). Participants who received active-rTMS reported fewer days-per-week of cannabis use over the final two-weeks of the follow-up period than those receiving sham-rTMS (Active vs. Sham: -0.72; Z=-2.33, p=0.02). CONCLUSIONS: This trial suggests rTMS is safe and feasible in individuals with CUD and may have a therapeutic effect on frequency of cannabis use, though further study is needed with additional rTMS-sessions and a longer follow-up period.

Reduced executive and reward connectivity is associated with smoking cessation response to repetitive transcranial magnetic stimulation: A double-blind, randomized, sham-controlled trial.

Repetitive transcranial magnetic stimulation (rTMS) can reduce cue-elicited craving, decrease cigarette consumption, and increase the abstinence rate in tobacco use disorders (TUDs). We used functional magnetic resonance imaging (fMRI) to investigate the effect of 10 sessions of rTMS on cortical activity and neural networks in treatment-seeking smokers. Smoking cue exposure fMRI scans were acquired before and after the 10 sessions of active or sham rTMS (10 Hz, 3000 pulses per session) to the left dorsal lateral prefrontal cortex (DLPFC) in 42 treatment-seeking smokers (≥ 10 cigarettes per day). Brain activity and functional connectivity were compared before and after 10 sessions of rTMS. Ten sessions of rTMS significantly reduced the number of cigarettes consumed per day (62.93%) compared to sham treatment (39.43%) at the end of treatment (p = 0.027). fMRI results showed that the rTMS treatment increased brain activity in the dorsal anterior cingulate cortex (dACC) and DLPFC, but decreased brain activity in the bilateral medial orbitofrontal cortex (mOFC). The lower strength of dACC and mOFC connectivity was associated with quitting smoking (Wald score = 5.00, p = 0.025). The reduction of cigarette consumption significantly correlated with the increased brain activation in the dACC (r = 0.76, p = 0.0001). By increasing the brain activity in the dACC and prefrontal cortex and decreasing brain activity in the mOFC, 10 sessions of rTMS significantly reduced cigarette consumption and increased quit rate. Reduced drive-reward and executive control functional connectivity was associated with the smoking cessation effect from rTMS. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02401672.

EEG synchronized left prefrontal transcranial magnetic stimulation (TMS) for treatment resistant depression is feasible and produces an entrainment dependent clinical response: A randomized controlled double blind clinical trial.

