Underdosed generic specialty medications: A prescription for patient harm?

The use of generic specialty medications amongst individuals with multiple sclerosis (MS) has expanded due to an increase in the number of available agents. We describe a woman who was denied continued use of brand name teriflunomide (AubagioⓇ), despite being clinically stable for 2.5 years, and switched to generic teriflunomide. She experienced a significant spinal cord exacerbation within a few months of starting treatment. We analyzed 3 generic teriflunomide agents, including the one used for treatment, in addition to AubagioⓇ. The generic teriflunomide used by our patient contained 55.5 % content of the labeled amount, well below U.S. FDA specifications.

Treatment transitions in neuromyelitis optica spectrum disorder increase risk for disease advancement.

BACKGROUND: People with neuromyelitis optica spectrum disorder (PwNMOSD) commonly switch between disease modifying therapies, yet the consequence of transitions remains unknown. We aimed to understand if treatment transitions due to medical, non-medical, and tolerability reasons were related to disease progression. METHODS: A retrospective study of medical records for PwNMOSD was performed between 2008 and 2022. A comprehensive clinical timeline was created for each person including details related to treatment history and associated clinical and radiological outcomes (i.e., hospital admission, relapses, and MRI advancement). If a transition occurred, the reason for the switch was categorized as being due to medical, non-medical, or tolerability issues. A proportional hazards model was created, and the assumptions were tested based on weighted residuals. RESULTS: The cohort included 164 aquaporin-4 IgG positive NMOSD subjects with 89 (79 female; median disease duration (range) = 10.1 years (y) (1.7-32.8)) people switching therapies at least once (once: 42; twice: 26; three times: 12; four times: 6; 5 or more times: 3). A similar amount of higher efficacy therapies was used by PwNMOSD that switched due to a non-medical/tolerability or a medical-related reason. The results of the recurrent event survival analysis revealed that after an initial transition due to non-medical/tolerability reasons, the risk of a hospital admission, relapse, and MRI advancement decreases by 40.3 % (p = 0.005), 53.1 % (p = 0.002), and 65.9 % (p = 0.005), respectively. However, with each additional discontinuation due to non-medical/tolerability reasons, the risk of hospitalization increased by 25.2 % (p = 0.0003) and risk for MRI advancement increased by 41.9 % (p = 0.03). For transitions due to medical reasons, a significant increased risk of MRI advancement by 32.2 % (p = 0.005) for the first switch was identified with no associated observed risk with each additional discontinuation (p = 0.33). Within the first six months after stopping a medication due to non-medical/tolerability reasons, the rate of starting a new medication was less (p<0.0001) when compared to a discontinuation due to a medical-related event. CONCLUSIONS: The risk associated with the time course of treatment transitions for people with NMOSD may assist in transforming the way healthcare providers bridge the gap between therapies and the approach to the timing of a switch. These data highlight additional factors that may be equatable to the efficacy of prescribed treatments in the prevention of acute neurological events.

Errorful learning improves recognition memory for new vocabulary for people living with memory and dysexecutive impairment following brain injury.

A widely accepted view is that errorless learning is essential for supporting new learning in people with anterograde amnesia, but findings are mixed for those with a broader range of memory impairments. People at a chronic stage of recovery from brain injury (BI) with impaired memory and executive function (N = 26) were compared with adults in a comparison group without any known risks to brain function (N = 25). Learning techniques were compared using a "Generate-and-correct" and "Read-only" condition when learning novel word pairs. At test, both groups scored above chance and showed benefits of Generate-and-correct (errorful learning). Poor learners in the BI group were classified from "flat" learning slopes extracted from an independent word-pair learning task. Critically, poor learners showed no benefit, but also no decrement to learning, using the Generate-and-correct method. No group was harmed by errorful learning; all, except the poorest learners, benefitted from errorful learning. This study indicates, that in some rehabilitation settings, encouraging clients to guess the meaning of unfamiliar material (e.g., from cards, magazines, newspapers) and then correct their errors, could have benefits for recognition memory. Determining when and how errorful learning benefits learning is a key aim for future research.

High-efficacy therapies reduce clinical and radiological events more effectively than traditional treatments in neuromyelitis optica spectrum disorder.