BACKGROUND: Synchronizing a TMS pulse with a person's underlying EEG rhythm can modify the brain's response. It is unclear if synchronizing rTMS trains might boost the antidepressant effect of TMS. In this first-in-human trial, we demonstrated that a single TMS pulse over the prefrontal cortex produces larger effects in the anterior cingulate depending on when it is fired relative to the individual's EEG alpha phase. OBJECTIVE/HYPOTHESES: We had three hypotheses. 1) It is feasible to synchronize repetitive TMS (rTMS) delivery to a person's preferred prefrontal alpha phase in each train of every session during a 30-visit TMS depression treatment course. 2) EEG-synchronized rTMS would produce progressive entrainment greater than unsynchronized (UNSYNC) rTMS. And 3) SYNC TMS would have better antidepressant effects than UNSYNC (remission, final Hamilton Depression Rating <10). METHODS: We enrolled (n = 34) and treated (n = 28) adults with treatment resistant depression (TRD) and randomized them to receive six weeks (30 treatments) of left prefrontal rTMS at their individual alpha frequency (IAF) (range 6-13 Hz). Prior to starting the clinical trial, all patients had an interleaved fMRI-EEG-TMS (fET) scan to determine which phase of their alpha rhythm would produce the largest BOLD response in their dorsal anterior cingulate. Our clinical EEG-rTMS system then delivered the first TMS pulse in each train time-locked to this patient-specific 'preferred phase' of each patient's left prefrontal alpha oscillation. We randomized patients (1:1) to SYNC or UNSYNC, and all were treated at their IAF. Only the SYNC patients had the first pulse of each train for all sessions synchronized to their individualized preferred alpha phase (75 trains/session ×30 sessions, 2250 synchronizations per patient over six weeks). The UNSYNC group used a random firing with respect to the alpha wave. All other TMS parameters were balanced between the two groups. The system interfaced with a MagStim Horizon air-cooled Fig. 8 TMS coil. All patients were treated at their IAF, coil in the F3 position, 120 % MT, frequency 6-13 Hz, 40 pulses per train, average 15-s inter-train interval, 3000 pulses per session. All patients, raters, and treaters were blinded. RESULTS: In the intent to treat (ITT) sample, both groups had significant clinical improvement from baseline with no significant between-group differences, with the USYNC group having mathematically more remitters but fewer responders. (ITT -15 SYNC; 13 UNSYNC, response 5 (33 %), 1 (7 %), remission 2 (13 %), 6 (46 %). The same was true with the completer sample - 12 SYNC; 12 UNSYNC, response 4, 4 (both 30 %), remission 2 (17 %), 3 (25 %)). The clinical EEG phase synchronization system performed well with no failures. The average treatment session was approximately 90 min, with 30 min for placing the EEG cap and the actual TMS treatment for 45 min (which included gathering 10 min of resting EEG). Four subjects (1 SYNC) withdrew before six weeks of treatment. All 24 completer patients were treated for six weeks despite the trial occurring during the COVID pandemic. SYNC patients exhibited increased post-stimulation EEG entrainment over the six weeks. A detailed secondary analysis of entrainment data in the SYNC group showed that responders and non-responders in this group could be cleanly separated based on the total number of sessions with entrainment and the session-to-session precision of the entrained phase. For the SYNC group only, depression improvement was greater when more sessions were entrained at similar phases. CONCLUSIONS: Synchronizing prefrontal TMS with a patient's prefrontal alpha frequency in a blinded clinical trial is possible and produces progressive EEG entrainment in synchronized patients only. There was no difference in overall clinical response in this small clinical trial. A secondary analysis showed that the consistency of the entrained phase across sessions was significantly associated with response outcome only in the SYNC group. These effects may not simply be due to how the stimulation is delivered but also whether the patient's brain can reliably entrain to a precise phase. EEG-synchronized clinical delivery of TMS is feasible and requires further study to determine the best method for determining the phase for synchronization.

Biomarkers predict the efficacy of closed-loop rTMS treatment for refractory depression.

Transcranial magnetic stimulation (TMS) is a non-invasive FDA-approved therapy for major depressive disorder (MDD), specifically for treatment-resistant depression (TRD). Though offering promise for those with TRD, its effectiveness is less than one in two patients (i.e., less than 50%). Limits on efficacy may be due to individual patient variability, but to date, there are no established biomarkers or measures of target engagement that can predict efficacy. Additionally, TMS efficacy is typically not assessed until a six-week treatment ends, precluding interim re-evaluations of the treatment. Here, we report results using a closed-loop phase-locked repetitive TMS (rTMS) treatment that synchronizes the delivery of rTMS based on the timing of the pulses relative to a patient's individual electroencephalographic (EEG) prefrontal alpha oscillation indexed by functional magnetic resonance imaging (fMRI). Among responders, synchronized rTMS produces two systematic changes in brain dynamics: a reduction in global cortical excitability and enhanced phase entrainment of cortical dynamics. These effects predict clinical outcomes in the synchronized treatment group but not in an active-treatment unsynchronized control group. The systematic decrease in excitability and increase in entrainment correlated with treatment efficacy at the endpoint and intermediate weeks during the synchronized treatment. Specifically, we show that weekly biomarker tracking enables efficacy prediction and dynamic adjustments through a treatment course, improving the overall response rates. This innovative approach advances the prospects of individualized medicine in MDD and holds potential for application in other neuropsychiatric disorders.

Use of non-invasive transcutaneous auricular vagus nerve stimulation: neurodevelopmental and sensory follow-up.