BACKGROUND: People with neuromyelitis optica spectrum disorder (pwNMOSD) experience debilitating neurological attacks, resulting in permanent disability. OBJECTIVE: To evaluate if high-efficacy treatment was better than traditional agents at preventing disease advancement in pwNMOSD. METHODS: A retrospective study of pwNMOSD at one academic center was performed. Timelines were created for treatments subjects were exposed to along with clinical/radiological events related to disease worsening. High-efficacy treatments included eculizumab, inebilizumab, satralizumab, rituximab, ocrelizumab, tocilizumab, and sarilumab while therapies such as azathioprine, methotrexate, cyclophosphamide, and mycophenolate mofetil were classified as traditional agents. Poisson regression and mixed effects logistics models were constructed, and a subject-specific random intercept was used for intrasubject correlation. RESULTS: Of 189 pwNMOSD identified, 161 were aquaporin-4 IgG positive (AQP4 +) with 92 (77 female; median disease duration (MDD) (range) of 6.6 years (y) (1.2-18.6)) exposed only to high-efficacy therapy, 33 (28 female; 10.4 y (0.8-32.7)) only to traditional therapy, and 64 (54 female; 10.8 y (0.7-20.2)) to both. High-efficacy treatments reduced the rate of MRI advancement by 62.4% (95% CrI = [- 86.9%, - 16.8%]), relapses by 99.8% (95% CrI = [- 99.9%, - 99.6%]), and hospitalizations by 99.3% (95% CrI = [- 99.6%, - 98.8%]) when compared to traditional treatments. For AQP4 + subjects, a 655.7-fold increase in the odds of new spinal cord lesion development (95% CrI = [+ 37.4-fold, + 3239.5-fold]) was observed with traditional agents (p < 0.0001). CONCLUSION: High-efficacy treatments maximize opportunity for preventing disease advancement in newly diagnosed and established pwNMOSD.

Factors associated with the misdiagnosis of neuromyelitis optica spectrum disorder.

BACKGROUND: Neuromyelitis optica spectrum disorder (NMOSD) is a rare autoimmune condition that is associated with severe disability. Approximately 40% of individuals are misdiagnosed with multiple sclerosis (MS) or other diseases. We aimed to define factors that influence the misdiagnosis of people with NMOSD and provide strategies for reducing error rates. METHODS: A retrospective study was performed involving all people with a confirmed diagnosis of NMOSD within a single academic institution. Comprehensive clinical timelines were constructed for each individual that included presenting symptoms, provider type and timing of evaluations, aquaporin 4-IgG (AQP4) results, and MRI scans. Two-sample comparisons of continuous and categorial variables were performed for people accurately diagnosed with NMOSD and those originally misdiagnosed with another medical condition. A subanalysis of only AQP4-IgG positive people was also performed. RESULTS: The study cohort included 199 people fulfilling International Panel criteria for NMOSD with 71 people (62 female; mean age at first symptom presentation (standard deviation (SD)) = 32.8 years (y) (SD 16.1)) being initially misdiagnosed and 128 people (106 female; 41.14y (SD 15.41)) who were accurately diagnosed. Of the 199 people with NMOSD, 166 had a positive serostatus. Identified factors associated with misdiagnosis, regardless of AQP4-IgG serostatus, were the presence of protracted nausea/vomiting/hiccups without any accompanying neurological symptoms, 23 (32.4%) versus 16 (12.5%) (p = 0.001), a longer median (range) time to see a neuroimmunology specialist 4.2y (0.14-31.8) versus 0.5y (0.0-21.2) (p<0.0001), and a delay in acquiring an MRI study, 4.7y (0.0-27.3) versus 0.3y (0.0-20.2) (p<0.0001). A greater proportion of people misdiagnosed were identified with a negative live-cell based AQP4-IgG serum test result, 13/13 (100%) versus 22/114 (19.3%) (p<0.0001). Additionally, the mean (SD) time between a first negative and successive live-cell based AQP4-IgG positive test result was greater for people misdiagnosed with another condition, 3.9y (SD 5.0) versus 1.5y (SD 2.1) (p = 0.01). Although not significant between groups, a rash was also reported in 63/199 people with NMOSD, with 31/63 having an anti-nuclear antibody titer ≥ 1:160. CONCLUSION: Defined factors can help guide both generalists and specialists in the pursuit of strategies aimed at efficiently diagnosing those with NMOSD such that effective care can be delivered.

Instrumental responses and Pavlovian stimuli as temporal referents in a peak procedure.

Three experiments investigated whether the nature of the temporal referent affects timing behaviour in rats. We used a peak procedure and assessed timing of food well activity as a function of whether the referent was an instrumental response (a lever press that resulted in the withdrawal of the lever) or a conditioned stimulus (CS) that was 2 s in Experiment 1, 500 ms in Experiment 2, and 800 ms in Experiment 3. In all experiments, the interval between the offset of the temporal referent and food was 5 s. The curve fits for each experiment revealed no differences in peak time, but magazine responding immediately following the CS was higher than following a lever press. This pattern of results was interpreted as reflecting a combination of (a) ambiguity in which component of the 500 ms-2-s auditory stimulus was serving as the referent and (b) response competition between lever pressing and magazine activity. Critically, these results suggest that peak timing in rats is unaffected by whether a lever press or CS serves as the referent. This conclusion is consistent with theoretical models of timing behaviour, but not with evidence from humans showing that the subjective perception of time is affected by whether the cause of an outcome was self-generated or not.

Dorsal medulla surface texture: Differentiating neuromyelitis optica spectrum disorder from multiple sclerosis.

BACKGROUND AND PURPOSE: The timely and accurate diagnosis of neuromyelitis optica spectrum disorder (NMOSD) is essential and exposure to multiple sclerosis (MS) disease-modifying therapies may result in permanent neurological disability. METHODS: Standardized 3-Tesla 3-dimensional brain MRI studies were retrospectively studied from people with NMOSD, MS, other CNS neurological diseases, and healthy control subjects. Comparisons of surface texture characteristics at the area postrema involving absolute introverted planar triangle counts, representing more complex and concave tissue topography, along with the spatial dissemination pattern of these triangles were performed cross-sectionally and longitudinally. An ideal introverted planar triangle threshold separating groups with NMOSD and MS was accomplished using the highest Youden's J statistic. For the classification of NMOSD, out-of-sample and in-sample measurements of the following were acquired: sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). RESULTS: The study cohort included 60 people with NMOSD, 100 people with MS, 12 with other neurological diseases, and five healthy controls. Significantly higher cross-sectional median introverted triangle counts were observed when the NMOSD (median [interquartile range]: 100 [23.5]) group was compared to MS (65 [20.25]; p < .0001) and other neurological diseases (66 [13.75]; p < .0001). Distinct spatial dissemination patterns of triangles extending craniocaudally at the region of interest within the dorsal medulla was also seen between groups with NMOSD and MS (p < .0001). For the identification of NMOSD, out-of-sample sensitivity (83%), specificity (100%), PPV (100%), and NPV (60%) were achieved. CONCLUSIONS: Cross-sectional and longitudinal dorsal medulla surface texture differences within selective regions of vulnerability differentiate NMOSD from MS.

Evaluating Cognitive Enrichment for Zoo-Housed Gorillas Using Facial Recognition.

The use of computer technology within zoos is becoming increasingly popular to help achieve high animal welfare standards. However, despite its various positive applications to wildlife in recent years, there has been little uptake of machine learning in zoo animal care. In this paper, we describe how a facial recognition system, developed using machine learning, was embedded within a cognitive enrichment device (a vertical, modular finger maze) for a troop of seven Western lowland gorillas (Gorilla gorilla gorilla) at Bristol Zoo Gardens, UK. We explored whether machine learning could automatically identify individual gorillas through facial recognition, and automate the collection of device-use data including the order, frequency and duration of use by the troop. Concurrent traditional video recording and behavioral coding by eye was undertaken for comparison. The facial recognition system was very effective at identifying individual gorillas (97% mean average precision) and could automate specific downstream tasks (for example, duration of engagement). However, its development was a heavy investment, requiring specialized hardware and interdisciplinary expertise. Therefore, we suggest a system like this is only appropriate for long-term projects. Additionally, researcher input was still required to visually identify which maze modules were being used by gorillas and how. This highlights the need for additional technology, such as infrared sensors, to fully automate cognitive enrichment evaluation. To end, we describe a future system that combines machine learning and sensor technology which could automate the collection of data in real-time for use by researchers and animal care staff.