Objective: To assess the impact of non-invasive transcutaneous auricular vagal nerve stimulation (taVNS) paired with oral feeding on long-term neurodevelopmental and sensory outcomes. Method: We tested 21 of 35 children who as infants were gastrostomy tube (G-tube) candidates and participated in the novel, open-label trial of taVNS paired with oral feeding. To evaluate possible effects on development at 18-months after infant taVNS, we performed the Bayley-III (n = 10) and Sensory Profile (SP-2, n = 12) assessments before the COVID pandemic, and Cognitive Adaptive Test (CAT), Clinical Linguistics and Auditory Milestone (CLAMS), Ages and Stages Questionnaire (ASQ), and Peabody Developmental Motor Scales-2 gross motor tests as possible during and after the pandemic. We compared outcomes for infants who attained full oral feeds during taVNS ('responders') or received G-tubes ('non-responders'). Results: At a mean of 19-months, taVNS 'responders' showed significantly better general sensory processing on the SP-2 than 'non-responders'. There were no differences in other test scores, which were similar to published outcomes for infants who required G-tubes. Conclusion: This is the first report of neurodevelopmental follow-up in infants who received taVNS-paired feeding. They had similar developmental outcomes as historical control infants failing oral feeds who received G-tubes. Our data suggests that infants who attained full oral feeds had better sensory processing.

Differences in quality of life of patients undergoing total pelvic exenteration compared with standard rectal cancer surgery: a scoping review.

AIM: Rectal cancer is often treated surgically with an anterior resection (AR) or abdominoperineal excision (APE). However, for patients with locally advanced disease or local recurrence total pelvic exenteration (TPE) surgery can be performed. The magnitude of surgery varies, and little research has been done to consider how quality of life (QoL) may vary according to the extent of surgery. METHOD: A search was conducted on MEDLINE and PubMed for papers published from 2010 to 2021. Inclusion criteria consisted of observational studies comparing adult populations with rectal cancer undergoing APE, AR or TPE, reporting QoL using validated tools. Risk of bias was assessed using the Risk of Bias in Non-Randomized Studies of Interventions (ROBINS-I) tool. Outcomes of interest were global QoL, gastrointestinal (GI) symptoms (nausea and vomiting, diarrhoea, and constipation) and pain. RESULTS: Seven studies including 1402 patients were analysed. QoL following TPE generally improves over time, back to baseline or better. AR and APE groups have similar patterns of improvement between baseline and 12 months after surgery, although scores declined in some studies at 12 months. TPE scores are lower overall, and the pattern of improvement differs, with patients tending to have worse nausea and vomiting symptoms. AR and APE patients tend to experience more lower GI symptoms. CONCLUSION: It is not possible to draw firm conclusions based on the studies analysed. However, QoL returns to baseline following TPE, APE and AR. Preoperative QoL appears to be an indication of postoperative outcomes. Further observational studies are required.

Increased entrainment and decreased excitability predict efficacious treatment of closed-loop phase-locked rTMS for treatment-resistant depression.

Transcranial magnetic stimulation (TMS) is an FDA-approved therapy for major depressive disorder (MDD), specifically for patients who have treatment-resistant depression (TRD). However, TMS produces response or remission in about 50% of patients but is ineffective for the other 50%. Limits on efficacy may be due to individual patient variability, but to date, there are no good biomarkers or measures of target engagement. In addition, TMS efficacy is typically not assessed until a six-week treatment ends, precluding the evaluation of intermediate improvements during the treatment duration. Here, we report on results using a closed-loop phase-locked repetitive TMS (rTMS) treatment that synchronizes the delivery of rTMS based on the timing of the pulses relative to a patient's individual electroencephalographic (EEG) prefrontal alpha oscillation informed by functional magnetic resonance imaging (fMRI). We find that, in responders, synchronized delivery of rTMS produces two systematic changes in brain dynamics. The first change is a decrease in global cortical excitability, and the second is an increase in the phase entrainment of cortical dynamics. These two effects predict clinical outcomes in the synchronized treatment group but not in an active-treatment unsynchronized control group. The systematic decrease in excitability and increase in entrainment correlated with treatment efficacy at the endpoint and intermediate weeks during the synchronized treatment. Specifically, we show that weekly tracking of these biomarkers allows for efficacy prediction and potential of dynamic adjustments through a treatment course, improving the overall response rates.

The Distribution of Additional Residency Slots to Rural and Underserved Areas.

This study analyzes data from the Centers for Medicare & Medicaid Services to identify whether new residency training slots went to rural and underserved areas with the greatest need.

Transcutaneous Auricular Vagus Nerve Stimulation Attenuates Early Increases in Heart Rate Associated With the Cold Pressor Test.

INTRODUCTION: Transcutaneous auricular vagus nerve stimulation (taVNS) may be useful in treating disorders characterized by chronic parasympathetic disinhibition. Acute taVNS decreases resting heart rate in healthy individuals, but little is known regarding the effects of taVNS on the cardiac response to an acute stressor. To investigate effects on the acute stress response, we investigated how taVNS affected heart rate changes during a cold pressor test (CPT), a validated stress induction technique that reliably elicits a sympathetic stress response with marked increases in heart rate, anxiety, stress, and pain. MATERIALS AND METHODS: We recruited 24 healthy adults (ten women, mean age = 29 years) to participate in this randomized, crossover, exploratory trial. Each subject completed two taVNS treatments (one active, one sham) paired with CPTs in the same session. Order of active versus sham stimulation was randomized. Heart rate, along with ratings of anxiety, stress, and pain, was collected before, during, and after each round of taVNS/sham + CPT. RESULTS: In both stimulation conditions, heart rate was elevated from baseline in response to the CPT. Analyses also revealed a difference between active and sham taVNS during the first 40 seconds of the CPT (Δ heart rate [HR] = 12.75 ± 7.85 in the active condition; Δ HR = 16.09 ± 11.43 in the sham condition, p = 0.044). There were no significant differences in subjective ratings between active and sham taVNS. CONCLUSIONS: In this randomized, sham-controlled study, taVNS attenuated initial increases in HR in response to the CPT. Future studies are needed to investigate the effects of various taVNS doses and parameters on the CPT, in addition to other forms of stress induction. CLINICAL TRIAL REGISTRATION: The Clinicaltrials.gov registration number for the study is NCT00113453.

Adverse Outcome Following Mild Traumatic Brain Injury Is Associated with Microstructure Alterations at the Gray and White Matter Boundary.

The gray matter/white matter (GM/WM) boundary of the brain is vulnerable to shear strain associated with mild traumatic brain injury (mTBI). It is, however, unknown whether GM/WM microstructure is associated with long-term outcomes following mTBI. The diffusion and structural MRI data of 278 participants between 18 and 65 years of age with and without military background from the Department of Defense INTRuST study were analyzed. Fractional anisotropy (FA) was extracted at the GM/WM boundary across the brain and for each lobe. Additionally, two conventional analytic approaches were used: whole-brain deep WM FA (TBSS) and whole-brain cortical thickness (FreeSurfer). ANCOVAs were applied to assess differences between the mTBI cohort (n = 147) and the comparison cohort (n = 131). Associations between imaging features and post-concussive symptom severity, and functional and cognitive impairment were investigated using partial correlations while controlling for mental health comorbidities that are particularly common among military cohorts and were present in both the mTBI and comparison group. Findings revealed significantly lower whole-brain and lobe-specific GM/WM boundary FA (p < 0.011), and deep WM FA (p = 0.001) in the mTBI cohort. Whole-brain and lobe-specific GM/WM boundary FA was significantly negatively correlated with post-concussive symptoms (p < 0.039), functional (p < 0.016), and cognitive impairment (p < 0.049). Deep WM FA was associated with functional impairment (p = 0.002). Finally, no significant difference was observed in cortical thickness, nor between cortical thickness and outcome (p > 0.05). Findings from this study suggest that microstructural alterations at the GM/WM boundary may be sensitive markers of adverse long-term outcomes following mTBI.

A Preliminary Investigation Of Repetitive Transcranial Magnetic Stimulation Applied To The Left Dorsolateral Prefrontal Cortex In Treatment Seeking Participants With Cannabis Use Disorder.