Hiding in plain sight: The magnitude of unused disease modifying therapies in multiple sclerosis and strategies for reducing the economic burden of care.

BACKGROUND: The rising costs associated with multiple sclerosis (MS) disease modifying therapies (DMTs) creates challenges for patients and the healthcare system in the United States (U.S.). Within a specialty medicine waste project, we quantified the magnitude of unused medications and corresponding value, the primary factors driving treatment switches, and explored reasons for discontinuations by race and ethnicity. METHODS: Over one calendar year, MS DMTs were recovered from new and existing patients from a single neuroimmunologist within a tertiary MS care center. Baseline demographic and clinical information, including reasons for medication discontinuation or transitions were captured. Patients were stratified into three treatment transition categories: (i) non-medical, (ii) medical, or (iii) tolerability reasons. Cause-specific Cox proportional hazard functions were fit for possible causes for treatment changes. RESULTS: A total of 422 patients (female: 73.2%, median age at diagnosis: 32.9 years (y)) comprised of 86.3% Whites, 11.6% Black or African Americans, 1.4% Asians, and 0.7% Native Americans were included, representing 23% of patients evaluated within 2018, with a mean disease duration of 12.8 years (y) (standard deviation (SD): 8.2) and treatment duration of 2.9y (3.4). Women were more likely to switch due to injection fatigue or desire for an oral DMT when compared to men (95% CI [0.26, 0.78], p = 0.01). Being Black or African American people with MS increased the hazard of switching treatment due to injection fatigue and desire for an oral medication relative to White patients with MS by 91% (95% CI [1.07, 3.42], p = 0.03) and switching to a new DMT based on the subjective report of a perceived lack of efficacy was 221% greater (95% CI [1.04, 4.70], p = 0.04), but not in relation to side effects, being 50% less likely to switch (95% CI [0.28, 0.90], p = 0.02). In the passive recruitment phase over a single calendar year, DMTs with a retail value of $5.2 million (Average Wholesale Price (AWP)) were recovered. In the 1-month active recruitment phase within the same year involving 49 people with MS, unused MS DMTs of $1.1 million (AWP) were acquired. Of the 471 patients studied, 56.2% reported transitions in DMTs for reasons other than adequate disease control and tolerability at one point in their treatment history, underscoring the need for individualized therapy selections that enhance persistence and increase the likelihood of reducing further neurological disability. CONCLUSION: The magnitude of unused and wasted MS DMTs is staggering and these findings allude to a larger, more pervasive problem within the healthcare system with financial resources being applied to therapies that go unused.

High-Tech and Tactile: Cognitive Enrichment for Zoo-Housed Gorillas.

The field of environmental enrichment for zoo animals, particularly great apes, has been revived by technological advancements such as touchscreen interfaces and motion sensors. However, direct animal-computer interaction (ACI) is impractical or undesirable for many zoos. We developed a modular cuboid puzzle maze for the troop of six Western lowland gorillas (Gorilla gorilla gorilla) at Bristol Zoo Gardens, United Kingdom. The gorillas could use their fingers or tools to interact with interconnected modules and remove food rewards. Twelve modules could be interchanged within the frame to create novel iterations with every trial. We took a screen-free approach to enrichment: substituting ACI for tactile, physically complex device components, in addition to hidden automatic sensors, and cameras to log device use. The current study evaluated the gorillas' behavioral responses to the device, and evaluated it as a form of "cognitive enrichment." Five out of six gorillas used the device, during monthly trials of 1 h duration, over a 6 month period. All users were female including two infants, and there were significant individual differences in duration of device use. The successful extraction of food rewards was only performed by the three tool-using gorillas. Device use did not diminish over time, and gorillas took turns to use the device alone or as one mother-infant dyad. Our results suggest that the device was a form of cognitive enrichment for the study troop because it allowed gorillas to solve novel challenges, and device use was not associated with behavioral indicators of stress or frustration. However, device exposure had no significant effects on gorilla activity budgets. The device has the potential to be a sustainable enrichment method in the long-term, tailored to individual gorilla skill levels and motivations. Our study represents a technological advancement for gorilla enrichment, an area which had been particularly overlooked until now. We wholly encourage the continued development of this physical maze system for other great apes under human care, with or without computer logging technology.