Background: Cannabis use disorder (CUD) is a common and consequential disorder. When applied to the dorsolateral prefrontal cortex (DLPFC), repetitive transcranial magnetic stimulation (rTMS) reduces craving across substance use disorders and may have a therapeutic clinical effect when applied in serial sessions. The present study sought to preliminarily determine whether serial sessions of rTMS applied to the DLPFC had a therapeutic effect in CUD. Methods: This study was a two-site, phase-2, double-blind, randomized-controlled-trial. Seventy-two treatment-seeking participants (37.5% Women, mean age 30.2±9.9SD) with ≥moderate-CUD were randomized to active or sham rTMS (Beam-F3, 10Hz, 20-total-sessions, with cannabis cues) while undergoing a three-session motivational enhancement therapy intervention. The primary outcome was the change in craving between pre- and post-treatment (Marijuana Craving Questionnaire Short-Form-MCQ-SF). Secondary outcomes included the number of weeks of abstinence and the number of days-per-week of cannabis use during 4-weeks of follow-up. Results: There were no significant differences in craving between conditions. Participants who received active rTMS reported numerically, but not significantly, more weeks of abstinence in the follow-up period than those who received sham rTMS (15.5%-Active; 9.3%-Sham; rate ratio = 1.66 [95% CI: 0.84, 3.28]; p=0.14). Participants who received active rTMS reported fewer days-per-week of cannabis use over the final two-weeks of the follow-up period (Active vs. Sham: -0.72; Z=-2.33, p=0.02). Conclusions: This trial suggests rTMS is safe and feasible in individuals with CUD and may have a therapeutic effect on frequency of cannabis use, though further study is needed with additional rTMS-sessions and a longer follow-up period.

Performance Characteristics of Mass Spectrometry-Based Analytical Procedures for Quantitation of Nitrosamines in Pharmaceuticals: Insights from an Inter-laboratory Study.

With the discovery of carcinogenic nitrosamine impurities in pharmaceuticals in 2018 and subsequent regulatory requirements for risk assessment for nitrosamine formation during pharmaceutical manufacturing processes, storage or from contaminated supply chains, effective testing of nitrosamines has become essential to ensure the quality of drug substances and products. Mass spectrometry has been widely applied to detect and quantify trace amounts of nitrosamines in pharmaceuticals. As part of an effort by regulatory authorities to assess the measurement variation in the determination of nitrosamines, an inter-laboratory study was performed by the laboratories from six regulatory agencies with each of the participants using their own analytical procedures to determine the amounts of nitrosamines in a set of identical samples. The results demonstrated that accurate and precise quantitation of trace level nitrosamines can be achieved across multiple analytical procedures and provided insight into the performance characteristics of mass spectrometry-based analytical procedures in terms of accuracy, repeatability and reproducibility.

Attitudes and Behavioral Intentions of Pet Amphibian Owners About Biosecurity Practices.

Global trade has been linked with the emergence of novel pathogens and declines in amphibian populations worldwide. The potential for pathogen transmission within and between collections of captive amphibians and spillover to wild populations makes it important to understand the motivations, knowledge, attitudes and behaviors of pet amphibian owners. We surveyed US pet amphibian owners to understand their characteristics and evaluated whether and how they were associated with behavioral intentions to adopt biosecurity practices. We found that the majority of pet amphibian owners are aware of the threat of emerging pathogens, concerned about potential spillover of pathogens from captive to wild populations and willing to adopt biosecurity practices to mitigate pathogen threats. Intentions to adopt such practices were driven more by psychosocial constructs such as attitudes, perceptions and beliefs than demographic characteristics. Pet amphibian owners also expressed a strong interest in acquiring, and willingness to pay a price premium for, certified disease-free animals. These findings advance our understanding of the characteristics, motivations and behaviors of pet owners, a key stakeholder in global amphibian trade, which could help to inform new policies and outreach strategies to engage them in mitigating pathogen threats. Moreover, our results imply the economic viability of a market-based program to promote pathogen-free, sustainable trade of amphibians.